U.S. patent application number 13/183214 was filed with the patent office on 2011-11-03 for pharmaceutical composition of complex carbohydrates and essential oils and methods of using the same.
Invention is credited to Harold G. Brown, Karen K. Brown, Carol A. Cooper, Kristina J. Hennessy.
Application Number | 20110269710 13/183214 |
Document ID | / |
Family ID | 27537501 |
Filed Date | 2011-11-03 |
United States Patent
Application |
20110269710 |
Kind Code |
A1 |
Brown; Harold G. ; et
al. |
November 3, 2011 |
PHARMACEUTICAL COMPOSITION OF COMPLEX CARBOHYDRATES AND ESSENTIAL
OILS AND METHODS OF USING THE SAME
Abstract
The invention discloses the discovery that a pharmaceutical
composition containing complex carbohydrates with or without
natural or synthetic essential oils can work effectively as a
topical, oral or mucosal pharmaceutical composition. Such
pharmaceutical compositions reduce inflammation, assist in wound
healing, protect against bruising, relieve itching, relieve pain
and swelling and treat topical bacterial infections such as acne
and decubitus ulcers and prevent and treat numerous other
conditions and diseases. Such pharmaceutical compositions can be
administered to mammals including humans. Also included in this
invention are methods to deliver topically applied macromolecules
into the tissue of mammals and methods of blocking the adhesion,
metastatic and coronary cascades.
Inventors: |
Brown; Harold G.;
(Parkville, MO) ; Cooper; Carol A.; (Pittsburgh,
PA) ; Hennessy; Kristina J.; (Parkville, MO) ;
Brown; Karen K.; (Parkville, MO) |
Family ID: |
27537501 |
Appl. No.: |
13/183214 |
Filed: |
July 14, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09890425 |
Feb 19, 2002 |
8003782 |
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PCT/US2000/002328 |
Feb 1, 2000 |
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13183214 |
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60117988 |
Feb 1, 1999 |
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60127749 |
Apr 5, 1999 |
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60137098 |
Jun 2, 1999 |
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60142306 |
Jul 3, 1999 |
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60166326 |
Nov 19, 1999 |
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Current U.S.
Class: |
514/54 |
Current CPC
Class: |
A61K 31/715 20130101;
A23L 33/10 20160801; A61P 35/00 20180101; A61K 31/736 20130101;
Y02A 50/30 20180101; A23K 20/163 20160501; A61K 47/44 20130101;
Y02A 50/406 20180101; A61K 31/726 20130101; A61K 9/0014 20130101;
A61K 31/737 20130101; A61K 31/727 20130101; A61P 35/04 20180101;
A61K 31/728 20130101 |
Class at
Publication: |
514/54 |
International
Class: |
A61K 31/715 20060101
A61K031/715; A61P 35/00 20060101 A61P035/00; A61P 35/04 20060101
A61P035/04; A61K 31/702 20060101 A61K031/702 |
Claims
1. A method for inhibiting tumor formation and tumor metastasis
which comprises administering to a subject in need of inhibiting
tumor formation and tumor metastasis a pharmacologically effective
amount of at least one low purity complex carbohydrate selected
from the group consisting of oligosaccharides, sialylated
oligosacharides, polysaccharides and glycosaminoglycans.
2. A method for preventing or treating tumor development and
metastasis which comprises orally or mucosally administering to a
mammal in need thereof for preventing or treating tumor development
and metastasis a composition which comprises as an active
ingredient a pharmacologically effective amount of at least one low
purity complex carbohydrate selected from the group consisting of
oligosaccharides, sialylated oligosaccharides, polysaccharides and
glycosaminoglycans.
3. A method for preventing or treating tumor development and
metastasis which comprises orally administering to a mammal in need
thereof for preventing or treating tumor development and metastasis
a composition which comprises as an active ingredient 0.005 to 50
mg/kg body weight of at least one complex carbohydrate selected
from the group consisting of oligosaccharides, sialylated
oligosaccharides, polysaccharides, and glycosaminoglycans
optionally with 0.0001 to 20% by vol. Essential oil.
4. A method for preventing or treating tumor development and
metastasis which comprises mucosally administering to a mammal in
need thereof for preventing or treating tumor development and
metastasis a composition which comprises as an active ingredient
0.005 to 50 mg/kg body weight of at least one complex carbohydrate
selected from the group consisting of oligosaccharides, sialylated
oligosaccharides, polysaccharides, and glycosaminoglycans
optionally with 0.0001 to 20% by vol. Essential oil.
5. The method of claim 3, wherein the tumor development and
metastasis result from inflammation.
6. The method of claim 3 wherein the tumor development or
metastasis are selected from the group consisting of sunburn,
gastritic, ulcers and colitis.
7. The method according to claim 1, wherein said complex
carbohydrate is a polysaccharide.
8. The method according to claim 1, wherein said complex
carbohydrate is an oligosaccharide.
9. The method according to claim 3, wherein said essential oil is
natural or synthetic.
10. The method according to claim 9, wherein said natural or
synthetic essential oils are selected from the group consisting of
Eucalyptus Oil, Rosemary Oil, Pine Needle Oil, Tea Tree Oil,
Wintergreen Oil, Peppermint Oil, Spearmint Oil, Sweet Birch Oil,
Camphor Oil, Sage Oil, Jojoba Oil, Cinnamon Oil, Anise Oil, Lemon
Oil, Lime Oil, Orange Oil, Clove Oil Almond Oil, White Pine Oil
Cardamon Oil, Cedar Leaf oil, Sweet Birch and EMU Oil.
11. The method according to claim 7, wherein said polysaccharides
are selected from the group consisting of a glycosaminoglycan and a
mannan.
12. The method according to claim 11, wherein said
glycosaminoglycan is selected from the group consisting of
hyaluronic acid, heparin, heparin sulfate, low molecular weight
heparin, dermatan sulfate, chondroitin sulfate, polysulfated
glycosaminoglycan, keratan sulfate, salts thereof and derivatives
thereof.
13. The method according to claim 7, wherein said polysaccharide is
obtained from an extract of the Aloe Vera plant.
14. The method according to claim 8, wherein said oligosaccharide
is a sialylated sugar.
15. The method according to claim 9, wherein said essential oil is
an aromatic oil.
16. The method according to claim 1, wherein said complex
carbohydrates comprise a mixture of molecular weight ranges.
17. The method according to claim 16, wherein said complex
carbohydrates comprise a mixture of a high molecular weight complex
carbohydrate and a low molecular weight complex carbohydrate.
18. The method according to claim 16, wherein the high molecular
weight and low molecular weight complex carbohydrate differ by
molecular weight and chemical structure.
19. The method according to claim 16, wherein said high molecular
weight and low molecular weight complex carbohydrates range from
two different size polymers of the same complex carbohydrates.
20. The method according to claim 1, wherein said complex
carbohydrates are in a concentration ranging from 0.1% to 99%
wt/vol.
21. The method according to claim 1, wherein said complex
carbohydrates are in a concentration ranging from 0.5% to 3.0%
wt/vol.
22. The method according to claim 1, wherein said complex
carbohydrates are in a concentration ranging from 0.01% to 5.0%
wt/vol in an Aloe Vera gel concentrate base with a concentration of
between 50% and 99% vol/vol.
23. The method according to claim 1, wherein said complex
carbohydrates are in a concentration ranging from 0.01% to 5.0%
wt/vol.
24. The method according to claim 1, wherein said at least one
complex carbohydrate has a molecular weight in the range of from
1,000 to less than 50,000 daltons.
25. The method according to claim 1, wherein said at least one
complex carbohydrate has a molecular weight in the range of from
100,000 to 300,000 daltons.
26. The method according to claim 1, wherein said at least one
complex carbohydrate has a molecular weight in the range of greater
than 1,000,000 daltons.
27. The method of claim 1, wherein the low purity complex
carbohydrate contains up to 5% by weight contaminants.
28. The method of claim 1, wherein the low purity complex
carbohydrate contains less than 98% by weight hyaluronic acid.
29. The method of claim 1, wherein the active ingredient is present
in an amount of at least 0.01% wt/vol.
30. The method of claim 1, wherein the active ingredient is present
in an amount of at least 1% wt/vol.
31. The method of claim 1, wherein said at least one low or
cosmetic or food grade complex carbohydrate has a molecular weight
in the range of from 1,000 to less than 50,000, from 100,000 to
500,000, or greater than 1,000,000 daltons.
32. The method according to claim 1, wherein the complex
carbohydrate is a hyaluronic acid or salt or derivative thereof.
Description
[0001] This application is a Divisional Application of co-pending
Application No. 09/890,425 filed on Feb. 19, 2002, which is the
U.S. National Phase of PCT/US2000/002328, filed on Feb. 1, 2000,
which claims priority under 35 USC 119(e) on Provisional
applications U.S. Ser. Nos. 60/117,988, 60/127,749, 60/137,098,
60/142,306 and 60/166,326 filed on Feb. 1, 1999, Apr. 6, 1999, Jun.
2, 1999, Jul. 3, 1999 and Nov. 19, 1999, respectively. Each of the
above applications are herein incorporated by reference.
BACKGROUND AND FIELD OF THE INVENTION
[0002] The invention relates to a method of preventing and treating
diseases and conditions of mammals associated with the adhesion,
metastatic and coronary cascades comprising applying a composition
of complex carbohydrates and essential oils topically, orally or
mucosally on a repeated basis. The invention also encompasses a
method of preventing and treating diseases and conditions
associated with the adhesion, metastatic and coronary cascades
comprising orally or mucosally applying complex carbohydrates as
the sole active ingredient.
[0003] Complex carbohydrates, for purposes of this invention are
defined as any polymer comprising more than two sugar moieties
including such classes of compounds as polysaccharides and
oligosaccharides. Polysaccharides include mucopolysaccharides and
mannans whereas oligosaccharides are comprised of branched
polysaccharides such as sialylated sugars including milk
sugars.
[0004] Mucopolysaccharides are glycosaminoglycans which can be
obtained from numerous sources (e.g. rooster combs, trachea,
umbilical cords, skin, articular fluids and certain bacteria such
as Streptococci spp). Most glycosaminoglycans (hyaluronic acid,
chondroitin sulfates A, B, and C, heparin sulfate, heparin, keratan
sulfate, dermatan sulfate, etc.) are composed of repeating sugars
such as n-acetylglucosamine, glucuronic acid and n-acetyl
galactosamine (these are known as non-sulfated glycosaminoglycans).
If such glycosaminoglycans contain sulfur groups they are known as
sulfated glycosaminoglycans.
[0005] Mannans are mannose-based polysaccharides which are normally
extracted from plants. The most noteworthy is acemannan which is a
beta 1,4-linked acetylated mannan extracted from the Aloe Vera
plant (Aloe barbadensis Miller). This plant has been thought for
centuries to have certain healing powers. Not until the 1980s was
the active ingredient isolated and proven to have an effect on the
immune system (see J. Pharm. Sci., 73 (1), Jan. 1984). Sialylated
sugars are oligosaccharides which contain sialyl groups (e.g.
sialic acid) and often contain fucose. Sialyl Lewis.sup.x and its
derivatives are examples from this group (Tyrell et al, Proc. Natl.
Acad. Sci. USA, 88, Nov. 1991). At present, this oligosaccharide is
so difficult to prepare/obtain that the cost is prohibitive and
limits research activities to determine its mechanism of action.
Some of the milk sugars (also called hexaoses) are also
incorporated in this general class of compounds. Examples of these
are difucosyllacto-N-hexaose a and b,
Disialyl-monofucosyllacto-N-hexaose and monofucosyllacto-N-hexsaose
I, II, and II (obtainable from Oxford Glycosystems, Inc.).
[0006] Heparin, hyaluronic acid and chondroitin sulfate are the
most studied complex carbohydrates. They fall in the class called
mucopolysaccharides or glycosaminoglycans. Heparin has been used
for a number of years as an anticoagulant. Hyaluronic acid has been
used therapeutically since the 1970s as a replacement for the
vitreous humor of the eye post surgery and, more recently, as
replacement for joint fluid in arthritic joints. An extensive
discussion of its various utilities is found in U.S. Pat. No.
4,141,973 to Balazs. The mode of action for hyaluronic acid
injected directly into joints for treatment of arthritis has been
proposed to be lubrication and replacement of the degraded joint
fluid with highly viscous hyaluronic acid (see J. Bone Jt. Surg.
54A, 1972). High molecular weight (>1,000,000 daltons) and high
viscosity have been reported to be critical. (For purposes of this
application, all molecular weights are expressed as daltons. The
unit designation will not be added hereafter.)
[0007] In the 1980s, it was discovered that chondroitin sulfate, or
polysulfated glycosaminoglycan (known by its commercial name as
ADEQUAN.quadrature.) could be injected intramuscularly for
reduction of pain and inflammation associated with arthrosis of
horses. The mechanism of action of this glycosaminoglycan has been
speculated to be inhibition of certain degradative enzymes present
in the joint fluid which are up-regulated by trauma.
[0008] In the 1990s, chondroitin sulfate had developed into a
popular nutritional supplement being used extensively to treat
joint disease. Such treatment requires oral doses between 1000 and
3000 mg/day of for humans. Even with these high doses, relief from
joint pain often takes 6-9 months.
[0009] In 1989, it was discovered that intravenous, intramuscular
or subcutaneous delivery of hyaluronic acid could reduce the pain
of arthritis (U.S. Pat. No. 4,808,576 by Schultz et al) when the
hyaluronic acid was delivered remote to the site of the arthritis
(not into the joint). This patent specifically states that the
hyaluronic acid is administered remote to the site and that the
hyaluronic acid must be of high purity (>99% pure hyaluronic
acid). Schultz et al. does not disclose or suggest the use of
hyaluronic acid in combination with essential oils, use of other
complex carbohydrate macromolecules, oral application or mucosal
application. Schultz et al. specifically teaches away from use of
low purity complex carbohydrates. By low purity is meant complex
carbohydrates that would be considered food grade or cosmetic
grade, which could be <98% pure and could contain such
contaminants as endotoxins, lipoteichoic acids, proteins, nucleic
acids, etc. The low purity hyaluronic acid or salt thereof useful
in the present invention (<98% pure hyaluronic acid) can be of a
cosmetic grade or food grade which can contain up to 5%
contaminants. Such material would not pass the owl monkey eye test
used to select high purity hyaluronic acids and salts thereof
(described by Balazs in U.S. Pat. No. 4,141,973) in that it would
produce an inflammatory response in the eye. It also would not pass
the horse joint injection test described by Schultz et al (U.S.
Pat. No. 4,808,576). However, it does not produce a reaction when
applied to the skin or mucous membranes of mammals including
humans, dogs, cats, horses, cattle, swine, rabbits, guinea pigs and
mice.
[0010] The importance of high molecular weight for effectiveness of
hyaluronic acid in the treatment of arthritis is emphasized by
Balazs (U.S. Pat. No. 4,141,973) and in a publication by Howard and
McIlraith (see The Compendium, 15(3), March 1993) who summarize
several clinical studies conducted to determine the most
efficacious molecular weight range of hyaluronic acid injected
intra-articularly to treat traumatic arthritis in horses. The
conclusion from these studies is that hyaluronic acid with a
molecular weight below 1.times.10.sup.6 is not as effective as
hyaluronic acid with a molecular weight above this value. More
recently, della Valle et al (U.S. Pat. No. 5,166,331) claimed that
there are two distinct pharmacologically active molecular weight
ranges of hyaluronic acid or salts thereof. These moieties are
utilized separately (purified one from the other) and defined as
50,000-100,000 (Hylastine) and 500,000-730,000 (Hylectin).
Hylastine is specified for use in wound healing while Hylectin is
specified for use in ocular surgery.
[0011] Whereas Balazs (U.S. Pat. No. 4,141,973), Schultz (U.S. Pat.
No. 4,808,576) and della Valle (U.S. Pat. No. 5,166,331) all
specify use of highly purified hyaluronic acid and whereas Balazs
(U.S. Pat. No. 4,141,973) discards the fractions containing
hyaluronic acid or their salts having molecular weights less than
750,000; and whereas della Valle (U.S. Pat. No. 5,166,331) discards
impurities having molecular weights less than 30,000 and does not
use hyaluronic acid with molecular weights between 100,000 and
500,000 and, thus, specifies use of clearly-defined molecular
weights of hyaluronic acid for topical or ocular use; and whereas
Schultz prefers use of hyaluronic acid with a molecular weight
between 1.2.times.10.sup.6 and 4.0.times.10.sup.6 in topical
formulations, we have discovered that all molecular weights of
complex carbohydrates such as hyaluronic acids or salts thereof and
all purities of these compounds are useful in topical, oral or
mucosal preparations for the treatment of numerous diseases and
conditions.
[0012] The most recent studies on hyaluronic acid discuss treatment
of various types of cancer with very large doses of this
macromolecule (Falk, WO 97/40841). The Falk application suggests
that doses should exceed 750 mg. per 70 kg person, preferably,
exceeding 1 g. per 70 kg person. Such doses are given
intermittently post diagnosis and are not suggested to be
preventative or administered in low doses. Additionally, it is
clear that the sodium hyaluronate of Falk needs to be pure enough
for injection even though oral administration is used in addition
to intravenous injection.
[0013] Essential oils are natural components of plants and animals
that are extracted by various methods known to the art. They are
generally very complex, containing numerous compounds (see Perfumer
and Flavorist, 17, Nov./Dec. 1992). More recently, some of the
essential oils have been chemically synthesized. Most uses of these
oils are as flavorings for foods and candies and as bath, cosmetic
and perfume ingredients to provide pleasant aromas. Several of the
essential oils (i.e. Menthol, Eucalyptus Oil, Camphor, Peppermint
Oil and Wintergreen Oil) are currently used in over-the-counter
topical preparations such as BenGay, Mineral Ice, Flexall 454, etc.
at concentrations as high as 50%. These topical medications claim
pain relief but, according to FDA, act to relieve pain by producing
a counterirritation, not by penetrating the skin and acting
systemically to reduce inflammation and swelling which are the
causes of pain.
[0014] The Adhesion Cascade was first described in the early 1990s.
In a summary by Adams and Shaw (The Lancet, 343, Apr. 2, 1994) the
adhesion cascade which is stimulated when trauma occurs is divided
into four sequential steps of tethering, triggering, strong
adhesion and motility. Tethering interactions are mediated by a
family of three lectin-like carbohydrate-binding molecules
(selectins). These interactions are strong enough to cause the
leukocytes to roll along the blood vessel walls to the site of
trauma instead of flowing freely through such vessels, but not
strong enough to cause these leukocytes to slow down. The
triggering response is stimulated by factors such as cytokines and
mediated by adhesion molecules called integrins. Integrins, by
themselves, do not bind well to epithelium. However, when
activated, integrins promote strong adhesion of the leukocyte to
the epithelial surface. Leukocytes bind to the epithelial cells via
their receptor sites such as CD44, CD31, etc. During strong
adhesion, the interaction of these integrins with their ligands on
the surface of the leukocytes are responsible for cessation of
movement and flattening of the leukocyte. Finally, a process
involving VCAM-1 and LFA-1 and other such integrins allows
leukocytes to pass between endothelial cell junctions and into the
tissue that has been traumatized. Collection of leukocytes at the
site of trauma produces inflammation which is then followed by pain
or other sequelae.
[0015] The present invention is based upon the premise that complex
carbohydrates, including but not limited to glycosaminoglycans,
bind to the receptor sites on leukocytes blocking their ability to
tether to the blood vessel walls thus inhibiting the motility and
interrupting the Adhesion cascade.
[0016] The metastatic cascade is very similar to the adhesion
cascade. It has been proposed that tumor cells of all types contain
CD44 receptor sites on their surface. These CD44 receptor sites
appear to be involved in metastasis functioning similar to the
receptor sites on leukocytes--tethering the tumor cells to the
blood vessel wall and providing the motility necessary for movement
from one site to another in the mammalian body. Once again, it is
the premise of the present invention that complex carbohydrates,
including but not limited to glycosaminoglycans, bind to the
receptor sites on tumor cells blocking their ability to tether to
the blood vessel walls and inhibiting the motility which, in turn,
interrupts the potential for metastasis.
[0017] A Coronary cascade has recently been described in the
Harvard Health Letter (December 1999, pg. 4-5). This cascade leads
to the development of heart disease and stroke by causing plaque
formation in the blood vessels. The theory is based on the premise
that there are stable and unstable plaques produced on blood vessel
walls. Unstable plaques are "swarming with T cells and macrophages"
causing inflammation and make these plaques unstable. The T cells
are described as sending macrophages a signal to release a protein
called tissue factor which "spills out and encounters circulating
blood, attracting platelets and triggers formation of a clot that
quickly blocks up the artery". The compositions of the present
invention are believed to inhibit the macrophages from infiltrating
into the unstable plaques, thus preventing and treating heart
disease and stroke.
[0018] It is unexpected that complex carbohydrates of the present
invention could be administered topically, orally or mucosally in
low doses to inhibit the various cascades preventing and treating
such a broad spectrum of diseases and conditions.
OBJECTS AND SUMMARY OF THE INVENTION
[0019] Although not bound by any theory, the invention relates to a
method of preventing and treating diseases associated with the
Adhesion and Metastatic cascades comprising applying a composition
of complex carbohydrates and essential oils topically, orally or
mucosally on a repeated basis. The invention also encompasses a
method of preventing and treating diseases associated with the
Adhesion and Metastatic cascades comprising mucosally applying
complex carbohydrates as the sole active ingredient.
[0020] More specifically, this invention describes a mechanism by
which inflammation, including diseases and conditions associated
therewith, tumor growth, tumor metastasis and/or allergies and
allergy-related diseases can be prevented or treated.
[0021] It is understood that this invention describes the
prevention and treatment of numerous diseases and conditions
including but not limited to arthritis (osteoarthritis and
rheumatoid arthritis), gastritis, colitis, esophagitis, bronchitis,
sore throat, tonsilitis, tendonitis, fibromyalgia, sunburn, heat
burns, temporomandibular joint (TMJ) condition, dental pain,
itching associated with allergies and hypersensitivity, poison ivy,
asthma, anaphylaxis, Attention Deficit Hyperactivity Disorder
(ADHD), plaque formation associated with heart disease and stroke,
increased degradation of spinal nerves post spinal cord injury,
adhesion formation post surgery, scar formation post surgery, wound
healing, decubutis ulcers, ganglion formation, Alzheimer's disease,
HIV, cancer, Diabetes, skin problems such as acne, psoriasis,
wrinkles, and even hair loss.
[0022] Such prevention and treatment are accomplished by topically,
orally or mucosally applying complex carbohydrates with or without
essential oils to mammals in an amount and number of applications
so as to be effective in preventing and treating the target disease
or condition. It is proposed that such prevention or treatment
results from blockage of the Adhesion, Metastatic, or Coronary
cascades.
[0023] The delivery of these compounds to the site of trauma is
accomplished by topical application of said compounds whereby the
compounds are combined with essential oils, by oral delivery of
said compounds whereby the compounds are mixed with essential oils,
coated with protective oral delivery materials such as hydrogels,
carbopols, etc., or delivered without a coating wherein the complex
carbohydrates are the sole active ingredients(e.g. without the
essential oil(s) being present as an active ingredient), and/or
delivered mucosally wherein the complex carbohydrates are the sole
active ingredients (e.g. without the essential oil(s) being present
as an active ingredient).
[0024] Mucosal delivery includes but is not limited to application
of the compounds to the mucous membranes of the nose, eyes, mouth,
throat, gums, tonsils, eyes, esophagus, stomach, colon, rectum,
vagina, or any other mucous membrane.
[0025] It is a further advantage of this invention that ultrapure
or purified complex carbohydrates do not need to be used.
Therefore, cosmetic or food grade complex carbohydrates, are
acceptable for use to prevent or treat the above diseases or
conditions if they are applied topically, orally or mucosally. The
preferred complex carbohydrates of this invention are
mucopolysaccharides (glycosaminoglycans) including hyaluronic acid
and salts, sulfates or derivatives thereof, chondroitin sulfate and
polysulfated forms, salts or derivatives thereof, sialyl
Lewis.sup.x and salts or derivatives thereof, heparin and sulfates,
salts or derivatives thereof, dermatan, and sulfates, salts or
derivatives thereof, keratin and salts, sulfates and derivatives
thereof, as well as combinations of the above. The most preferred
complex carbohydrates are hyaluronic acid including salts,
sulfates, esters, or derivatives thereof, chondroitin sulfate
including polysulfated forms, low molecular weight heparin
including salts, sulfates and derivatives thereof and sialyl
Lewis.sup.x including salts and derivatives thereof and
combinations of the above.
[0026] It is an additional discovery that all sizes of complex
carbohydrates are effective in this invention. Therefore,
glycosaminoglycans, including chondroitin sulfate, heparin and
hyaluronic acids of molecular weights <1,000, between 500,000
and 4,000,000, as well as above 4,000,000 are effective and
non-reactive.
[0027] It is a further discovery that essential oils can be used to
topically, orally or mucosally deliver macromolecules (molecules
with a molecular weight >1000) into the dermal tissue and,
consequently, into the blood stream or to deliver said
macromolecules mucosally. Additionally, it is a discovery that said
macromolecules can be absorbed mucosally without the assistance of
a delivery system and that said mucosally-absorbed macromolecules
are effective at low doses.
[0028] Finally, it has been discovered that the Adhesion cascade
which when stimulated by trauma, an allergen or other trigger
mechanism which results in build up of leukocytes at the site of
trauma or the trigger site can be blocked by delivering the complex
carbohydrates of this invention according to the methods of this
invention.
[0029] Therefore, it has unexpectedly been found that essential
oils when formulated with complex carbohydrates including
polysaccharides, oligosaccharides, sialylated sugars,
glycosaminoglycans or even monoclonal antibodies specific for the
Adhesion or Metastatic cascades, can effectively treat the
above-mentioned diseases and conditions when applied topically,
orally, or mucosally.
[0030] Neither the complex carbohydrates nor the essential oils
alone, when administered topically (e.g. topically as used in the
present application does not include orally or mucosally) on the
site of pain and inflammation, produce a significant preventative
or therapeutic effect. However, when combined in the mixtures
described herein, there is a definite therapeutic effect which can
be felt within 30 minutes of the application.
[0031] Even more unexpectedly, it has been discovered that the
complex carbohydrates alone can be applied orally or mucosally
without essential oils to obtain an even better response
(prevention or treatment) with a smaller dose.
[0032] This invention also describes a composition of matter
comprising at least one complex carbohydrate and at least one
essential oil and also the method for effecting transdermal
migration resulting in topical delivery of compounds, including
macromolecules, through the skin of mammals and into the
bloodstream by combining such compounds with essential oils.
[0033] This invention also encompasses a composition of matter
comprising complex carbohydrate macromolecules as the sole active
ingredient (e.g. without the essential oil(s) being present as an
active ingredient), applied orally or mucosally to inhibit the
Adhesion, Metastatic or Coronary cascades thus preventing or
treating numerous diseases and conditions related thereto.
[0034] Macromolecules as used herein means any molecule with a
molecular weight >1000. Mammals as used herein includes humans,
dogs, cats, horses, cattle, swine, rabbits, guinea pigs, mice, and
all other mammalian animals.
DETAILED DESCRIPTION OF THE INVENTION
[0035] As discussed above, there have been no previous
investigations describing use of complex carbohydrates in
combination with essential oils to prevent and/or treat diseases
and conditions associated with the Adhesion, Metastatic and
Coronary cascades. There have also been no previous investigations
describing use of complex carbohydrates as the sole active
ingredient (e.g. without the essential oil(s) being present as an
active ingredient) to prevent and treat diseases associated with
the Adhesion, Metastatic and Coronary cascades when delivered
orally or mucosally, especially in low doses. By low doses is meant
from 0.00005 mg/kg to 50 mg/kg, preferably from 0.005 mg/kg to 40
mg/kg, more preferably from 0.05 mg/kg to 20 mg/kg.
[0036] The diseases and conditions that are preventable or
treatable according to this invention (e.g. composition using the
present active ingredient (complex carbohydrate) with or without
essential oil(s)) include but are not limited to arthritis
(osteoarthritis and rheumatoid arthritis), gastritis, colitis,
esophagitis, bronchitis, sore throat, tonsilitis, tendonitis,
fibromyalgia, headaches including migraines, pancreatitis,
vaginitis, hemorroids, sunburn, heat burns, TMJ, dental pain,
gingivitis, dental caries, post surgical pain, menstrual pain,
anaphylaxis, pain prior to and during childbirth, itching
associated with allergies and hypersensitivity, poison ivy, asthma,
Attention Deficit Hyperactivity Disorder (ADHD), plaque formation
associated with heart disease and stroke, increased degradation of
spinal nerves post spinal cord injury, adhesion formation post
surgery, scar formation post surgery, lack of wound healing,
decubutis ulcers, irritation of nerve bundles, ganglion formation,
Alzheimer's disease, HIV, cancer, Diabetes, skin problems such as
acne, psoriasis, wrinkles, and even hair loss.
[0037] The invention also describes a process for reducing the
sequelae of trauma in irritated or inflamed tissue of mammals by
the topical application of a mixture of an essential oil or oils
and a complex carbohydrate or mixture thereof. The pharmaceutical
composition described is applied directly on or over the
traumatized site.
[0038] Finally, the invention describes a process for reducing the
sequelae of trauma in irritated or inflamed tissue of mammals by
oral or mucosal application of a complex carbohydrate or mixture
thereof as the only active ingredient (e.g. without the essential
oil(s) being present as an active ingredient).
[0039] Particularly amenable conditions for such prevention or
treatment include but are not limited to irritated or inflamed
muscles, cramped muscles, inflamed tendons, fibromyalgia, swollen
and painful joints, bruised tissue, tired feet, allergic conditions
of the skin, other allergic conditions including psoriasis, asthma,
anaphylaxis, ADHD, open wounds, decubitis ulcers, burns, sunburns,
inflamed stomach or intestinal lining (gastritis, colitis), dental
problems, inflamed bronchi or esophagial lining, inflamed nerve
bundles (ganglia), adhesions formed after surgery or trauma, post
surgical pain, pain during and after childbirth, plaques formed on
veins or arteries leading to heart disease and stroke, inflammation
associated with Alzheimer's Disease, tumor formation and tumor
metastasis.
[0040] A significant advantage of this invention is that
pharmaceutical grade complex carbohydrates are not required. The
invention preferably uses cosmetic or food grade complex
carbohydrates. Such complex carbohydrates can be obtained from any
source as long as the source is not contaminated with undesirable
adventitious agents (disease-producing viruses, bacteria, fungi,
parasites, etc.). For instance, cosmetic grade hyaluronic acid
which is of low purity (containing up to 5% impurities such as
proteins, nucleic acids, teichoic acids and endotoxins) costs
approximately $2,000/Kg, whereas high purity pharmaceutical grade
hyaluronic acid required for injection into mammals costs at least
$100,000/Kg and contains less than 0.5% impurities. Low purity
complex carbohydrates such as mucopolysaccharides may be
contaminated with up to 5% wt/vol proteins, 5% wt/vol nucleic
acids, 1% wt/vol teichoic acids, 5% wt/vol lipids, fractions of
hyaluronic acid .sub.<30,000 (defined as reactive by both Balazs
in U.S. Pat. No. 4,141,973 and della Valle in U.S. Pat. No.
5,166,331), 5% wt/vol endotoxins and other small molecules.
Preferably "low purity" means containing up to about 5% impurities,
more preferably from about 0.6-5% impurities, still more preferably
from about 1-5% impurities. They will cause reactions when injected
into monkey eyes or joints of horses but will not cause reactions
when applied to the skin of mammals or when delivered orally or
mucosally to such mammals. Because the pharmaceutical compositions
of this invention are applied topically, orally or mucosally, these
contaminants produce no adverse reactions (e.g. irritation or
blistering of skin). Additionally, if one must select and use only
certain molecular weight ranges of hyaluronic acid or salts
thereof, the cost would be prohibitive. In fact, the presence of
multiple molecular weight fractions in compositions of the present
invention is preferable for the efficacy.
[0041] In order to assure freedom from contaminating
microorganisms, the formulations of this invention can include
preservatives allowable in foods or topical preparations. Allowable
preservatives include but are not limited to methyl and propyl
parabens, propylene glycol, ethylenediamine tetraacetic acid
(EDTA), sorbitol, ascorbic acid, sorbate and sorbic acid, benzoic
acid, and any other acceptable preservative, including mixtures
thereof. Preservatives that would not be allowable in oral or
mucosal formulations include those that are know carcinogens such
as formaldehyde, phenol, glutaraldehyde, and alcohols that are
toxic to mammals (e.g. isopropyl, propyl, denatured alcohol).
[0042] All molecular weight ranges of complex carbohydrates are
effective in formulations of this invention. For instance,
hyaluronic acid with a molecular weight of <1,000, 1,000 to
30,000, 100,000-500,000, >1,000,000 or >4,000,000 have proven
to be effective. It has been found that complex carbohydrates,
especially glycosaminoglycans with lower molecular weights (e.g.
<50,000, preferably <30,000) act more quickly than those with
high molecular weights (e.g. >1,000,000). However, the high
molecular weight glycosaminoglycans provide a longer-lasting
effect. It is believed that the latter macromolecules are broken
down by enzymes in the body to smaller molecules. Therefore, there
is a longer release of the more active smaller molecules producing
a longer period of efficacy. Therefore, the preferred formulation
includes a mixture of low and high molecular weight complex
carbohydrates.
[0043] The complex carbohydrates useful in combination with
essential oils for direct topical application on sites of trauma
may be of any type already recognized as useful for parenteral
treatment. Additionally, complex carbohydrates, polysaccharides,
glycosaminoglycans or their derivatives which bind to leukocyte
receptor sites and/or bind to selectins, integrins, or any other
receptor sites which are involved with the mechanism by which
leukocytes move to sites of trauma or which enable metastasis of
tumors and which, when bound, serve to inhibit any of the steps of
the Adhesion or Metastatic cascades would be useful in such
pharmaceutical compositions. Such compounds may be obtained from
any source. They can be extracted from rooster combs (U.S. Pat. No.
4,141,973), produced by fermentation of bacteria (U.S. Pat. No.
4,782,046), or extracted from trachea, skin, umbilical cords, etc.
and need only be pure enough to be used as a cosmetic in that they
do not cause reactions when administered topically. These molecules
include but are not limited to polysaccharides, glycosaminoglycans
such as hyaluronic acids and derivatives or salts thereof (Genzyme,
Lifecore Biomedicals, Meiji Seika Kaisha, Ltd.), chondroitin
sulfates A, B, or C or their derivatives (SIGMA Chemical Company),
keratan sulfate and derivatives thereof (SIGMA Chemical Company),
heparin or heparin sulfate and derivatives thereof (SIGMA Chemical
Company, Rhone Poulenc Rorer Pharmaceuticals), dermatan sulfate and
derivatives thereof (SIGMA Chemical Company), mannans and
derivatives thereof (SIGMA Chemical Company), acemannan (Carrington
Laboratories) and derivatives thereof, extracts of the Aloe Vera
plant and derivatives thereof (Aloe Vera gel concentrate supplied
by Lily of the Desert, Irving, Tex.) and certain sialylated sugars
such as trifucosyllacto-N-hexaose and sialyl Lewis.sup.x (Oxford
Glycosystems). The sources listed are exemplary only and not
limitations of the invention.
[0044] It is a preferred embodiment of this invention that at least
two molecular weight ranges of complex carbohydrates be included in
the pharmaceutical composition. At least one should be from a low
molecular weight range {from 1000 to <50,000 (e.g. 49,000)} and
the other one or more should be from a higher molecular weight
range (from 100,000 to 500,000 or >1,000,000). Such complex
carbohydrates may or may not be a mixture of two or more different
types of complex carbohydrates. For instance, one complex
carbohydrate providing the high molecular weight moiety could be
selected from the group consisting of hyaluronic acid and mannans
and another complex carbohydrate in the same pharmaceutical
composition providing the low molecular weight moiety could be a
second polysaccharide or a sialylated sugar selected from the group
consisting of chondroitin sulfate, keratan sulfate, heparin,
heparin sulfate, dermatan sulfate, acemannan, sialyl Lewis.sup.x,
and hexaoses.
[0045] A more preferred embodiment would comprise a mixture of at
least two polysaccharides in the pharmaceutical composition. One of
these polysaccharides would be of a low molecular weight range of
<30,000 (e.g. 1000-29,000) and one polysaccharide would be of a
high molecular weight >1,000,000. An even more preferred
embodiment of this invention comprises a mixture of equal parts of
at least two polysaccharides. One of the polysaccharides would be
of a low molecular weight range (<30,000). The second
polysaccharide would of be a high molecular weight hyaluronic acid
or salt or derivative thereof (>1,000,000).
[0046] The most preferred embodiment of this invention comprises
equal amounts of two or more molecular weight ranges of hyaluronic
acid or salts or derivatives thereof. Such a composition would
comprise for instance, a hyaluronic acid or salt or derivative
thereof with a low molecular weight of <30,000 combined with a
hyaluronic acid or salt or derivative thereof which has a high
molecular weight >1,000,000.
[0047] When heparin is used, it is advantageous to use low
molecular weight heparin as it has been demonstrated to be free of
anti-coagulant activity. However, it is expected that high
molecular weight heparin will be broken down to low molecular
weight heparin when administered orally or mucosally.
[0048] When Aloe Vera is used to supply the complex carbohydrate,
it is used as the base ingredient at a concentration of between 50%
and 99% vol/vol Aloe Vera gel concentrate. A second complex
carbohydrate such as a polysaccharide can be added to a
concentration up to 5.0% wt/vol. This is then combined with an
essential oil at a concentration of between 0.1% vol/vol and 20%
vol/vol. The remaining portion of the formulation would be
distilled deionized water (DI) and/or a cream or ointment base. A
preferred embodiment comprises a 50% to 99% vol/vol Aloe Vera gel
concentrate combined with a complex carbohydrate such as a
polysaccharide at a concentration of between 0.01% and 5.0% wt/vol
and an essential oil at a concentration of between 0.5% and 10.0%
vol/vol. The remaining portion of the formulation would be DI water
and/or a cream or ointment base. A more preferred embodiment of an
Aloe Vera-containing formulation comprises 95% to 99% vol/vol Aloe
Vera gel concentrate combined with hyaluronic acid at a
concentration between 0.01% and 3.0% vol/vol and an essential oil
at a concentration of between 0.5% and 5.0% vol/vol, the remainder
being DI water. The most preferred embodiment of this formulation
comprises a 98% vol/vol Aloe Vera gel concentrate (99% pure) as a
base combined with high molecular weight hyaluronic acid at a
concentration of between 0.1% and 1.0% vol/vol and an essential oil
at a concentration between 1.0% and 3.0% vol/vol, the remainder
being DI water. The essential oils would be selected from the group
comprising Tea Tree Oil, Rosemary Oil, Oil of Wintergreen,
Eucalyptus Oil, Camphor Oil and Menthol.
[0049] Unlike the essential oils used in current over-the-counter
products and described in the above-mentioned publications, the
essential oils used in this invention are incorporated into the
formulation at minimal levels. The concentrations used are
generally from 0.0001% to 20% vol/vol with a preferred embodiment
containing from 0.5% to 10% vol/vol of such oils. A more preferred
embodiment comprises a formulation containing a total concentration
of 1.0% to 5.0% vol/vol essential oils. The most preferred
embodiment comprises a formulation containing a total concentration
of 1.0% to 3.0% vol/vol essential oils. The essential oils of the
invention may be either natural or synthetic and may be obtained
from any source. For instance, natural Eucalyptus Oil, Rosemary
Oil, Pine Needle Oil, Tea Tree Oil, Sage Oil, Jojoba Oil, Cinnamon
Oil, Anise Oil, Lemon Oil, Lime Oil, Orange Oil, Peppermint Oil,
Spearmint Oil, Wintergreen Oil, Sweet Birch Oil, Clove Leaf Oil,
Almond Oil, White Pine Oil, Camphor Oil, Cardamon Oil, Cedar Leaf
Oil Sweet Birch Oil and many others can be purchased from Lorann
Oils. Synthetic Wintergreen Oil, Anise Oil, Fir Tree Oil, Rose Oil
and Camphor Oil can be obtained from the same source. Menthol and
derivatives thereof can be obtained from SIGMA Chemical Company.
The purity of these essential oils is of little concern as long as
they meet the requirements for a cosmetic and do not produce
adverse reactions when applied to the skin of mammals. An example
of an animal-derived essential oil is EMU oil, extracted from the
skin of the EMU.
[0050] For the purposes of this invention, the phrase "amount
effective to allow penetration of the dermis of mammals" is
preferably 0.1 to 20% vol/vol, more preferably 0.5 to 10% vol/vol
and most preferably 1.0 to 5.0% vol/vol. The phrase "amount
effective to allow penetration of the mucous membranes of mammals"
is preferably 0.0001 to 0.09% vol/vol, more preferably 0.0001 to
0.01% vol/vol and most preferably 0.0001 to 0.001% vol/vol.
[0051] The formulation of a complex carbohydrate with a natural or
synthetic essential oil should be adequate to form an emulsion,
suspension, solution, cream or ointment at the time of application.
A liquid formulation will not be effective if the oil is separated
from the aqueous phase. However, a suspension or solution which may
be resuspended by shaking prior to application is acceptable for
use. Any cream or ointment base which does not interfere with the
effectiveness of the active ingredients may be included in the
formulation. Therefore, one embodiment of this invention is a cream
base containing at least one complex carbohydrate and at least one
essential oil. Another embodiment is an ointment base containing at
least one complex carbohydrate and at least one essential oil. Yet
another embodiment of the invention is an Aloe Vera base containing
at least one complex carbohydrate and at least one essential oil.
However, the preferred embodiment is a liquid formulation in an
aqueous base which contains at least one complex carbohydrate and
at least one essential oil. A significant advantage of this liquid
formulation is that the preparation is not greasy or oily, does not
leave a greasy or oily film on the skin and does not leave a
lingering odor on the skin.
[0052] The treatment of irritated or inflamed mammalian tissue by
direct topical application requires a dose or total dose regimen
effective to reduce or alleviate the results of the trauma. It is
preferred to administer at least about 0.000001 mg/lb of body
weight of each ingredient over the site of trauma at least once per
day or as often as necessary (e.g. 3 times per day, preferably 4
times per day, and most preferably 8 times per day, or simply "as
needed"). The components of this formulation are
naturally-occurring substances and are safe when applied topically.
It is believed that there is no inherent upper limit to the
tolerable dose. However, as in all medicinal treatments it is
prudent to use no more than is necessary to achieve the desired
effect. It has been noted that more intense inflammation and pain
require more dose applications for relief. A dose of 100 mg/lb of
body weight has been used safely and could serve as an upper limit
for use. Similar dose regimens are recommended for wound healing
whereas the pharmaceutical composition is applied on the wound
until adequate promotion of granulation of the wound has occurred
and healing is complete.
[0053] A convenient topical application formulation is a
combination of one or more complex carbohydrates such as mannans,
polysaccharides, oligosaccharides, or Aloe Vera extracts at a total
concentration of between 0.1% and 99% wt/vol with one or more
essential oils at a total concentration of between 0.5% and 20%
vol/vol with the remainder of the formulation being made up of a
liquid, cream or ointment base.
[0054] Another embodiment of the topical application formulation is
a combination of one or more glycosaminoglycans at a total
concentration of between 0.1% and 99% wt/vol with one or more
essential oils at a total concentration of between 0.5% and 20%
vol/vol with the remainder of the formulation being a cream,
ointment or aqueous base.
[0055] Another embodiment of the topical application formulation is
a combination of one or more mannans at a total concentration of
between 0.1% and 99% wt/vol with one or more essential oils at a
total concentration of between 0.5% and 20% vol/vol, the remainder
being a cream, ointment or aqueous base.
[0056] A preferred embodiment of the invention is a combination of
equal amounts of two or more complex carbohydrates of widely
varying molecular weights (one below 30,000 and one above 500,000)
at a combined concentration of between 0.5% and 3.0% wt/vol with
two or more essential oils having a total concentration of between
0.5% and 5.0% vol/vol with the remainder of the formulation being
an aqueous, cream or ointment base.
[0057] A more preferred embodiment of the topical application
formulation is a combination of one or more glycosaminoglycans or
mannans (at least one with a molecular weight <30,000 and at
least one with a molecular weight between 100,000 and 500,000 or
>750,000) at a concentration of between 0.5% and 5.0% wt/vol and
at least one essential oil at a total concentration of between 0.5%
and 5.0% vol/vol with the remainder being DI water.
[0058] An even more preferred embodiment of the topical application
formulation is a combination of one glycosaminoglycan or mannan
with a molecular weight <30,000 and one glycosaminoglycan or
mannan with a molecular weight >750,000 (the total concentration
of the polysaccharide component being between 0.5% and 3.0% wt/vol)
and one or more essential oils with a total concentration of
between 1.0% and 3.0% vol/vol, the remainder being DI water.
[0059] The most preferred embodiment of the topical application
formulation is a combination of hyaluronic acid with a molecular
weight <30,000 with hyaluronic acid with a molecular weight
between 100,000 and 500,000 or >750,000 at a total hyaluronic
acid concentration of between 0.5% and 3.0% wt/vol and an essential
oil selected from the group comprising Rosemary Oil, Tea Tree Oil,
Wintergreen Oil, Spearmint Oil, Peppermint Oil, Sweet Birch Oil,
Eucalyptus Oil, Menthol and Camphor at a concentration of between
1.0% and 3.0% vol/vol with the remainder of the formulation being
DI water. In order to provide the most effective, most acceptable
(aroma and spreadability) and least expensive embodiment of this
invention the formulation would contain 1.0% wt/vol hyaluronic acid
(made up of equal volumes of low molecular weight hyaluronic acid
and high molecular weight hyaluronic acid) combined with 2% wt/vol
of a combination of Wintergreen Oil, Spearmint Oil, and/or
Peppermint Oil with the remainder of the formulation being DI
water.
[0060] Complex carbohydrates which we have specifically utilized in
successful pharmaceutical compositions include heparin, hyaluronic
acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, and
acemannan (active ingredient of Aloe Vera).
[0061] Essential oils which we have specifically utilized in
successful pharmaceutical compositions include Tea Tree Oil,
Rosemary Oil, Eucalyptus Oil, Wintergreen Oil, Sage Oil, Jojoba
Oil, White Pine Oil, Camphor Oil, Cinnamon oil, Oil of Clove,
Spearmint Oil, Peppermint Oil, EMU Oil, Sweet Birch Oil and
Menthol.
[0062] The oral formulations of the immediate invention can include
any of the complex carbohydrates, alone or in combinations and
either with or without the presence of essential oil as an active
ingredient, whereby the formulation is administered as a form
selected from the group consisting of a liquid, an emulsion, a
suspension, a cream, an ointment, a gel, a foam, a solid, a powder
and a gum. It is contemplated that the liquid could be added to a
drink or drink mix, to food, be a part of a soft drink, another
type of carbonated drink, a supplement drink, used as a mouthwash
or added to a mouthwash, as a toothpaste, as a gargle, as a spray,
added to a vaporizor, as a liquid center of a gum or throat
lozenge, or used in any other way so as to retain the effectiveness
of the complex carbohydrate. A gel form could include a gel applied
by mouth, to the gums, to the tongue, under the tongue, to the
eyes, to the nose, to the vaginal area or vagina, or to the rectum.
A foam could be added to wounds, to the mouth, to the gums, to the
vagina or any other mucous membrane. A solid can be incorporated
into food, treats such as candy or treats for animals, a chewing
gum, a dissolvable gum, a lozenge, capsules, tablets, dissolvable
tablets, suppositories and any other form that would not damage the
effectiveness of the complex carbohydrates or the essential oils if
used in the formulation. Other additives may be added to said oral
formulations to improve taste and palatability or enhance the
flavor. For instance, treats for horses may include sugar or a
liquid or gel may be applied to a sugar cube. Treats for dogs may
include liver or yeast flavoring.
[0063] The same formulations as mentioned for oral use can be used
for mucosal delivery of the complex carbohydrates. The only
limitation is that the formulation remain in contact with a mucosal
surface for a period of at least a few seconds, preferably between
5 and 10 seconds.
[0064] Although the complex carbohydrates may be added to foods
which are then baked, it is preferred to add the complex
carbohydrates to the surface of the food after baking is complete.
This retains the greatest activity.
[0065] It is contemplated that the complex carbohydrates of the
present invention may be added to nutritional supplements to
enhance their effectiveness. For instance, a mixture of complex
carbohydrates and zinc, zinc gluconate, zinc gluconate glycine
could be used for more effective treatment of sore throat and
colds. A mixture of the complex carbohydrates of this invention and
capsaisin may produce an even more effective treatment for joint
pain and swelling. Addition of vitamins, minerals and other
nutritional additives may produce enhancement of the nutritional
activity by the complex carbohydrates.
[0066] The present invention has been found to be particularly
effective in the treatment of any type of inflammation, pain and/or
itching which is associated with the Adhesion cascade defined and
described earlier. It is preferable for: treatment of muscle and
joint inflammation and pain resulting from athletic injuries,
treatment of inflammation and pain associated with arthritis and
bursitis, and relief from pain often referred to as "tired feet",
reduction of inflammation (edema) in extremities resulting from
diabetes, reduction of inflammation and pain in addition to wound
healing of decubitus ulcers resulting from poor circulation by
diabetic patients or bedridden patients, treatment of inflammation
and itching of skin resulting from allergic reactions such as
poison ivy and insect bites/stings, treatment of inflammation and
pain associated with tendonitis, treatment of inflammation and pain
associated with muscle cramps, inhibition of bruising and
inflammation post trauma or surgery if applied immediately,
dissolution of bruises which have already formed, wound healing in
superficial cuts and scrapes as well as wound healing after surgery
to reduce scarring and adhesions, treatment of inflammatory skin
conditions such as acne or psoriasis and treatment of dry skin,
burns, or sunburn.
[0067] The most recent theories to explain heart attacks and stroke
(Harvard Health Letter, December 1999, pgs 4 and 5, and SCIENCE
vol:285, 23 Jul., 1999, pg 595-599) involves the eruption of
unstable plaques which have been found to be infiltrated with
T-cells and macrophages (leukocytes which cause inflammation) thus
linking this disease syndrome to the Adhesion cascade. Therefore,
it is expected that heart disease (heart attacks and stroke) can be
prevented and treated with the complex carbohydrates of this
invention. Therefore, it is expected that the complex carbohydrates
of this invention can be used to prevent and/or treat heart
disease. For example, it is contemplated that hyaluronic acid,
salts or derivatives thereof could be taken daily as a preventative
for heart disease, and/or stroke. Amounts from 1 mg/day to 20
mg/day would be expected to prevent heart disease and stroke. This
could be taken orally. Preferably, it would be taken mucosally.
Alternately, a mixture of hyaluronic acid and chondroitin sulfate
could be taken daily for prevention of heart disease and stroke.
Again, the daily dose would be expected to be less than a total of
100 mg. Repeated low doses have been demonstrated to be between
0.0001 mg and 100 mg.
[0068] The most recent theory to explain the significant
neurological degeneration that occurs in Alzheimer's Disease
involves a substantial inflammatory component (SCIENCE, vol: 286,
17 Dec., 1999, pgs 2352-2355) which appears to be related to the
Adhesion cascade. Therefore, it is expected that the complex
carbohydrates of this invention can be used to prevent and/or treat
Alzheimer's Disease. For example, it is contemplated that
hyaluronic acid, salts or derivatives thereof could be taken daily
as a preventative for Alzheimer's Disease. Amounts from 1 mg/day to
20 mg/day would be expected to prevent the degradation apparent in
Alzheimer's Disease. This could be taken orally. Preferably, it
would be taken mucosally. Alternately, a mixture of hyaluronic acid
and chondroitin sulfate could be taken daily for prevention of
Alzheimer's Disease. Again, the daily dose would be expected to be
less than a total of 100 mg.
[0069] The most recent theory to explain the significant
neurological degeneration that occurs after spinal cord injuries
that leads to irreparable paralysis, is attack by the leukocytes
rushing to the site of trauma (Adhesion cascade) to help repair the
traumatized area, but instead, degrading the ends of the nerves in
the spinal cord, fraying them which effectively inhibits their
potential realignment and partial or complete repair . It is
expected that paralysis resulting from spinal cord injuries could
be prevented or treated effectively using the complex carbohydrates
of this invention. In this case, since the patient may not be able
to take an oral medication, the medication may be administered
mucosally using suppositories (rectal or vaginal). The dose may
need to be higher, in the range of 100 mg to 1,000 mg per day. It
is also expected that drugs to assist repair of nerves would be
administered concurrently.
[0070] The invention described herein is for use with any mammal
including but not limited to humans, dogs, cats, horses, cattle
swine, sheep, goats, etc.
[0071] The invention is further illustrated but is not intended to
be limited by the following examples.
EXAMPLE 1
[0072] High molecular weight (>750,000) cosmetic grade
hyaluronic acid obtained from Meiji Seika Kaisha, Ltd, was
dissolved in distilled/deionized water (DI) to a concentration of
from 1.1 to 1.5% wt/vol. This solution was treated with high pH and
high temperature to break down the molecular weight to <30,000.
The latter treatment involved raising the pH of the solution to
11.0 and mixing the hyaluronic acid at 37-60.degree. C. for at
least 4 hours. The viscosity of a 1% solution measured at
37.degree. C. in a Cannon-Manning Viscometer dropped from >1000
c/s to <10 c/s as a result of this treatment. This hyaluronic
acid was adjusted to 1.0% wt/vol by dilution in DI water. The 1.0%
hyaluronic acid solution was aliquoted into 10 vials with 100 mL
each. Various essential oils were added to each vial at a
concentration of 2.0% vol/vol. The resulting suspensions were mixed
at room temperature for 2-3 hours. The following essential oils
were tested in this experiment: Rosemary Oil, Tea Tree Oil, Camphor
Oil, Oil of Wintergreen, Eucalyptus Oil, Cinnamon Oil, Sage Oil,
Jojoba Oil, Lemon Oil and Oil of Clove. All of the essential oils
were obtained from Loranne Oils. All preparations were held at
4.degree. C. for 14 days after which they were evaluated for their
suspension characteristics and for their sterility. Suspension
characteristics were evaluated visually while sterility was
evaluated by placing a 0.1 mL sample onto a blood agar plate,
incubating the plate at 37.degree. C. for 7 days and observing the
plates for the presence of colonies.
[0073] Tea Tree Oil, Eucalyptus Oil and Camphor Oil produced the
best suspensions. These suspensions remained stable while the
others separated out with the oil either dropping out or rising to
the top of the hyaluronic acid solution.
[0074] Each suspension was remixed and aliquoted into 10 mL amounts
in 25 mL vials. Five patients with localized chronic pain
complaints were given one vial of each preparation over a period of
2 months. After using the first preparation, they were interviewed
about effectiveness, safety (development of rashes or other adverse
reactions), spreadability/feel and odor. Effectiveness was
evaluated on a scale of 1 to 5 with 5 being the most effective
(most relief of their condition). Safety was evaluated by noting
any adverse effects. Spreadability was evaluated on a 1 to 3 scale
with 3 being best. Odor was evaluated on a scale of 1 to 3.
Pleasing was defined as 3 while unpleasing was given a value of 0.
At this point, they were given the second preparation to evaluate.
The third through 11th preparations were evaluated in the same
manner. The 11th preparation contained hyaluronic acid without
essential oils. Results are summarized in Table 1.
[0075] Interviews with all patients were positive in that all
patients reported immediate relief within 5 minutes of applying the
topical preparations. Two reported relief within 30 seconds of
treatment. None of the patients reported that the hyaluronic acid
alone was effective. None of the patients noticed untoward
reactions. Spreadability was not ideal and most of the patients
complained that the suspension was too thin and difficult to apply.
However, they liked the fact that the preparations were not oily.
The odors of the preparations were generally pleasing. Only Tea
Tree Oil and Sage Oil produced "unpleasing" comments. All patients
commented that even though the preparation had an odor at
application, there was no residual odor noted within a few minutes
after application.
[0076] The medical complaints of the patients being treated in this
study included: [0077] 1. Chronic knee pain/swelling post knee
surgery for chondromalacia [0078] 2. Chronic knee pain/swelling as
a result of torn cartilage [0079] 3. Chronic pain/swelling in first
and second finger of right hand diagnosed as arthritis [0080] 4.
Chronic foot pain (undiagnosed) [0081] 5. Chronic pain in left
thumb/wrist post reconstructive surgery
TABLE-US-00001 [0081] TABLE 1 EVALUATION OF COMBINATIONS OF
ESSENTIAL OILS WITH LOW MOLECULAR WEIGHT HYALURONIC ACID Oil
Effectiveness Safety Spreadability Odor Rosemary 5 No Rxs 2 3 Tea
Tree 5 No Rxs 2 1.7 Camphor 4 No Rxs 1 3 Wintergreen 5 No Rxs 2 3
Eucalyptus 5 No Rxs 1.7 3 Cinnamon 4 No Rxs 2 3 Sage 4 No Rxs 1.7 1
Jojoba 4 No Rxs 1.7 1.7 Lemon 3 No Rxs 1.7 2 Clove 4 No Rxs 1.7 3
None * 0 No Rxs 2 3 * Control-Contains only hyaluronic acid with no
essential oils No Rxs = No reactions observed by patients The
Effectiveness, Spreadability and odor scores are averages of the 5
responses.
EXAMPLE 2
[0082] High molecular weight (>750,000) cosmetic grade
hyaluronic acid was obtained from Meiji Sieka Kaisha, Ltd. It was
dissolved in distilled/deionized water (DI) to a concentration of
1.0% wt/vol. The viscosity of this solution at 37.degree. C. was
>1000 c/s and the molecular weight was >750,000. The 1.0%
hyaluronic acid solution was aliquoted into 10 vials with 100 mL
each. Various essential oils were added to each vial at a
concentration of 2.0% vol/vol. The resulting suspensions were mixed
at room temperature for 2-3 hours. The following essential oils
obtained from Loranne Oils were tested in this experiment: Rosemary
Oil, Tea Tree Oil, Camphor Oil, Oil of Wintergreen, Eucalyptus Oil,
Cinnamon Oil, Sage Oil, Jojoba Oil, Lemon Oil and Oil of Clove. All
preparations were held at 4.degree. C. for 7 days after which they
were evaluated for their suspension characteristics and for
sterility according to procedures described in EXAMPLE 1. All oils
remained in suspension due to the viscosity of the hyaluronic acid.
All of the preparations appeared sterile. Each suspension was
remixed and aliquoted into 10 mL amounts in 25 mL vials. The same
five patients with localized chronic pain complaints who evaluated
the preparations in EXAMPLE 1 evaluated these preparations. At the
same time that they were given the vials in Example 1, they were
given the corresponding vial from this example. They were
instructed to compare the two preparations with the same essential
oil (denoted by numbers). After using the first preparation, they
were interviewed about effectiveness, safety (development of rashes
or other adverse reactions), feel (spreadability) and odor.
Effectiveness was evaluated on a scale of 1 to 5 with 5 being the
most effective (most relief of condition). Safety was evaluated by
noting any adverse effect. Spreadability was evaluated on a 1 to 3
scale with 3 being best. Odor was evaluated on a scale of 1 to 3.
Pleasing was defined as 3 while unpleasing was defined as 0. At
this point, they were given the second preparation to evaluate. The
third through 11th preparations were evaluated in the same manner.
Results are summarized in Table 2. All numbers shown in this table
are averages of the responses.
[0083] Patients indicated that although these preparations were as
effective as the preparations in EXAMPLE 1, it took from 45 to 60
minutes for the effect to be significant. However, they indicated
that the effect lasted for 4-8 hours. The effectiveness of
preparations in EXAMPLE 1 seemed to last only 1-3 hours. All
patients liked the spreadability of the preparations in EXAMPLE 2.
All except the Camphor Oil spread smoothly and left the skin
feeling soft. The Camphor Oil seemed to absorb rapidly leaving the
skin feeling dry. Again, no adverse reactions were noted.
The complaints of the patients in this study included: [0084] 1.
Chronic knee pain/swelling post knee surgery for chondromalacia
[0085] 2. Chronic knee pain/swelling as a result of torn cartilage
[0086] 3. Chronic pain/swelling in first and second finger of right
hand diagnosed as arthritis [0087] 4. Chronic foot pain
(undiagnosed) [0088] 5. Chronic pain in left thumb/wrist post
reconstructive surgery
TABLE-US-00002 [0088] TABLE 2 EVALUATION OF A COMBINATION OF
ESSENTIAL OILS WITH HIGH MOLECULAR WEIGHT HYALURONIC ACID Oil
Effectiveness Safety Spreadability Odor Rosemary 4 No Rxs 3 3 Tea
Tree V 4 No Rxs 3 1.7 Camphor 3 No Rxs 2 3 Wintergreen 4 No Rxs 3 3
Eucalyptus 4 No Rxs 3 3 Cinnamon 2 No Rxs 3 3 Sage 2 No Rxs 3 1
Jojoba 3 No Rxs 3 1.7 Lemon 2 No Rxs 3 2 Clove 2 No Rxs 3 3 None *
0 No Rxs 3 3 * Control-Contains only hyaluronic acid with no
essential oils No Rxs = No Reactions Effectiveness, Spreadability
and odor scores are averages of the 5 responses.
EXAMPLE 3
[0089] A 1.0% wt/vol solution of dermatan sulfate (chondroitin
sulfate B obtained from SIGMA Chemical Company) was prepared using
DI water. The viscosity of this preparation was <10 c/s. The
molecular weight was 15,000. This preparation was mixed 1:1 with
the 1.0% wt/vol high molecular weight hyaluronic acid solution
described in EXAMPLE 2. Five aliquots of 30 mL each were dispensed
into vials. To the first aliquot was added 2.0% vol/vol Rosemary
Oil. To vials 2-4 was added either Eucalyptus Oil, Wintergreen Oil
or Tea Tree Oil (all obtained from Loranne Oils). No essential oils
were added to the fifth vial. All preparations were held at
4.degree. C. for 7 days after which they were evaluated for their
suspension characteristics. All oils remained in suspension due to
the viscosity of the hyaluronic acid. Each suspension was remixed
and aliquoted into 10 mL amounts in 25 mL vials. Three patients
with chronic pain/swelling complaints were given one vial of each
preparation to evaluate. They were asked to compare effectiveness,
safety, spreadability and odor. The same numerical scales for
evaluation of these parameters were used as is noted in EXAMPLES 1
and 2. Results are listed in Table 3.
[0090] The general response was that all preparations provided
relief within 5 minutes and such relief lasted up to 6 hours. Also,
spreadability was totally acceptable to all patients. It appears
that this combination is more effective than the lower molecular
weight preparation described in EXAMPLE 1 in that it provides both
quicker and longer-lasting relief from pain. The control
preparations containing only the essential oils did not provide
relief and were not acceptable for spreadability. The control which
contained only the dermatan sulfate and hyaluronic acid components
("NONE") was not effective.
The complaints of these patients included: [0091] 1. Chronic pain
in left leg resulting from diagnosed osteoarthritis of the left hip
[0092] 2. Chronic neck pain resulting from diagnosed stenosis and
bone spur formation requiring surgery [0093] 3. Chronic tired feet
(patient on feet on concrete floors all day)
TABLE-US-00003 [0093] TABLE 3 COMPARISON OF MIXTURES CONTAINING
DERMATAN SULFATE, HIGH MOLECULAR WEIGHT HYALURONIC ACID AND VARIOUS
ESSENTIAL OILS Oil Effectiveness Safety Spreadability Odor Rosemary
5 No Rxs 3 3 Eucalyptus 5 No Rxs 3 3 Wintergreen 5 No Rxs 3 3 Tea
Tree 5 No Rxs 3 1.7 None * 0 No Rxs 3 3 Rosemary only ** 0 No Rxs 0
3 Wintergreen Oil ** 0 No Rxs 0 3 Tea Tree Oil ** 0 No Rxs 0 1.7 *
= Control-Contains only dermatan sulfate and hyaluronic acid with
no essential oils ** = Contains only the listed essential oil and
no hyaluronic acid No Rxs = No reactions Numerical values for
effectiveness, spreadability and odor are averages of the 3
responses.
EXAMPLE 4
[0094] In order to determine whether a combination of a high and
low molecular weight mixture of a salt of hyaluronic acid would
produce results similar to those described in EXAMPLE 3, the
following experiment was conducted. High molecular weight
(>750,000) cosmetic grade hyaluronic acid (obtained from Meiji
Seika Kaisha, Ltd.) was prepared as in EXAMPLE 2. The concentration
of this solution was adjusted to 1.0% wt/vol. The viscosity of this
solution at 37.degree. C. was >1000 c/s and the molecular weight
was >750,000. Low molecular weight cosmetic grade hyaluronic
acid (from the same source) was prepared as described in EXAMPLE 1.
The resulting hyaluronic acid solution was adjusted to 1.0% wt/vol
by dilution in DI water. Equal volumes of high molecular weight and
low molecular weight hyaluronic acid solutions were mixed and
aliquoted into 50 mL portions. To the first aliquot was added 2.0%
vol/vol Rosemary Oil. To vials 2-4 were added either Eucalyptus
Oil, Oil of Wintergreen or Tea Tree Oil, each at 2.0% vol/vol. No
essential oils were added to the fifth vial. All preparations were
held at 4.degree. C. for 7 days after which they were evaluated for
their suspension characteristics. All oils remained in suspension
due to the viscosity of the hyaluronic acid solution. Each
suspension was remixed and aliquoted into 10 mL amounts. Three
patients with chronic pain/swelling complaints were given one vial
of each preparation to evaluate. They were asked to compare
effectiveness, safety, spreadability and odor. The same numerical
scales for evaluation were used as noted in EXAMPLES 1-3. Again,
the results are listed as averages of the three responses. Results
are listed in TABLE 4.
[0095] The general response was that all preparations provided
relief within 5 minutes and such relief lasted up to 6 hours. Also,
spreadability was totally acceptable to all patients. It appears
that this combination is as effective as a mixture of low molecular
weight dermatan sulfate and high molecular weight hyaluronic acid
in that it provides quicker and longer relief from pain. The
control preparations containing only the hyaluronic acid (NONE *)
did not provide relief. The control preparations containing only
essential oils (Tea Tree Oil or Wintergreen Oil) did not provide
relief.
[0096] Patients generally commented that the preparations were not
oily upon application, a quality that all appreciated. Also, all
patients commented that although there is some odor upon topical
application, there is no residual odor--no odor could be detected
by a few minutes after application.
The complaints of these patients included: [0097] 1. Chronic pain
in left leg resulting from diagnosed osteoarthritis of the left hip
[0098] 2. Chronic neck pain resulting from diagnosed stenosis and
bone spur formation requiring surgery [0099] 3. Chronic tired feet
(patient on feet on concrete floors all day)
TABLE-US-00004 [0099] TABLE 4 EVALUATION OF A MIXTURE OF HIGH AND
LOW MOLECULAR WEIGHT HYALURONIC ACIDS Oil Effectiveness Safety
Spreadability Odor Rosemary 5 No Rxs 3 3 Eucalyptus 5 No Rxs 3 3
Wintergreen 5 No Rxs 3 3 Tea Tree 5 No Rxs 3 1.7 None * 0 No Rxs 3
3 Tea Tree ** 0 No Rxs 0 1 Wintergreen ** 0 No Rxs 0 3 *
Control-Contains only hyaluronic acids and no essential oils **
Contains only the essential oil listed but no hyaluronic acid No
Rxs = No reactions Numerical scores for effectiveness,
spreadability and odor are averages of the three responses
EXAMPLE 5
[0100] Heparin sulfate has long been known as an anticoagulant when
administered intramuscularly, intravenously or subcutaneously.
However, to our knowledge it has never been used topically. Since
dermatan sulfate and hyaluronic acid are topically effective when
mixed with essential oils, it was of interest to determine whether
heparin sulfate could also be topically effective. Heparin sulfate
was purchased from Rhone Poulenc Rorer in liquid form at a
concentration of 30 mg/0.3 mL. This preparation was diluted to 30
mg/mL (3.0% wt/vol) with DI water and aliquoted in 1.0 mL amounts.
One percent vol/vol Rosemary Oil was added to one aliquot, 2.0%
vol/vol Rosemary Oil was added to a second aliquot and 2.0% vol/vol
Wintergreen Oil was added to a third aliquot. One aliquot contained
no essential oils and was used as a control (Hep Only in TABLE 5).
All essential oils were obtained from Loranne Oils.
[0101] These formulations were compared in their ability to treat
various medical complaints. Patients were given one of each
preparation and requested to evaluate the effectiveness of the
preparations. Effectiveness was evaluated on the basis of good (G),
fair (F) or poor (P). After use of the preparations for a period of
at least one month, patients were interviewed as to their
satisfaction with the products. Results of these interviews are
presented in TABLE 5.
[0102] TABLE 5 indicates that Heparin sulfate mixed with essential
oils appears to work effectively when applied topically to treat
bruising, torn muscles, sprains and tendonitis. According to the
interviews, the 1.0% solution may have had a slightly shorter
effect with some of the more painful medical complaints. Heparin
sulfate alone (without essential oils) had no effect when applied
topically.
TABLE-US-00005 TABLE 5 ACCEPTABILITY OF HEPARIN/ESSENTIAL OIL
MIXTURES Patient Effectiveness Complaint Hep 1% R 2% R 2% TT Only
Comments Extensive G 4 cm .times. 8 cm bruise bruise resolved much
faster than normal Torn muscle in G Noticed short-term rt. thigh
improvement, multiple applications necessary for resolution Ankle
sprain G Bruise resolved in 3 with bruising days, ankle supported
and swelling full weight in 2 days Tendonitis- G Required 3-4 rt.
Elbow treatments/day for 3 months for complete resolution Torn
muscle in G Patient supported full left calf weight in 2 days
Chronic G Cramps resolved within cramping of 1 minute and did not
Foot return for 4 hours Acute muscle G Cramp was relieved
cramp-rt.calf within 30 seconds Chronic knee P No Relief was noted
pain:chondro- malacia Torn muscle in P No effect was noted rt.
thigh 1% R = A mixture containing 3% heparin plus 1% Rosemary Oil
2% R = A mixture containing 3% heparin plus 2% Rosemary Oil 2% TT =
A mixture containing 3% heparin plus 2% Tea Tree Oil Hep only =
Control-A mixture containing 3% heparin without an essential
oil
EXAMPLE 6
[0103] In order to determine the effect of an extract of the Aloe
Vera plant, Aloe Vera gel concentrate which has acemannan as one of
its active ingredients, was obtained from Lily of the Desert.
Thirty milliliter aliquots of this Aloe Vera gel concentrate (99.0%
pure) were placed into vials. To one aliquot was added 1.0% vol/vol
Wintergreen Oil, to a second aliquot was added 2.0% vol/vol
Wintergreen oil, to a third aliquot was added 2.0% vol/vol Tea Tree
Oil, to a fourth aliquot was added 2.0% vol/vol Rosemary Oil and to
a 5th aliquot was added 2.0% vol/vol Eucalyptus Oil. One aliquot
contained no oil and was used as a control (NONE * in TABLE 6). All
aliquots were held at 4.degree. C. for 7 days after which they were
evaluated for their suspension characteristics. All oils remained
in suspension due to the viscosity of the Aloe Vera gel
concentrate. Each suspension was remixed and aliquoted into 10 mL
amounts. Three patients with chronic problems resulting in pain and
swelling were given one vial of each preparation to evaluate. They
were asked to compare effectiveness, safety, spreadability and
odor. The same numerical scales for evaluation of these parameters
were used as described previously in EXAMPLE 1. Results are listed
in TABLE 6. All numerical values are averages of the responses of
the 3 patients.
TABLE-US-00006 TABLE 6 EVALUATION OF A MIXTURE OF ALOE VERA AND
ESSENTIAL OILS Preparation (Oil) Effectiveness Safety Spreadability
Odor Tea Tree 4 No Rxs 1.7 1 Wintergreen 1% 3 No Rxs 1.7 3
Wintergreen 2% 4 No Rxs 1.7 3 Rosemary 4 No Rxs 1.7 3 Eucalyptus 4
No Rxs 1.7 3 None * 0 No Rxs 1.7 3 Control-Contains Aloe Vera
Only--no essential oil added No Rxs = No reactions Numerical values
for effectiveness, spreadability and odor are averages of the 3
responses
The complaints of the patients in this study included: [0104] 1.
Acute tendonitis of the right elbow [0105] 2. Torn muscle in the
right calf [0106] 3. Chronic knee pain/swelling as a result of torn
cartilage
[0107] Patients indicated that all preparations produced equivalent
results reducing pain and swelling. The positive effects were noted
within 5 minutes and lasted for 2-4 hours. Spreadability was
acceptable to all patients. None of the preparations produced
adverse reactions. The control preparation containing only the Aloe
Vera gel concentrate was ineffective.
EXAMPLE 7
[0108] An 83 year old male suffering from terminal colon cancer was
bedridden for 5 months. The family of caregivers was informed that
bedsores would be a major problem for the patient and that they
should notify the hospice nurses when such condition began to
develop. Hospice nurses checked the patient two times per week
during the first three months of the patient's incapacitation.
Later, the Hospice nurses visited three days per week checking on
the patient's well-being. The patient was given a combination of
low and high molecular weight hyaluronic acids formulated with Oil
of Wintergreen (prepared as in EXAMPLE 4) as a preventative before
any indication of bedsores was noted. Areas of the body which
appeared reddened from pressure (e.g. buttocks, rib cage on back
and shoulder blades) were massaged with the formulation once or
twice per day (depending on the patient's tolerance to movement).
The patient never developed bedsores. It should be noted that the
patient was not routinely turned as suggested by the nurses because
this procedure was too painful. Therefore, the development of
bedsores was expected. The Hospice nurses were amazed and commented
repeatedly about the use of the formulation to prevent
bedsores.
EXAMPLE 8
[0109] A 93 year old male who was bedridden as a result of
Alzheimer's disease for 1.5 years was treated with a formulation
containing 2.0% Rosemary Oil (Rosemary Oil was obtained from
Loranne Oils) and 1.01; dermatan sulfate (chondroitan sulfate B
obtained from SIGMA Chemical Company) for one year while at home.
The treatment included massaging the buttocks, back and shoulders
with the formulation once or twice per day. During this period of
treatment the patient developed no bedsores. After transfer to a
nursing home which did not allow the use of the formulation, the
patient developed bedsores within 2 weeks. He had continuing
problems with such ulcers until his death.
EXAMPLE 9
[0110] A 45 year old female who was extremely sensitive to poison
ivy was given a formulation containing a combination of 1.0% wt/vol
high molecular weight hyaluronic acid (400,000-500,000) and 2.0%
Rosemary Oil to use on an active case of poison ivy. The
formulation was prepared by using hyaluronic acid obtained from
LIPO CHEMICALS, INC. and Rosemary Oil obtained from Loranne Oils.
Other topical treatments such as Benadryl, Dermarest,
Hydrocortisone 0.5%, etc. provided only temporary relief and the
dermatitis with weeping pustules remained active. The individual
was so sensitive that poison ivy desensitization injections were
not tolerated. This individual reported that topical use of the
hyaluronic acid combined with Rosemary Oil applied directly onto
the weeping pustules caused an initial stinging but that relief
from itching occurred "within minutes". The relief was temporary as
with cortisone creams. However, she reported that the pustules
dried up and resolved "within a few days". In the past this
individual noted that the poison ivy pustules would remain up to 6
weeks.
EXAMPLE 10
[0111] The same 45 year old female from EXAMPLE 9 was exposed to
poison ivy again while she was using a weed-eater to trim around
the house. This time, after the pustules appeared all over the
legs, she was given a formulation which contained 0.01% high
molecular weight hyaluronate (Lifecore Biomedical, Inc.) mixed with
99.99% Peppermint Oil. She reported that this mixture provided
significantly longer relief from itching (approximately 8 hours)
but that the oils were so volatile that the preparation bothered
her eyes. The preparation was substituted for one which contained a
mixture of high and low molecular weight sodium hyaluronate (as
prepared in EXAMPLE 4 mixed with 1% Wintergreen Oil, 1% Spearmint
Oil and 0.5% Peppermint Oil. This provided the same relief from
itching for 6-8 hours and did not bother her eyes. She reported
that the preparation felt cool after application to the pustules
and at the point that the cooling effect was noted, the itching
disappeared. Therefore, for treatment of conditions involving
itching, it is desirable to include an essential oil that provides
a cooling effect.
EXAMPLE 11
[0112] A 57 year old bedridden diabetic patient suffering from
edema of the lower extremities complicated by chronic problems with
decubitus ulcers obtained one of the formulations of this invention
to try. This patient was given a formulation containing a
combination of 1.0% wt/vol high molecular weight hyaluronic acid
and 1.0% wt/vol dermatan sulfate (in a 1:1 ratio) formulated with
2.0% vol/vol Oil of Wintergreen. The hyaluronic acid for this
formulation was obtained from Genzyme, Inc., the Dermatan sulfate
was obtained from SIGMA Chemical Company and the essential oils
were obtained from Loranne Oils. The preparation was applied three
times per day onto the decubitus ulcers and generally onto the
lower extremities. The patient reported that within one week the
edema was resolved and the ulcers were healing. Within one month he
was out of bed and back to work. This was a significant improvement
since he had not been able to work for 6 months. This patient has
continued to use this formulation over a two year time period with
no adverse side effects and no return of his condition.
EXAMPLE 12
[0113] A 27 year old female with chronic acne since puberty was
given a preparation containing 1.0% wt/vol hyaluronic acid in
combination with 1.0% vol/vol Wintergreen Oil. The molecular weight
of the hyaluronic acid used to formulate this preparation was
obtained from Genzyme, Inc. and had a molecular weight of between
550,000 and 650,000. The Wintergreen Oil was obtained from Lorann
Oils. This individual applied the preparation twice per day
(morning and evening). After 2 weeks she reported a significant
improvement in healing of the active eruptions and also reported
smoothing of the skin. After one month she reported that her face
was free of eruptions and that the skin felt smoother than ever
before. This individual has continued using the preparation for 2
years without return of her acne problem and without development of
any adverse reactions.
EXAMPLE 13
[0114] A preparation containing 99% Aloe Vera gel concentrate
(obtained as 99% pure from Lily of the Desert) to which was added
2.0% vol/vol Wintergreen Oil (obtained from Lorann Oils) and 0.2%
vol/vol high molecular weight (>1,000,000) hyaluronic acid
(obtained from Lifecore Biomedical, Inc.) was given to three
individuals suffering from knee problems involving pain and
swelling. The first patient had been diagnosed with chondromalacia,
the second patient with torn cartilage and the third patient had
been diagnosed with osteoarthritis. Each patient used the
preparation for a period of one month after which they were
interviewed about the effectiveness, safety and spreadability of
the formulation. The responses are summarized in TABLE 7.
[0115] Each of the patients commented that they were impressed that
the preparation was not oily and that there was no lingering odor
after topical application.
TABLE-US-00007 TABLE 7 SUMMARY OF RESULTS ON USE OF A COMBINATION
OF ALOE VERA, OIL WINTERGREEN AND HYALURONIC ACID TO TREAT PAIN AND
ASSOCIATED WITH KNEE PROBLEMS Diagnosis Effectiveness Safety
Spreadability Chondromalacia Excellent at a No Too thin use rate of
3 Reactions applications/day Torn cartilage Good-relief for No
Would prefer 1-2 hours after Reactions something treatment thicker
Osteoarthritis Excellent at a No Excellent use rate of 2 Reactions
results applications/day
EXAMPLE 14
[0116] A preparation containing a 1:1 ratio of 1.0% wt/vol low
molecular weight hyaluronic acid (prepared from a liquid 1.0%
solution obtained from Lifecore Biomedical and treated according to
the description in EXAMPLE 1 to produce a molecular weight of
<30,000) and 1.0% wt/vol high molecular weight hyaluronic acid
(obtained from Lifecore Biomedical and containing a molecular
weight >500,000) and 2.0% vol/vol Rosemary Oil (obtained from
Loranne Oils) was provided to two patients with diagnosed
psoriasis. The patients were instructed to use the preparation for
one month and report their results during an interview. The
interviews indicated that both patients noted immediate improvement
in the skin texture and a reduction in pain. This occurred within
two days of initiating the treatment. The lesions were beginning to
resolve by the one month interview. These individuals have been
followed for 6 months and report continued improvement.
EXAMPLE 15
[0117] A 42 year female indoor soccer player who played goalie and
suffered from repeated rug (indoor turf) burns on the knees was
given a preparation of 1.0% wt/vol dermatan sulfate combined with
2.0% vol/vol wintergreen oil. This preparation was produced by
adding 1.0g of chondroitin sulfate B (obtained from SIGMA Chemical
Company) to 100 mL of DI water and mixing until dissolved. To this
solution was added the essential oil. This individual applied the
solution immediately after the injury occurred and twice more at 4
hours and 12 hours after the injury. The patient commented that the
solution caused great stinging and pain upon application. However,
the rug burn was almost healed within 72 hours. This was compared
to similar burns which she had sustained in past months which took
up to 3 weeks to heal because they kept weeping. Since the patient
was concerned about the stinging and pain upon application, a
second formulation was prepared for her to try on the next rug
burn. This second formulation contained the same chondroitin
sulfate B mixed with 2.0% vol/vol Tea Tree Oil. Several weeks later
the individual suffered another rug burn that was treated with the
Tea Tree Oil preparation. The patient commented that this
preparation was much better, causing only minimal discomfort upon
application. The healing process again required only 96 hours
instead of weeks. General comments were that the preparation caused
the wound to produce a scab within a few hours and that this scab
became dry and fell off within a few days. Additionally, the
patient liked the fact that the solution was not greasy nor did it
leave a lingering odor.
EXAMPLE 16
[0118] A 48 year old female suffered from chronic eczema--scaly and
red areas on her neck and arms. She had tried all types of
treatments, including cortisone with no effect. She was given a
preparation containing a mixture of low and high molecular weight
sodium hyaluronate (prepared as in EXAMPLE 4) mixed with 1%
Wintergreen Oil, 1% Spearmint Oil, and 0.5% Peppermint Oil. She
applied it for one week. She noted that the eczema disappeared
after the 3.sup.rd day of treatment but continued treatment to make
sure that it would not return. She has not treated the area for 2
months and has noted no return of signs of eczema.
EXAMPLE 17
[0119] A 45 year old female softball player tore the quadriceps
muscles of both the right and left thighs. Within 4 hours of the
injury, this individual was given a preparation containing 1.0%
wt/vol high molecular weight (>750,000) hyaluronic acid
(Genzyme, Inc.) mixed with 2.0% vol/vol Tea Tree Oil and 2.0%
Wintergreen Oil (both oils obtained from Lorann Oils). The
individual was also given FLEXALL 454 to use as a control. She used
no ice or heat treatments after the injury. To the right quadriceps
she applied the hyaluronic acid/Tea Tree Oil/Wintergreen Oil
(preparation of this invention). To the left quadriceps she applied
the FLEXALL 454 (Control). Three applications of each preparation
were made during the late afternoon and evening on the day of the
injury. By the time the first applications were made, this
individual could not walk and both quadriceps were extremely
painful. By the third application, the individual noted that the
right quadriceps felt less painful. When the individual awoke the
morning after the injury she immediately applied both preparations
to the respective quadriceps and stayed in bed for one hour longer.
After the one hour time period she decided to try to walk. The
right quadriceps was reportedly much better and she was able to
support weight on this leg (the quadriceps receiving the treatment
of this invention). The left quadriceps was still as painful as it
was the day before (no relief was noted). On the second day, 4 more
applications of each preparation were made to the respective
quadriceps. By the end of the day, the right quadriceps was
"significantly improved" whereas the left quadriceps was more
painful than the day before. On the morning of the third day post
injury, after the morning application of the respective
preparations, the individual reported that the right quadriceps
felt "essentially normal" but the left quadriceps was still
unchanged and very painful. At this time, the individual began
using the treatment of this invention on the left quadriceps
instead of the FLEXALL 454. Within 24 hours she reported that she
could walk on the left leg and by 48 hours after switching
treatments she was able to walk normally. In this direct comparison
the hyaluronic acid/Tea Tree Oil/Wintergreen Oil formulation of
this invention relieved the pain and inflammation of the muscle
tear within 72 hours and, obviously stimulated healing, whereas an
over-the-counter product suggested for this purpose was
ineffective.
EXAMPLE 18
[0120] A 53 year old male burned his right forearm while working on
the muffler of his motorcycle. The burned area was 8 cm.times.12 cm
and was beginning to redden and raise at the time that a
formulation of this invention was applied to the area. This
individual had received a formulation prepared by combining 1.0%
wt/vol high molecular weight hyaluronic acid (obtained from
Lifecore Biomedicals, Inc. and demonstrating a molecular weight
>500,000) with 1.0% chondroitin sulfate B (obtained from SIGMA)
and adding 2.0% Rosemary Oil, approximately 8 months before this
accident in order to treat a severe sunburn. He still had some of
the formulation of this invention left and applied it immediately
to the burn. He reported that it immediately felt cool and that
within 5 minutes the severe pain had dissipated. The burn did not
blister as he had expected. Within 24 hours all that was noticeable
was a reddened area of skin which was not painful and not
granulated. Within 5 days there was no indication that a burn had
occurred.
EXAMPLE 19
[0121] A 52 year old male suffered a severe sunburn while boating.
He tried several sunburn lotions to relieve the pain and redness
but none of these preparations provided relief. He was feverish
(temperature 101.degree. F.). He was given a preparation containing
1.0% wt/vol high molecular weight hyaluronic acid (Lifecore
Biomedical), 1.0% wt/vol low molecular weight hyaluronic acid (same
preparation as described in EXAMPLE 1), 2.0% vol/vol Tea Tree Oil
and 2.0% vol/vol Wintergreen Oil in an aqueous base. This was
applied to his back, shoulders and arms. Within 5 minutes he
commented that the burning sensation was gone. One hour after the
application this patient's body temperature was back to normal. He
continued to apply the preparation for 24 hours after which he
discontinued treatment because he felt normal. The sunburned areas
never peeled nor caused additional problems.
EXAMPLE 20
[0122] A 76 year old male developed a severe case of poison ivy
which had already spread over both legs from the ankles to the
upper thighs as well as to the back prior to treatment. He reported
that the itching was intolerable during the night and that he
inadvertently scratched his legs so much that they were raw and
bleeding. He had tried commercial products including Cortaid,
Benzacaine and Caladryl with no significant relief. All provided
only a few minutes of relief or none at all. His physician had
suggested cortisone injections. Instead of subjecting himself to
cortisone injections, he decided to try a preparation comprising an
essential oil and a complex carbohydrate. The first formulation
that was prepared for this patient consisted of 0.01% vol/vol
hyaluronic acid mixed with 1% vol/vol Wintergreen Oil and 98.99%
vol/vol Peppermint Oil. The patient was instructed to apply the
preparation onto all of the areas covered by poison ivy. After the
first application, the patient reported that the treated area
burned for about 15 minutes and then felt cool. After the first 15
minutes the itching was relieved for approximately 6 hours. He
complained of the burning sensation. A new formulation was
provided. This latter formulation contained no Wintergreen Oil.
Therefore, it contained 0.01% vol/vol hyaluronic acid and 99.99%
vol/vol Peppermint Oil. This preparation was reported to burn much
less after application. The patient continued treatment, reporting
that the itching was relieved for 8-10 hours after application.
Additionally, the poison ivy quit spreading and healed very
quickly. In fact, this patient was able to discontinue treatment 5
days after starting his first treatment. The patient reports
excellent results in treatment of poison ivy. It is believed that
the essential oil which provides the best effect against itching
(anti-pruritic) is one which provides a cooling sensation on the
skin. Therefore, the Peppermint Oil and other similar cooling oils
provide longer relief than Wintergreen Oil or Menthol which produce
a hot sensation and the Peppermint Oil does not produce a burning
sensation on the skin.
EXAMPLE 21
[0123] The following example describes use of a composition
comprising a 1% wt/vol low molecular weight (<300,000) sodium
hyaluronate plus 2% Wintergreen oil. Three individuals were stung
by yellow jackets or bees. The composition was applied to the area
over and around the sting within about 15 minutes. The following
table indicates the effectiveness of the composition. Each patient
reported immediate relief of the pain upon application of the
composition. Additionally, each patient reported a lack of swelling
post treatment. Only one treatment was used in each case. Even a
person who was normally allergic to stings reported no allergic
side effects.
EXAMPLE 22
[0124] A 55 year old female who was known to be very susceptible to
reaction to poison ivy was provided a mucosal composition
comprising a mixture of high and low molecular weight sodium
hyaluronate (as described in EXAMPLE 4) with no oils added. She had
been helping other with cutting wood and noticed that there was a
poison ivy vine wound around one of the logs that she was carrying
in her bare arms. After completing the wood-cutting, she began
taking the hyaluronate preparation orally. She took 10 mg in the
morning and 10 mg at night for a period of 5 days. Twenty four
hours after her exposure she noticed 2 "pinpoint" pustules on her
arms. These never spread and disappeared by the third day. It is
apparent by this example that oral glycosaminoglycans can prevent
the development of an allergic reaction such as a rash caused by
poison ivy.
EXAMPLE 23
[0125] An 18 year old female suffered from chronic fibromyalgia of
the face and neck. This condition had existed for approximately 5
years. There was nothing that provided relief for her condition.
She was given a formulation containing a mixture of high and low
molecular weight sodium hyaluronate (prepared according to EXAMPLE
4) to use orally. She took 10 mg two times per day (AM and PM). She
reported that after only 1 day, her symptoms disappeared. She has
continued to take the same dose for 6 months and has reported no
return of her fibromyalgia. Therefore, a condition that has
historically remained untreatable, is treatable with the
compositions of the present invention.
EXAMPLE 24
[0126] A 9 year old male suffering from severe Attention Deficit
Hyperactivity Disorder (ADHD) complicated by Turret's Syndrome, who
was being treated by diet control with little success, was given a
sample of the mixture used in EXAMPLE 23. He took 10 mg in the
morning and 10 mg in the evening, using the solution as a mouthwash
(holding it in his mouth for about 10 to 20 seconds and then
swallowing). His parents kept very strict records of his activity
and noted that his ADHD was fully controlled and he suffered no
"tics" while taking the sodium hyaluronate. The one day that he
forgot to take his morning dose he had a recurrence of his "tics"
and became almost uncontrollable. However, within 15 minutes of his
receiving the missing dose, he became calm and returned to normal.
This boy has remained totally under control for 2 months. This has
never been observed before, even when he was taking Ridlin. He had
discontinued taking Ridlin 1.5 year before because of problems with
side effects. The sodium hyaluronate has provided no adverse
reactions or side effects.
EXAMPLE 25
[0127] A 60 year old male and 55 year old female (brother and
sister) who routinely suffered severe sunburns the first few times
that they were in the sun each summer, had been taking oral sodium
hyaluronate gel for treatment of pain associated with a cervical
disc stenosis (male) and chronic osteoarthritis of both knees
(female). Pain from the conditions being treated was totally
controlled by taking 5-10 mg twice per day. The sodium hyaluronate
gel was prepared by adding sodium hyaluronate (Collaborative
Laboratories, Inc) to a 1% concentration. This preparation had a
molecular weight of >1,000,000. The gel was being applied
directly on the tongue by dropper bottle. Both went on vacation
together and spent most of 5 days in the bright sun in a boat. They
did not use a sun blocker. Each previous year both had suffered
severe discomfort from sunburn after the first day's exposure. This
time, at the end of the 5 days, both noted that they were not
sunburned, had suffered no discomfort and were developing a nice
tan. It is believed that the preparation of this invention
prevented sunburn, allowing tanning to occur.
EXAMPLE 26
[0128] A 60 year old male suffering from colon cancer had been
unable to tolerate his colostomy and demanded that his surgeon
reconnect his intestines. He refused chemotherapy but requested a
preparation prepared according to this invention. He was given a
formulation of sodium hyaluronate (Collaborative Laboratories, Inc)
which was prepared with a mixture of molecular weights of
hyaluronate (as in EXAMPLE 4). When he began taking the hyaluronate
preparation, his CEA was 70.1. He has taken the hyaluronate at a
dose of 10 mg three times per day mucosally and after 6 months of
treatment his CEA has dropped to 4.1. He has taken no other
treatments. This patient had also suffered from polymyositis for 15
years. For this he was taking 50 mg of Prednisone daily without
much relief. He reported that after 1 week of taking the
hyaluronate preparation he felt complete relief from the pain
caused by his polymyositis. After 6 months he has been able to
reduce his Prednisone to 5 mg per day. He physician has reported
that his polymyositis has gone into remission.
EXAMPLE 27
[0129] A gum was prepared by mixing 100g of presweetened gum base
with 10 g of 1% high molecular weight (>1,000,000) sodium
hyaluronate (Collaborative Laboratories, Inc.) and 2 mL of 100%
Spearmint Oil. The gum was heated for approximately 10 seconds in a
microwave until it was soft enough to knead in the
glycosaminoglycan and essential oil. All components were kneaded
together until a paste was produced. To the paste was added
powdered sugar until the consistency was acceptable to cut into
strips thus producing chewable gum. This gum, when chewed,
dissolved within approximately 5 minutes and was used to treat the
pain and inflammation of a sore throat, esophagitis, tonsilitis,
gastritis, headache, and arthritis. In all cases, the individuals
being treated reported that the gum was effective in treating their
condition or disease.
[0130] A more chewable gum can be produced by adding exicipients
which produce thickening. Also complex carbohydrates alone (e.g.
without essential oil(s)) can be used in the various formulations
to treat the conditions as described above also in the delivery
systems as mentioned above. The latter composition of one or more
glycosaminoglycans can be used alone or combined with other
mucosally or orally safe drugs or compounds to obtain similar
results.
EXAMPLE 28
[0131] A 54 year old female suffering from chronic osteoarthritis
of both knees and spondylosis in the lower back, was attempting to
control the pain in her knees and lower back by using Napralan (500
mg, BID), Pycnogenol (100 mg, BID), Glucosamine (750 mg, BID) and
Chondroitin Sulfate (1000 mg, BID). Even on this regimen, there was
a requirement for Depomedrol in the lower back approximately every
6 months. This individual presented suffering from sciatica
associated with the spondylosis as well as severe pain and swelling
in both knees, particularly in the left knee, which caused a
noticeable limp (left knee). X-rays indicated that there was no
cartilage remaining in either knee. She was asked what happened
when she did not take the Glucosamine and Chondroitin Sulfate. She
answered that she was almost unable to walk, certainly could not
easily go down stairs. If the Pynogenol was also removed from the
diet, the individual indicated that she could not tolerate the
pain. She also reported that she had an active gastric ulcer that
was controlled by taking 4 Pepcid AC per day. Initially, this
patient was told to stop taking the Chondroitin Sulfate and
Glucosamine and take 1.0 mL BID of liquid it sodium hyaluronate (10
mg) with an approximate molecular weight of 500,000 to 1,000,000.
One day after starting this regime (without the Chondroitin Sulfate
and Glucosamine) the patient reported feeling much better. She
reported that she had no knee pain and her sciatica had
disappeared. This patient continued the regimen and has been able
to discontinue the use of the Pycnogenol as well. The patient
reports a surprising improvement in her mobility. After taking the
sodium hyaluronate for 2 years she is able to exercise by
bicycling, walk without a limp and climb stairs easily.
Unexpectedly, this patient has been able to discontinue taking the
Pepcid AC and has had no exacerbation of her gastric ulcer and
gastritis. Follow x-rays of her stomach have indicated a cure of
her ulcer. It is believed that the mucosal glycosaminoglycan
provided a soothing effect for the gastric ulcer as she reported an
immediate improvement within one week of starting the mucosal
hyaluronic acid. She was able to discontinue taking the Pepcid AC
at that time.
EXAMPLE 29
[0132] The patient from EXAMPLE 28 had had extensive surgery on her
left hand approximately 20 years prior to joining this experiment.
The surgery had involved removal of a significant portion of the
tissue structure of the hand, an abdominal flap and skin grafts.
She had developed adhesions on the tendons of the hand and did not
have much use of this hand prior to taking the preparation of this
invention. Indeed, at the start of this experiment, the hand was so
swollen from adhesion irritation that the structure of the hand
could not be delineated. Within 9 months of beginning the mucosal
hyaluronic acid treatment she noted that she could easily make a
fist, that the swelling in the hand was non-existent and that the
structure of the hand, including blood vessels, could now be seen.
There was no more pain from the irritation of the adhesions.
Follow-up with her reconstructive surgeon indicated that the
adhesions were resolved. The surgeon was totally surprised - he had
not seen such extensive adhesions resolve. It is apparent that
preparations of this invention, when taken orally or mucosally can
treat and prevent adhesion formation post surgery.
EXAMPLE 30
[0133] In order to determine whether low doses of other complex
carbohydrates taken orally or mucosally could show effects similar
to hyaluronic acid, 3 patients presenting with oeteoarthritis,
rheumatoid arthritis and dental pain were treated with chondroitin
sulfate. The two patients with osteo and rheumatoid arthritis had
been using chondroitin sulfate (1000 mg BID) and glucosamine (500
mg BID) with some reported success. They were instructed to
discontinue taking these products and substitute the compositions
of the immediate invention. A 5% (wt/vol) solution of chondroitin
sulfate (Infinity Laboratories, Inc) without essential oil was
prepared. This was dispensed into 30 ml bottles and provided to the
three patients with instructions to take 1.0 mL orally BID, holding
it in the mouth for approximately 10 seconds prior to swallowing
it. This represented a dose of 5 mg BID. This provided relief
within 15 minutes. However, the relief lasted only 3-4 hours. The
patients reported that they had to take the chondroitin Sulfate
solution three times per day to treat their pain. After two months
of this regimen, the two arthritis patients were given a mixture of
the 5% chondroitin sulfate and 1% high molecular weight hyaluronic
acid. They were instructed to take this as often as necessary. Each
reported that this product was effective when taken only 2 times
per day and the effect lasted from 8 to 10 hours. This demonstrates
that a mixture of low and high molecular weight complex
carbohydrates is more effective and that significantly lower doses
(100 to 1000 fold less) of chondroitin sulfate are required for
effective treatment of osteoarthritis and rheumatoid arthritis than
are used in oral solid forms currently sold for these uses.
EXAMPLE 31
[0134] A batch of lozenges containing hyaluronic acid was prepared
as follows: [0135] 1. Prepare a sodium hyalurate solution
containing 1% sodium hyaluronate obtained from Lifecore Biomedical
(approx. 500,000 mw) by mixing 500 mL of the sodiumhyaluronate, 5.0
mL Oil of Wintergreen to produce a final concentration of 1%
vol/vol, 2.5 mL Peppermint Oil to produce a final concentration of
0.5% vol/vol and 1.0 mL Spearmint Oil to produce a final
concentration of 0.2% vol/vol. [0136] 2. Add 2 cups of cane sugar,
2/3 cup of corn syrup and 3/4 cup water to a kettle. Bring the
mixture to a boil by heating to 290-300.degree. F. as measured
using a candy thermometer (without stirring). A lid was kept on the
kettle initially to wash down the sides of the kettle for the first
few minutes. [0137] 3. Add 50 mL of the 1% hyaluronic acid mixture.
[0138] 4. Add 6-8 drops of green liquid food coloring. [0139] 5.
Spread the boiling liquid onto a cookie sheet and spray the top
lightly with PAM. Cut immediately into small squares using a pizza
cutter sprayed with PAM. [0140] 6. After the squares (lozenges)have
cooled weigh groups of 10 pieces to determine consistency.
TABLE-US-00008 [0140] Group 1 26.4 g 2.64 g/lozenge Group 2 29.7 g
2.97 g/lozenge Group 3 25.4 g 2.54 g/lozenge Group 4 26.1 g 2.61
g/lozenge Group 5 28.6 g 2.86 g/lozenge Average weight per lozenge
= 2.7 g Total weight of all lozenges = 587.4 g The amount of
hyaluronic acid per lozenge = approx. 2.3 mg
[0141] A 42 year old female raquetball professional suffering from
chondromalacia of both knees and who had been using the topical
preparation was given 10 lozenges to use for determination of the
effect of the mucosally-administered hyaluronic acid on her
chondromalacia. After sucking on the first two lozenges, she noted
that her knees did not bother her while playing raquetball. She has
reported that if she sucks a lozenge prior to playing raquetball,
her knees do not bother her for several hours. Chondromalacia is a
condition similar to osteoarthritis wherein there is degradation of
the cartilage.
EXAMPLE 32
[0142] A 55 year old female who suffers from a bulging cervical
disc at C5-C6 agreed to try the hyaluronic lozenges (from Example
29) in place of Naproxen to suppress her constant headaches and
neck pain. She was given 10 lozenges to use for determination of
the effect of the hyaluronic acid lozenges. The patient was told to
discontinue use of Naproxen and to report any effect, if any, after
sucking each lozenge. After using all 10 lozenges, the patient
reported the following:
TABLE-US-00009 Day 1 After finishing 1 lozenge No noticeable effect
After finishing 2 lozenges Perhaps an effect, not sure After
finishing 3 lozenges Headache gone (the 3 lozenges were used over a
period of 8 hours) Day 2 First thing in AM took 1 lozenge Headache
significantly reduced Took a second lozenge Headache gone within 30
minutes Took a 3.sup.rd lozenge later in day Headache did not
return (the 3 lozenges were used over a period of 8 hours) Day 3
Woke up with headache- Headache 1 lozenge significantly reduced
Took a second lozenge Headache gone within 15 minutes Took a
3.sup.rd lozenge in PM Headache did not return (the 3 lozenges were
used over a period of 8 hours)
Patient did not take Naproxen or any other anti-inflammatory drug
during these three days. She reported that she normally could not
have gone one day without taking Naproxen.
EXAMPLE 33
[0143] The 42 year old female of EXAMPLE 29 developed a sore throat
as a result of post nasal drip from a cold or sinus infection. She
requested additional lozenges to determine their effect on her sore
throat. After taking a single lozenge, she reported that her throat
felt much better and her post nasal drip seemed to be significantly
reduced. She was able to suppress her sore throat by taking 3
lozenges per day.
EXAMPLE 34
[0144] A 54 year old female was suffering from post nasal drip
associated with allergies. She began taking the hyaluronic acid
lozenges as described in EXAMPLE 29 and reported that her post
nasal drip was greatly reduced. She reported that she could take 3
lozenges per day and control the postnasal drip.
EXAMPLE 35
[0145] A 48 year old female singer who was suffering from chronic
bronchitis (3 months) to the point that she was unable to sing was
given a solution containing a mixture of a low and high molecular
weight hyaluronic acid (Prepared as in EXAMPLE 4). She was told to
take 5 drops morning and evening, holding it in her mouth for about
10 seconds before swallowing. This represented a dose of 5 mg twice
per day (10 mg/day total). She reported that within 3 days of
starting the oral/mucosal hyaluronic acid her sinuses began to
drain profusely. This lasted for 2 days after which her bronchitis
disappeared. She continued taking the hyaluronic acid for a period
of 14 days and reported that her bronchitis had cleared up and she
was, once again, able to sing.
EXAMPLE 36
[0146] A 46 year old female was taking mucosally-administered
sodium hyaluronate prepared as in EXAMPLE 4 for treatment of bone
spurs on her feet (ball and heal of both feet). She worked in
retail sales and was on her feet on concrete floors for 8 hours
each day. She reported that taking 10 mg twice per day allowed her
to work comfortably each day.
[0147] Prior to taking the hyaluronic acid preparation of this
invention, this patient had visited a hand surgeon to have a
ganglion at the base of the middle finger on her left hand removed.
It was the size of a pea and had been getting larger for the past 3
years. She had not been able to schedule surgery due to her work
requirements. After taking the hyaluronic acid of this invention
for a period of 3 months, she noticed that the ganglion was
disappearing. By 5 months post initiation of mucosal hyaluronic
acid, the ganglion was completely resolved. It appears that
inflamed nerve bundles (ganglion) can be treated and prevented with
the compositions of this invention.
[0148] All cited patents, provisional applications and publications
referred to in this application are herein incorporated by
reference.
[0149] Although the invention has been described in detail in the
foregoing for the purpose of illustration, it is to be understood
that such detail is solely for that purpose and that variations can
be made therein by those skilled in the art without departing from
the spirit and scope of the invention except as it may be limited
by the claims.
* * * * *