NZ618389B2 - Orally administrable compositions comprising avocado/soybean unsaponifiables and lipoic acid and methods of administration - Google Patents
Orally administrable compositions comprising avocado/soybean unsaponifiables and lipoic acid and methods of administration Download PDFInfo
- Publication number
- NZ618389B2 NZ618389B2 NZ618389A NZ61838912A NZ618389B2 NZ 618389 B2 NZ618389 B2 NZ 618389B2 NZ 618389 A NZ618389 A NZ 618389A NZ 61838912 A NZ61838912 A NZ 61838912A NZ 618389 B2 NZ618389 B2 NZ 618389B2
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- lipoic acid
- connective tissue
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- avocado
- derivatives
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- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 235000020240 turmeric extract Nutrition 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 150000003700 vitamin C derivatives Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The disclosure relates to an orally administrable composition comprising avocado/soybean unsaponifiables and lipoic acid (abstract figure) or derivatives thereof. The composition may include 5-[1,2]-dithiolan-3-yl-pentanoic acid 3-(5-[1,2]-dithiolan-3-yl-pentanoyloxy)-propyl ester; 5-[1,2]-dithiolan-3-ylpentanoic acid 3-(5-[1,2]-dithiolan-3-yl-pentanoylamino)-propyl-amide; coumarinlipoic acid conjugates; 5-[1,2]dithiolan-3-yl-pentanoic acid [1-(4-fluoro-benzyl)-1H-indole-5-yl]-amide; N-lactobionyl-Ne-(5-[1,2]-dithiolan-3-yl-penoyl)-L-lysinyl-1H,1H,2H-perfluorooctylamide; 1,2-diselenolane-3-pentanoic acid; and 1,2-dithiolane derivatives of lipoic acid containing catechol moieties linked through heteroaromatic rings. The disclosure also relates to the use of these compositions in preventing, treating, repairing, protecting, or reducing damage to connective tissues or reducing symptoms associated with damage to connective tissue and reducing levels of one or more inflammatory mediators in connective tissue. -3-ylpentanoic acid 3-(5-[1,2]-dithiolan-3-yl-pentanoylamino)-propyl-amide; coumarinlipoic acid conjugates; 5-[1,2]dithiolan-3-yl-pentanoic acid [1-(4-fluoro-benzyl)-1H-indole-5-yl]-amide; N-lactobionyl-Ne-(5-[1,2]-dithiolan-3-yl-penoyl)-L-lysinyl-1H,1H,2H-perfluorooctylamide; 1,2-diselenolane-3-pentanoic acid; and 1,2-dithiolane derivatives of lipoic acid containing catechol moieties linked through heteroaromatic rings. The disclosure also relates to the use of these compositions in preventing, treating, repairing, protecting, or reducing damage to connective tissues or reducing symptoms associated with damage to connective tissue and reducing levels of one or more inflammatory mediators in connective tissue.
Description
ORALLY ADMINISTRABLE COMPOSITIONS COMPRISING
AVOCADO/SOYBEAN UNSAPONIFIABLES AND LIPOIC ACID
AND METHODS OF ADMINISTRATION
FIELD OF THE INVENTION
The present invention provides methods comprising administration of:
(i) avocado/soybean unsaponifiables and (ii) lipoic acid or derivatives thereof, to a
non-human mammalian or an avian subject. The present invention also provides
orally administrable compositions comprising avocado/soybean unsaponifiables and
lipoic acid or derivatives thereof.
BACKGROUND OF THE INVENTION
Connective tissue is the structural framework of cartilage, bone,
synovium, ligament, meniscus, and tendon in articulating joints. Components of
connective tissue are produced by resident cells and then secreted to form the
extracellular matrix (ECM) characteristics of the tissue. In addition to serving as
structural framework, the ECM also plays a critical role in cell communication and
function. In articular cartilage, chondrocytes are aligned in a distinct pattern within
the type II collagen ECM framework. Bone forming osteoblasts and osteocytes, as
well as bone resorbing osteoclasts, are organized in mineralized type I collagen
ECM. The few fibroblast-like and macrophage-like cells in the synovium are also
held in place by ECM. Similarly, tenocytes and ligament cells are assembled
together within the ECM. The synthesis and breakdown of connective tissue ECM is
controlled by a network of regulatory molecules which are also produced by the
resident tissue cells. This network includes growth factors and a wide array of
molecules known as pro-inflammatory mediators. They include cytokines,
chemokines, prostaglandins and nitric oxide. These molecules exhibit many
biological activities. They can induce cell proliferation or cell death. These
substances can also induce anabolic pathways for production of ECM or induce
catabolic enzymes that can break down the ECM. Under physiological conditions,
cell survival or death, the production or breakdown of connective tissue ECM is
tightly controlled to maintain balanced homeostasis. The production and function of
regulatory molecules is modulated by many factors including mechanical forces,
physical factors such as temperature and pH, chemicals, microbes and their
products. Under certain conditions, these factors can elicit excessive and untimely
production of regulatory molecules leading to irreparable tissue damage, loss of
function and death.
Inflammation and pro-inflammatory mediators
Tissues react to mechanical, physical, chemical insults and infection by
an inflammatory response. The inflammation process is known to lead to recovery, to
healing, defense against infection and is usually life preserving. The inflammatory
response in humans and animals consists of two phases. The initial phase is
characterized by the local synthesis of pro-inflammatory mediators such
prostaglandins and leukotrienes. They are derived from arachidonic acid through the
action of cyclooxygenases and lipoxygenases. These pro-inflammatory mediators
increase local blood flow and enhance the permeability of endothelial cells to allow
leukocyte recruitment and accumulation. Other pro-inflammatory mediators which
are subsequently produced include cytokines (IL-1β, TNF-α), chemokines (IL-8), and
nitric oxide. In the second phase, the resolution phase, prostaglandins generated
during the initial phase activate enzymatic pathways along which arachidonic acid is
converted to chemical mediators with anti-inflammatory properties. It has been
reported that prostaglandin E (PGE ) activates the expression of 15-lipoxygenase
which generates anti-inflammatory lipoxins from arachidonic acid. Thus, the
resolution of inflammation is driven by the pro-inflammatory response. These
studies indicate that the initiation, progression and termination of the inflammation
process are tightly controlled. Prolonged, exaggerated inflammation has been
associated with many disorders including osteoarthritis (OA), rheumatoid arthritis
(RA), Alzheimer’s disease and cardiovascular disease.
In joint tissues, chondrocytes, synoviocytes, osteoblasts, osteoclasts,
ligament cells, and tenocytes produce a wide array of pro-inflammatory mediators.
Among these is prostaglandin E (PGE ), which is known to play a regulatory role by
inducing the production of other mediators including cytokines, nitric oxide, and
connective tissue degrading metalloproteinase (MMP) enzymes. Due to its ability to
induce metalloproteinases (MMPs), PGE contributes to the breakdown of cartilage
ECM. In addition, PGE promotes bone resorption and osteophyte formation. PGE
sensitizes nociceptors on peripheral nerve endings, thereby contributing to the
development of inflammatory pain. PGE levels are locally regulated by the inducible
cyclooxygenase-2 (COX-2) enzyme, a nitric oxide synthase in chondrocytes that
inhibits cartilage and proteoglycan degradation. In pathologic conditions such as
osteoarthritis, COX-2 expression is up-regulated with a concomitant increase in
PGE production.
The role of other tissues in the inflammation process is also well
established. Inflammation of the synovial membrane is now recognized to be a key
event in cartilage degradation in osteoarthritis, particularly during the early stages of
the disease. Synovitis is characterized by activation of resident macrophage-like
cells and fibroblast-like cells in the synovial membrane which leads to production of
excessive amounts of pro-inflammatory mediators including TNF-α, IL-1β and PGE .
Recent evidence suggests that synovial macrophages are the main source of the
cytokines in the earliest stages of osteoarthritis and that they are important
contributors to the cartilage damage in osteoarthritis throughout the course of the
disease. Cytokines also induce production of PGE and active metalloproteinases
(MMPs). It is now well accepted that these mediators control the balance between
ECM destruction and repair, which has made these molecules preferred targets for
therapeutic intervention. Other tissues in the joint such as the subchondral bone
also produce pro-inflammatory mediators that modulate joint health.
In addition to pro-inflammatory mediators such as cytokines and prostaglandins,
reactive oxygen species (ROS) have also been implicated in joint degeneration
observed in osteoarthritis. Oxidative stress induced by ROS such as nitric oxide and
hydrogen peroxide has been shown to cause chondrocyte apoptosis and cartilage
ECM breakdown. Moreover, ROS have been reported to activate signal transduction
pathways that lead to an increased production of pro-inflammatory mediators
including cytokines and prostaglandins. Studies in vitro have demonstrated a
linkage between the pathways involved in the production of ROS and pro-
inflammatory mediators. These studies support the notion that agents capable of
inhibiting both oxidative stress and inflammation pathways would be particularly
useful in the modulation of inflammation.
Treatment of inflammation in joint tissues using drugs
The central role of COX-2 and PGE in the pathophysiology of
osteoarthritis is reflected in the widespread use of selective COX-2 inhibitors and a
variety of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the
treatment of the disorder. However, prolonged administration of these drugs has
adverse side effects, including gastrointestinal pathologies and disruption of cartilage
proteoglycan metabolism. Studies in human and animal models have demonstrated
impaired bone healing and repair with the use of COX inhibitors. Therefore, there is
a need for alternative treatments for the management of inflammation that do not
center on the use of NSAIDs to inhibit the production of PGE and other pro-
inflammatory mediators.
Treatment of inflammation in joint tissues using nutraceuticals
Avocado/soybean unsaponifiables (ASU)
Many studies have documented the benefits of avocado/soybean
unsaponifiables (ASU) for promoting joint health and the management of
osteoarthritis. Clinical studies have reported beneficial effects of ASU in human and
equine osteoarthritis patients as well as in experimental animal models of OA. The
mechanisms that could account for the beneficial effects of ASU for osteoarthritis
have been studied in vitro using bovine and human joint tissue cells. These studies
showed that ASU inhibits the expression and production of cytokines, chemokines,
PGE nitric oxide, and MMPs. ASU also exerts anabolic effects on cartilage
metabolism by enhancing synthesis of cartilage matrix components while
suppressing their degradation.
Earlier studies using human osteoarthritic chondrocyte cultures found
that ASU significantly reduces the stimulating effect of IL-1β on PGE production. Of
the two isoforms of cyclooxygenases involved in prostaglandin synthesis, COX-2 is
highly inducible in response to cytokine exposure. High levels of COX-2 expression
have been demonstrated in human synovial tissue). Several studies in experimental
animals and humans have shown that PGE synthesis and COX-2 expression are
upregulated in synovial membranes in OA. Increased levels of PGE have been
detected in synovial tissue and in synovial fibroblasts in OA. There is experimental
evidence that synovial tissue is the major source of eicosanoids found in
osteoarthritic synovial fluid. Cytokines IL-1β and TNF-α enhance synoviocyte
production of PGE . The reported decrease in PGE synthesis by ASU appears to
be associated with a decrease in COX-2 gene expression.
Lipoic Acid (LA)
Lipoic acid (LA), also known as 1,2 dithiolanepentanoic acid, 1,2-
dithiolanevaleric acid, or 6,8-thioctic acid, is a potent, naturally occurring, low
molecular weight antioxidant. Lipoic acid is synthesized enzymatically in the
mitochondrion from octanoic acid. It is a critical cofactor of mitochondrial
decarboxylation reactions and is essential for adequate ATP production. Lipoic acid
exists in enantiomeric forms: R-lipoic acid (R-LA) and S-lipoic acid (S-LA). In
biological systems, only R-LA is conjugated to lysine residues in the amide linkage.
The oxidized (LA) and reduced (DHLA) forms represent a potent redox couple. The
biological effect of LA include scavenging of reactive oxygen species, regeneration
of endogenous antioxidants such as glutathione and vitamin E, metal ion chelating,
and repair oxidative damage in macromolecules. Both LA and DHLA are capable of
scavenging reactive oxygen species (ROS) and reactive nitrogen species (RNS),
and have the ability to prevent protein carbonyl formation. LA and DHLA can
regenerate other endogenous antioxidants such as vitamin C, vitamin E, and
glutathione, thereby protecting cells against oxidative stress. Recent evidence
suggests that LA not only acts as a true oxidant scavenger but in addition acts as an
activator of cellular stress response pathways.
Studies indicate that orally administered LA elicits biological activities
critical in the defense against oxidative stress related insults. There is a growing
body of evidence suggesting that orally administered LA is bioavailable, safe in
moderate doses and elicits several metabolic and clinical effects. Reported clinical
benefits of LA involve the following disorders: diabetic polyneuropathies (Ametov et
al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic
acid: the SYDNEY trial. Diabetes Care. 2003, 26:770-776, disorders affecting the
vascular system such as hypertension, inflammation associated diseases such as
coronary atherosclerosis, and cognition-neurological disorders such as Alzheimer’s
Disease (Hager et al., Alpha-lipoic acid as a new treatment option for Azheimer type
dementia, Archives of Gerontology and Geriatrics,, 2001, 32:275-282 and Hager et
al., Alpha-lipoic acid as a new treatment option for Alzheimer's disease--a 48 months
follow-up analysis J Neural Transm Suppl. 2007, 72:189-93. However, little is known
about the role of LA in joint inflammation. The effect of LA at the cellular level is
diverse and its mode of action involves biologic activities such as anti-oxidation, anti-
inflammation, anti-chelation and enhancement of kinases and phosphatases.
Derivatives of lipoic acid have been described in the art. Some
derivatives of lipoic acid provide improved biological activity, improved
pharmacokinetic properties such as longer half lives, improved bioavailability, and
decreased drug interaction profiles. Derivatives of lipoic acid have been described in
the following publications, hereby incorporated by reference: Gruzman et al.
Synthesis and characterization of new and potent alpha-lipoic acid derivatives.
Bioorganic & Medicinal Chemistry, 2004, 12:1183-1190; Melagraki et al. Synthesis
and evaluation of the antioxidant and anti-inflammatory activity of novel coumarin
aminoamides and their alpha-lipoic acid adducts. European Journal of Medicinal
Chemistry, 2009, 44:3020-3026; Gurkan et al., Syntheses of novel indole lipoic acid
derivatives and their antioxidant effects on lipid peroxidation. Archiv der Pharmazie,
2005, 338:67-73; Ortial et al., Fluorinated amphiphilic amino acid derivatives as
antioxidant carriers: a new class of protective agents. J Med Chem 2006; 12-2820;
and Koufaki et al. Sign and synthesis of antioxidant alpha-lipoic acid hybrids.
Methods Mol Biol, 2010, 594:297-309.
SUMMARY OF THE INVENTION
The present invention provides an orally administrable composition
comprising: (i) avocado/soybean unsaponifiables (ASU) and (ii) lipoic acid or
derivatives thereof. Other forms of administration, such as topical, rectal and
sublingual may also be used with this composition.
The present invention also provides a method of preventing, treating,
protecting, repairing or reducing damage to connective tissues or reducing
symptoms associated with damage to connective tissue in an avian or non-human
mammalian subject, comprising administering to the subject: (i) avocado/soybean
unsaponifiables and (ii) lipoic acid, or derivatives thereof.
The present invention additionally provides a method of reducing levels
of one or more inflammatory mediators in connective tissue, comprising
administering to an avian or non-human mammalian subject: (i) avocado/soybean
unsaponifiables and (ii) lipoic acid or derivatives thereof, in amounts effective to
decrease inflammation.
The present invention additionally provides use of (i) avocado/soybean
unsaponifiables and (ii) lipoic acid or derivatives thereof in the preparation of a
medicament for the prevention, treatment, repair, protection, or reduction of damage
to connective tissues or for the reduction of symptoms associated with damage to
connective tissue in an avian or mammalian subject.
The present invention additionally provides use of (i) avocado/soybean
unsaponifiables and (ii) lipoic acid or derivatives thereof, in amounts effective to
decrease inflammation, in the preparation of a medicament for the reduction of levels
of one or more inflammatory mediators in connective tissue in an avian or
mammalian subject.
The present invention additionally provides the composition of the
invention for use as a medicament.
The present invention additionally provides the composition of the
invention for preventing, treating, repairing, protecting, or reducing damage to
connective tissues or reducing symptoms associated with damage to connective
tissue in an avian or mammalian subject.
The present invention additionally provides the composition of the
invention for reducing levels of one or more inflammatory mediators in connective
tissue in an avian or mammalian subject.
Other novel features and advantages of the present invention will
become apparent to those skilled in the art upon examination of the following or
upon learning by practice of the invention.
In the description in this specification reference may be made to
subject matter which is not within the scope of the appended claims. That subject
matter should be readily identifiable by a person skilled in the art and may assist in
putting into practice the invention as defined in the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for methods comprising administration
of (i) avocado/soybean unsaponifiables (ASU), and (ii) lipoic acid or derivatives
thereof, to an avian or non-human mammalian subject. The avocado/soybean
unsaponifiables (ASU) and lipoic acid or derivatives thereof may be administered
together in one composition or dosage form, or they may be administered
separately. In preferred embodiments, the avocado/soybean unsaponifiables (ASU)
and lipoic acid or derivatives thereof, are administered together in one composition
or dosage form, or separately, within a period in which their therapeutic properties
overlap, preferably within 1 hour, more preferably within 30 minutes, and most
preferably within 5 minutes.
The term “comprising” as used in this specification and claims means
“consisting at least in part of”. When interpreting statements in this specification and
claims which include the term “comprising”, other features besides the features
prefaced by this term in each statement can also be present. Related terms such as
“comprise” are to be interpreted in similar manner.
The term “mammalian subject” is any mammal, including, but not
limited to humans, dogs, cats, horses, cows, and camels. The term “avian subject”
refers to birds.
The term “avocado/soybean unsaponifiables (ASU)” refers to a mixture
of avocado unsaponifiables and soybean unsaponifiables. “Unsaponifiables” are
compounds which do not react with alkali to form a soap. The term “avocado
unsaponifiables” refers to an extract of compounds obtained from any part of an
avocado (genus Persea). The avocado may be any species of avocado, such as but
not limited to Persea americana and Persea schiedeana The term “soybean
unsaponifiables” refers to an extract of compounds obtained from any part of a
soybean (Glycine max). The soybean may be any species of soybean, such as but
not limited to Glycine willd.
Avocado/soybean unsaponifiables are well known in the art and are
described in numerous patents and publications, including but not limited to: U.S.
Patent Nos. 6,797,289, 7,449,487, and 6,759,543; U.S. Patent Application
Publication Nos. 20080176935 and 20090087503; Their, "Unsaponifiable
constituents of avocado and soya oils. Treatment of certain forms of arthralgia," J.
Med. Lyon 53 (222): 195-8 (Feb. 1972); Trevoux, "Unsaponifiable fractions of the
avocado and soybean in gynecology," J. Gynecol. Obstet. Biol. Reprod. 6 (1): 99-
105 (Jan. 1977); Lamaud et al., "Biochemical modifications of connective tissue
induced by the non-saponifiables of avocado and soy-bean oils administered
percutaneously in the hairless rat," Pathol. Biol. 26 (5): 269-74 (May-Jun. 1978);
Boumediene et al., "Avocado/soya unsaponifiables enhance the expression of
transforming growth factor beta 1 and beta 2 in cultured articular chondrocytes,"
Arthritis Rheum. 42 (1): 148-56 (Jan. 1999); Henrotin et al., "Effects of three
avocado/soybean unsaponifiable mixtures on metalloproteinases, cytokines and
prostaglandin E2 production by human articular chondrocytes," Clin. Rheumatol. 17
(1): 31-9 (1998); Maheu et al., "Symptomatic efficacy of avocado/soybean
unsaponifiables in the treatment of osteoarthritis," Arthritis Rheum. 41 (1): 81-91
(Jan. 1998); and Blotman et al., "Efficacy and safety of avocado/soybean
unsaponifiables in the treatment of symptomatic osteoarthritis," Rev. Rheum. Engl.
Ed. 64 (12): 825-34 (Dec. 1997), which are each incorporated by reference in their
entirety. In addition, avocado/soybean unsaponifiables in combination with another
ingredient (glucosamine) are currently marketed in the United States under the trade
name AVOCA ASU . Avocado/soybean unsaponifiables are also marketed in
Europe under the trade name PIASCLEDINE .
Dosage calculations can be determined by those of skilled in the art by
evaluating body weight, surface area and species differences. The typical daily
dosage of avocado/soybean unsaponifiables (ASU) is about 1 mg/kg to about 12
mg/kg, preferably about 2 mg/kg to about 5 mg/kg, and more preferably about 3
mg/kg to about 4 mg/kg. In some embodiments, the typical daily dosage is at least 5
mg for small animals, and up to 12 g for large animals. The daily dosage refers to
the total dosage administered in a 24-hour period.
In some embodiments, the avocado/soybean unsaponifiables are
administered on a daily basis. In other embodiments, the avocado/soybean
unsaponifiables are administered less frequently, such as once every other day or
once a week or once a month. In some embodiments, the avocado/soybean
unsaponifiables are administered at a daily dose of about 1 mg/kg to about 12
mg/kg, preferably about 2 mg/kg to about 5 mg/kg, and most preferably about 3
mg/kg to about 4 mg/kg for three days to one month, preferably for about one week,
then the daily dose is decreased to about 25% to about 90% of the initial dose,
preferably about 50% to about 80% of the initial dose, and most preferably about
60% to about 75% of the initial dose. Dosage calculations can be determined by
those skilled in the art by evaluating body weight, surface area & species
differences.
The avocado/soybean unsaponifiables may be administered at a
frequency of one time per week to five times daily, preferably once every two days to
three times daily, more preferably one to two times daily. In preferred embodiments,
the avocado/soybean unsaponifiables are administered once daily. The
avocado/soybean unsaponifiables may be taken with or without the administration of
food.
The term “lipoic acid or derivates thereof” refers to a compound having
the following structure:
, and salts or derivatives thereof.
Lipoic acid is also known as α-lipoic acid; thioctic acid; 6,8-dithiooctanoic acid; and
1,2-dithiolanevaleric acid. Derivatives of lipoic acid include but is not limited to
esters and amides of lipoic acid, conjugates of lipoic acid, and analogues of lipoic
acid. Esters and amides of lipoic acid include but are not limited to 5-[1,2]-dithiolan-
3-yl-pentanoic acid 3-(5-[1,2]-dithiolanyl-pentanoyloxy)-propyl ester and 5-[1,2]-
dithiolanyl-pentanoic acid 3-(5-[1,2]-dithiolanyl-pentanoylamino)-propyl-amide.
Conjugates of lipoic acid include but are not limited to coumarin-lipoic acid
conjugates; indole-α-lipoic acid conjugates such as 5-[1,2]dithiolan-3yl-pentanoic
acid [1-(4-fluoro-benzyl)-1H-indoleyl]-amide; and amphiphilic lipoic acid
derivatives such N-lactobionyl-N -(5-[1,2]-dithiolanyl-penoyl)-L-lysinyl-1H,1H,,2H-
perfluorooctylamide. Analogues of lipoic acid include but are not limited to 1,2-
diselenolanepentanoic acid and 1,2-dithiolane derivatives of lipoic acid containing
catechol moieties linked through heteroaromatic rings. Derivatives of lipoic acid
have been described in the following publications, hereby incorporated by reference:
Gruzman et al. Synthesis and characterization of new and potent alpha-lipoic acid
derivatives. Bioorganic & Medicinal Chemistry, 2004, 12:1183-1190; Melagraki et al.
Synthesis and evaluation of the antioxidant and anti-inflammatory activity of novel
coumarinaminoamides and their alpha-lipoic acid adducts. European Journal of
Medicinal Chemistry, 2009, 44:3020-3026; Gurkan et al., Syntheses of novel indole
lipoic acid derivatives and their antioxidant effects on lipid peroxidation. Archiv der
Pharmazie, 2005, 338:67-73; Ortial et al., Fluorinated amphiphilic amino acid
derivatives as antioxidant carriers: a new class of protective agents. J Med Chem
2006;12-2820; Koufaki et al. Sign and synthesis of antioxidant alpha-lipoic acid
hybrids. Methods Mol Biol, 2010, 594:297-309; Sen et al., A positively charged
alpha-lipoic acid analogue with increased cellular uptake and more potent
immunomodulatory activity. Biochem Biophys Res Commun, 1998, 247:223-228;
Harnett et al., Novel lipoic acid analogues that inhibit nitric oxide synthase. Bioorg
Med Chem Lett, 2002,12:1439-1442; and Acker, Syntheses of Reduced Lipoic Acid
and Analogs of Lipoic Acid, Journal of Organic Chemistry, 1963, 28:2533-2536.
The lipoic acid and derivatives thereof may comprise racemates, enantiomers, or
mixtures thereof.
The typical daily dosage of lipoic acid or a derivative of lipoic acid can
range from about 1 mg/day to about 15,000 mg/day. The typical daily dosage of
lipoic acid or derivatives of lipoic acid can range from about 0.25 mg/kg/day to about
50 mg/kg/day. The daily dosage of lipoic acid refers to the total amount of lipoic acid
administered in a 24-hour period. The daily dosage can be provided in one or more
administrations. For example, the daily dosage can be administered once daily,
twice daily, or three or more times daily. In preferred embodiments, the daily dosage
is administered in one to five administrations, preferably one to three administrations,
and more preferably one or two administrations in a 24-hour period. The daily
dosage may vary according to the type of subject. For example, in humans, the daily
dosage is preferably about 25 to about 2,000 mg/day, more preferably about 50 to
about 1,500 mg/day, and most preferably about 100 to about 1200 mg/day, or
preferably about 0.5 to about 50 mg/kg/day, more preferably about 0.6 to about 40
mg/kg/day, and most preferably about 1.25 to about 30 mg/kg/day. In dogs, the daily
dosage is preferably about 1 to about 1,500 mg/day, more preferably about 10 to
about 750 mg/day, and most preferably about 20 to about 600 mg/day, or preferably
about 1 to about 100 mg/kg/day, more preferably about 10 to about 60 mg/kg/day,
and most preferably about 20 mg/kg/day. In cats, the daily dosage is preferably
about 1 to about 100 mg/day, more preferably about 3 to about 50 mg/day, and most
preferably about 3 to about 15 mg/day, or preferably about 0.5 to about 25
mg/kg/day, more preferably about 1 to about 20 mg/kg/day, and most preferably
about 3 to 15 mg/kg/day. In horses, the daily dosage is preferably about 125 to
about 15,000 mg/day, more preferably about 500 to about 12,500 mg/day, and most
preferably about 200 to about 10,000 mg/day, or preferably about 0.5 to about 100
mg/kg/day, more preferably about 1 to about 50 mg/kg/day, and most preferably
about 1 to 25 mg/kg/day.
In some preferred embodiments, the lipoic acid or derivatives,
analogues, racemates, or enantiomers of lipoic acid, or mixtures thereof, are
administered for three days to one month, preferably for about one week, then the
daily dose is decreased down to 75% of the initial dose. Dosage calculations can be
determined by those skilled in the art by evaluating body weight, surface area &
species differences.
The lipoic acid or derivatives thereof may be administered at a
frequency of one time per week to five times daily, preferably once every two days to
three times daily, more preferably one to two times daily. In preferred embodiments,
the lipoic acid or derivatives thereof are administered once daily. The lipoic acid or
derivatives thereof may be taken with or without the administration of food.
In some embodiments, the combination of (i) avocado/soybean
unsaponifiables and (ii) lipoic acid or derivatives thereof demonstrate synergy.
Synergy refers to the effect wherein a combination of two or more components
provides a result which is greater than the sum of the effects produced by the agents
when used alone. In preferred embodiments, the result is statistically significant and
greater than the additive effect. In some embodiments, the combination of
avocado/soybean unsaponifiables and lipoic acid or derivatives thereof have a
statistically significant, greater effect than each component alone. In preferred
embodiments, the combination of avocado/soybean unsaponifiables and lipoic acid
or derivatives thereof demonstrate synergy in one or more of the following:
preventing, treating, repairing or reducing damage to connective tissues; reducing
symptoms associated with damage to connective tissue in an avian or mammalian
subject; and reducing levels of one or more inflammatory mediators in connective
tissue.
The present invention provides a method of preventing, treating,
repairing, reducing damage, or controlling inflammation of connective tissues,
protecting cartilage, or reducing symptoms associated with damage to connective
tissue in an avian or non-human mammalian subject, comprising administering to the
subject: (i) avocado/soybean unsaponifiables and (ii) lipoic acid or derivatives
thereof. The term “connective tissue” includes but not limited to cartilage, bone,
synovium, ligament, meniscus, and tendon. In some embodiments, the
administration of avocado/soybean unsaponifiables and (ii) lipoic acid or derivatives
thereof may prevent, treat, repair or reduce damage to connective tissues. The
damage to connective tissue may be a result of physical injury or may represent
“wear and tear” from continual use, weight and age, for example, from osteoarthritis.
Damage to connective tissue may also result from disease such as rheumatoid
arthritis, synovial disorders, infection related rheumatic diseases and inflammatory
connective tissue disorders. In some embodiments, the administration of
avocado/soybean unsaponifiables and (ii) lipoic acid or derivatives thereof may
reduce symptoms associated with damage to connective tissue in an avian or
mammalian subject. Symptoms associated with damage to connective tissue
include, but are not limited to: pain, discomfort, pressure, inflammation, stiffness and/
or swelling.
The present invention also provides a method of reducing levels of one
or more inflammatory mediators in connective tissue, comprising administering to an
avian or non-human mammalian subject: (i) avocado/soybean unsaponifiables and
(ii) lipoic acid or derivatives thereof, in amounts effective to decrease inflammation.
The inflammatory mediators include, but are not limited to prostaglandins such as
prostaglandin E (PGE ), cytokines such as interleukin-1β (IL-1β) and tumor necrosis
factor-α (TNF-α), chemokines, leukotrienes, nitric oxide, and reactive oxygen
species.
The administration of avocado/soybean unsaponifiables and lipoic acid,
or derivatives thereof may also be useful for treating, preventing, and reducing
damage or reducing symptoms associated with conditions affecting the
cardiovascular system, nervous system, musculoskeletal system and gastrointestinal
system. The present invention also provides for an orally administrable composition
comprising: (i) avocado/soybean unsaponifiables and (ii) lipoic acid or derivatives
thereof. The orally administrable composition is any dosage form which can be
administered orally, such as, but not limited to: a capsule, a tablet, a powder that can
be dispersed in a beverage, a liquid such as a solution, suspension, or emulsion, a
soft gel/chew capsule, a chewable bar or other convenient dosage form such as oral
liquid in a capsule, as known in the art.
The orally administrable composition may contain one or more non-
active pharmaceutical ingredients (also known generally herein as “excipients”).
Non-active ingredients, for example, serve to solubilize, suspend, thicken, dilute,
emulsify, stabilize, preserve, protect, color, flavor, and fashion the active ingredients
into an applicable and efficacious preparation that is safe, convenient, and otherwise
acceptable for use. The excipients are preferably pharmaceutically acceptable
excipients. Examples of classes of pharmaceutically acceptable excipients include
lubricants, buffering agents, stabilizers, blowing agents, pigments, coloring agents,
flavoring agents, fillers, bulking agents, fragrances, release modifiers, adjuvants,
plasticizers, flow accelerators, mold release agents, polyols, granulating agents,
diluents, binders, buffers, absorbents, glidants, adhesives, anti-adherents,
acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers,
elastomers and mixtures thereof.
The orally administrable compositions may further comprise one or
more active ingredients. For example, the compositions may further comprise one or
more drugs or nutritional supplements. In some embodiments, the compositions
may further comprise compounds which are beneficial to connective tissue.
Example include, but are not limited to glycosaminoglycans such as chondroitin,
aminosugars such as glucosamine, methylsulfonylmethane (MSM), green tea
extracts, boswellia extracts, scutellaria extracts, acacia extracts, turmeric extracts,
curcumin, cetyl myristoleate complex (CMO) and egg shell membrane.
All references cited herein are incorporated by reference in their
entirety. In this specification where reference has been made to patent
specifications, other external documents, or other sources of information, this is
generally for the purpose of providing a context for discussing the features of the
invention. Unless specifically stated otherwise, reference to such external
documents is not to be construed as an admission that such documents, or such
sources of information, in any jurisdiction, are prior art, or form part of the common
general knowledge in the art.
EXAMPLES
Example 1: Effect of avocado/soybean unsaponifiables (ASU) and Lipoic Acid (LA)
on prostaglandin E (PGE ) production in lipopolysaccharide (LPS) activated equine
chondrocyte cultures.
Chondrocytes were pre-treated with avocado/soybean unsaponifiables (ASU)
at a concentration of 8.3 μg/ml and different concentrations of lipoic acid (LA) for 24
hrs, then activated with lipopolysaccharide (LPS) (1 ng/ml). Lipopolysaccharide
(LPS) is an endotoxin derived from the bacterial cell wall which is used as a broad
inflammatory stimulus to induce prostaglandin E (PGE ) production. After an
additional 24 hrs, supernatant was collected and assayed for PGE levels. Statistical
significance between the activated control and the pre-treated groups were analyzed
using Tukey post-hoc analysis (mean + 1 SD, n = 3).
The combination of avocado/soybean unsaponifiables (ASU) at a
concentration of 8.3 μg/ml and lipoic acid (LA) at concentrations of 2.5, 1.25 and
0.625 μg/ml reduced PGE levels significantly more than either ASU (<0.001) or LA
(p<0.001) alone. The results are graphed in Figure 1.
Example 2: Effect of ASU and Lipoic Acid (LA) on prostaglandin E (PGE )
production in hydrogen peroxide (H O ) activated equine chondrocyte cultures.
Chondrocytes were pre-treated with avocado/soybean unsaponifiables (ASU)
at a concentration of 8.3 μg/ml and different concentrations of lipoic acid (LA) for 24
hrs, then activated with hydrogen peroxide (500 μM). Hydrogen peroxide is a potent
oxidant used to induce prostaglandin E (PGE ) production. After an additional 24
hrs, supernatant was collected and assayed for PGE levels. Statistical significance
between the activated control and the pre-treated groups were analyzed using Tukey
post-hoc analysis (mean + 1 SD, n = 3). The combination of avocado/soybean
unsaponifiables (ASU) at a concentration of 8.3 μg/ml and lipoic acid (LA) at
concentrations of 2.5 and 1.25 μg/ml reduced PGE levels significantly more than
either ASU (<0.001) or LA (p<0.05) alone. The results are graphed in Figure 2.
Claims (30)
1. An orally administrable composition comprising: (i) avocado/soybean unsaponifiables and (ii) lipoic acid or derivatives thereof.
2. The composition of claim 1, comprising avocado/soybean unsaponifiables and lipoic acid.
3. The composition of claim 1, wherein the lipoic acid or derivatives thereof comprise a compound selected from the group consisting of: esters and amides of lipoic acid, conjugates of lipoic acid, and analogues of lipoic acid.
4. The composition of claim 1, wherein the lipoic acid or derivatives thereof comprise a compound selected from the group consisting of: 5-[1,2]-dithiolanyl- pentanoic acid 3-(5-[1,2]-dithiolanyl-pentanoyloxy)-propyl ester; 5-[1,2]-dithiolan yl-pentanoic acid 3-(5-[1,2]-dithiolanyl-pentanoylamino)-propyl-amide; coumarin- lipoic acid conjugates; 5-[1,2]dithiolanyl-pentanoic acid [1-(4-fluoro-benzyl)-1H- indoleyl]-amide; N-lactobionyl-N -(5-[1,2]-dithiolanyl-penoyl)-L-lysinyl-1H,1H, 2H-perfluorooctylamide; 1,2-diselenolanepentanoic acid; and 1,2-dithiolane derivatives of lipoic acid containing catechol moieties linked through heteroaromatic rings
5. The composition of claim 1 or 2, wherein the lipoic acid has the following structural formula:
6. A method of preventing, treating, repairing, protecting, or reducing damage to connective tissues or reducing symptoms associated with damage to connective tissue in an avian or non-human mammalian subject, comprising administering to the subject: (i) avocado/soybean unsaponifiables and (ii) lipoic acid or derivatives thereof.
7. The method of claim 6, wherein the connective tissue is selected from the group consisting of: cartilage, bone, synovium, ligament, meniscus and tendon.
8. The method of claim 6 or 7, wherein the non-human mammalian subject is a horse, dog, cat, camel, or cow.
9. The method of any one of claims 6 to 8, wherein the symptoms associated with damage to connective tissue are selected from the group consisting of: pain, discomfort, pressure, inflammation, stiffness and/or swelling.
10. A method of reducing levels of one or more inflammatory mediators in connective tissue, comprising administering to an avian or non-human mammalian subject: (i) avocado/soybean unsaponifiables and (ii) lipoic acid or derivatives thereof, in amounts effective to decrease inflammation.
11. The method of claim 10, wherein the one or more inflammatory mediators are selected from the group consisting of: prostaglandin E (PGE ), leukotrienes, nitric oxide, cytokines, chemokines, and reactive oxygen species.
12. The method of claim 10 or 11, wherein the avian or non-human mammalian subject is a bird, horse, dog, cat, camel or cow.
13. Use of (i) avocado/soybean unsaponifiables and (ii) lipoic acid or derivatives thereof in the preparation of a medicament for the prevention, treatment, repair, protection, or reduction of damage to connective tissues or for the reduction of symptoms associated with damage to connective tissue in an avian or mammalian subject.
14. The use of claim 13, wherein the connective tissue is selected from the group consisting of: cartilage, bone, synovium, ligament, meniscus and tendon.
15. The use of claim 13 or 14, wherein the mammalian subject is a human, horse, dog, cat, camel, or cow.
16. The use of any one of claims 13 to 15, wherein the symptoms associated with damage to connective tissue are selected from the group consisting of: pain, discomfort, pressure, inflammation, stiffness and/or swelling.
17. Use of (i) avocado/soybean unsaponifiables and (ii) lipoic acid or derivatives thereof, in amounts effective to decrease inflammation, in the preparation of a medicament for the reduction of levels of one or more inflammatory mediators in connective tissue in an avian or mammalian subject.
18. The use of claim 17, wherein the one or more inflammatory mediators are selected from the group consisting of: prostaglandin E (PGE ), leukotrienes, nitric oxide, cytokines, chemokines, and reactive oxygen species.
19. The use of claim 17 or 18, wherein the avian or mammalian subject is a bird, human, horse, dog, cat, camel or cow.
20. The composition of any one of claims 1 to 5 for use as a medicament.
21. The composition of any one of claims 1 to 5 for preventing, treating, repairing, protecting, or reducing damage to connective tissues or reducing symptoms associated with damage to connective tissue in an avian or mammalian subject.
22. The composition of claim 21, wherein the connective tissue is selected from the group consisting of: cartilage, bone, synovium, ligament, meniscus and tendon.
23. The composition of claim 21 or 22, wherein the mammalian subject is a human, horse, dog, cat, camel, or cow.
24. The composition of any one of claims 21 to 23, wherein the symptoms associated with damage to connective tissue are selected from the group consisting of: pain, discomfort, pressure, inflammation, stiffness and/or swelling.
25. The composition of any one of claims 1 to 5 for reducing levels of one or more inflammatory mediators in connective tissue in an avian or mammalian subject.
26. The composition of claim 25, wherein the one or more inflammatory mediators are selected from the group consisting of: prostaglandin E (PGE ), leukotrienes, nitric oxide, cytokines, chemokines, and reactive oxygen species.
27. The composition of claim 25 or 26, wherein the avian or mammalian subject is a bird, human, horse, dog, cat, camel or cow.
28. A composition of any one of claims 1 to 5 and 20 to 27 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
29. A method of any one of claims 6 to 12 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
30. Use of any one of claims 13 to 19 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/112,488 US9421234B2 (en) | 2011-05-20 | 2011-05-20 | Orally administrable compositions comprising avocado/soybean unsaponifiables and lipoic acid and methods of administration |
US13/112,488 | 2011-05-20 | ||
PCT/US2012/038168 WO2012162063A1 (en) | 2011-05-20 | 2012-05-16 | Orally administrable compositions comprising avocado/soybean unsaponifiables and lipoic acid and methods of administration |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ618389A NZ618389A (en) | 2015-08-28 |
NZ618389B2 true NZ618389B2 (en) | 2015-12-01 |
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