WO2014138372A1 - Composition et méthode de traitement de l'arthrose - Google Patents

Composition et méthode de traitement de l'arthrose Download PDF

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WO2014138372A1
WO2014138372A1 PCT/US2014/021139 US2014021139W WO2014138372A1 WO 2014138372 A1 WO2014138372 A1 WO 2014138372A1 US 2014021139 W US2014021139 W US 2014021139W WO 2014138372 A1 WO2014138372 A1 WO 2014138372A1
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extract
curcumin
composition according
absorbable
osteoarthritis
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Yoshinori Takeda
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Primavera Biosciences Inc
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    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • 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)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • 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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/488—Pueraria (kudzu)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the invention relates to compositions and methods for treating osteoarthritis, particularly, combined use of anti-inflammatory agent and an agent that enhances bone formation and chondrogenesisto ease and help reverse the progression of osteoarthritis.
  • Osteoarthritis is the most common form of arthritis, and according to the Center of Disease Control and Prevention (CDC), 25 - 27 million American adults suffer from
  • osteoarthritis which is one of the leading causes of disability in America. 80% of older adults suffer from the disease. Osteoarthritis occurs when the protective cartilages on the ends of the bones wear down over time, and while osteoarthritis can damage any joints in the body, the disease affects most commonly joints in hands, neck, lower back, knees, and hips.
  • Medications include pain killers such as acetaminophen (Tylenol (trademark)), non-steroidal anti-inflammatory drugs (NSAIDs; e.g., aspirin, ibuprofen and naproxen), or narcotics.
  • Pain killers such as acetaminophen (Tylenol (trademark)
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Physicians may recommend weight loss if patients are overweight or obese and instruct physical therapy and lifestyle changes. If osteoarthritis gets worse, there are surgical options such as lubricant injection, joint realignment, and joint replacement.
  • a composition according to the present invention includes an anti-inflammatory agent and an agent that enhances bone-formation andchondrogenesis in combinationat a
  • therapeutically effective amount thereof to treat osteoarthritis The combined use of the antiinflammatory agent and the agent that enhances bone-formation andchondrogenesiscan synergistically ease and reverse the progression of osteoarthritis.
  • the anti-inflammatory agent is an NF-kappaB inhibitor which is curcumin or turmeric extract, and/or the NF-kappaB inhibitor includeshighly-absorbable curcumin.
  • Highly-absorbablecurcuminis commercially availableas BCM-95 (trademark), Curcumin C3/Bioperine (trademark), and Theracurmin (trademark).
  • the agent that enhances bone-formation andchondrogenesis is phytonutrientthatincludes a PPAR-gamma inhibitor and/or
  • the phytonutrient may be selected from the group consisting of soybean extract, kudzu extract, ginkgo extract, and celery seeds extract.
  • the PPAR-gamma inhibitor and/or phytoestrogen may be selected from the group consisting of highly-absorbable genistein, daidzein, quercetin, kaempferol, and apigenin.
  • composition according to another embodiment includes a combination
  • the composition may includecurcumin, daidzein, genistein, quercetin, kaempferol and/or apigenin at a dose of 10 - 100 mg, most preferably 20 -30 mg, per day when a highly-absorbable ingredient is used; at a dose of 50 - 1000 mg, most preferably 200 - 600 mg, per day when a regular, low-absorbing ingredient is used.
  • composition according to another embodiment includeshighly-absorbable curcuminin combination with at least one phytonutrient selected from the group consisting of extracts containing highly-absorvablegenistein, daidzein, quercetin, kaempferol, and apigenin.
  • a pharmaceutical composition useful in treating osteoarthritisis whichincludes at a therapeutically effective amount to treat the disease a combination of synthetic compounds selected from the group consisting of curcumin, curcumin derivatives, daidzein, daidzein derivatives, quercetin, kaempferol, apigenin, and synthetic deidzein derivative equol, in the use of helping ease and reverse the progression of osteoarthritis.
  • the composition may include each synthetic compound at a dose of 5 - 50 mg per day.
  • any of the compositionsdescribed above is used in human and veterinary uses.
  • the agents listed above can be used in a process for producing a pharmaceutical composition for treating osteoarthritis.
  • an anti-inflammatory agent and an agent that enhances bone-formation andchondrogenesis are administered to a subject suffering from osteoarthritis at a therapeutically effective amount to treat the disease.
  • the anti-inflammatory agent is an NF-kappaB inhibitor
  • the agent that enhances bone-formation andchondrogenesis is a PPAR-gamma inhibitor and/or phytoestrogen.
  • the anti-inflammatory agent is selected from the group consisting of curcumin, andturmeric extract
  • the agent that enhances bone-formation andchondrogenesis is selected from the group consisting of soybean extract, kudzu extract, ginkgo extract, celery seeds extract, highly-absorbable genistein, daidzein, quercetin, kaempferol, and apigenin.
  • the daily dose for the highly-absorbable ingredient is administered at 10 - 100 mg, preferably, 20 - 40 mg
  • the daily dose for the regular low-absopbing ingredients may be administered at 50 - 1000 mg, preferably, 200 - 600 mg.
  • Any of the combinations of agents listed above can accompany instructions in paper or online to patients or doctors to use the agents in combination for oral administration. Such instructions may include required dose or frequency of administrations which can be determined based on guidance provided in this application and a common knowledge regarding the agents.
  • FIGURE 1 illustrates the roles phytonutrients play in bone formation and cartilage repair.
  • Osteoclasts bone-resorpting cells
  • Mesenchymal stem cells MSC
  • Isoflavones genistein, daidzein
  • flavonoids flavonoids
  • antagonizing PPAR-gamma inhibits adipogenesis (fat formation) and promotes production of osteoblasts and chondrocytes.
  • isoflavonesand flavonoids acting as phytoestrogen, suppress activities of osteoclasts and enhance activities of osteoblasts and chondrocytes. This leads to stronger bone formation and cartilage repair, opposing to aging that makes osteoclasts more active than osteoblasts, and adipogenesis more active than blastogenesis which leads to fat accumulation, bone loss and cartilage destruction.
  • FIGURE 2 illustrates improvements in walking or running capability of an osteoarthritis patient treated with a combination of curcumin and the kudzu extract (containing daidzin).
  • X- axis time (week);
  • Y-axis a speed of walking or jogging per hour.
  • Y-axis also represents an actual distance walked or jogged since a patient walked or jogged for one hour. More explanations are given in EXAMPLE 1.
  • the present invention was inspired by the recent observations that cartilage precursor mesenchymal stem cells (MSCs) exist in synovial fluids of osteoarthritic knees. Jones et al reported in 2004 & 2008 that they found pluripotent mesenchymal stem cells (MSCs) in synovial fluids of the knees of healthy individuals as well as osteoarthritis patients; in increased numbers in the latter.
  • MSCs cartilage precursor mesenchymal stem cells
  • the first finding is that although "wear and tear” is said to be responsible forcartilage destructions, pro-inflammatory mediators (cytokines and metallproteinases)appear to be more responsible for cartilage destructions. Therefore, in order to reverse osteoarthritis, pro-inflammatory mediators must be down-regulated and well managed over a long period of time.
  • the second finding is that in order to repair cartilage, bone formation must be encouraged andchondrogenesisbe activated. Bone formation and cartilage repair share many of the same growth hormones such as transforming growth factor-beta (TGF- beta) and insulin-like growth factor-1 (IGF-1).
  • TGF- beta transforming growth factor-beta
  • IGF-1 insulin-like growth factor-1
  • MSC mesenchymalstem cells
  • osteoblasts&chondroblasts is counter-balanced with its differentiation into adipocytes (fat forming cells).
  • adipocytes fat forming cells.
  • the key factor that divergently regulatesosteogenesisvsadipogenesis is nuclear transcription factor PPAR-gamma (peroxisome proliferator-activated receptor-gamma).
  • PPAR-gamma peroxisome proliferator-activated receptor-gamma
  • the inhibition of PPAR-gamma promotesosteogenesis and chondrogenesiswhile the activation of PPAR-gamma promotesadipogenesis.
  • the following ingredients among others influence the above factors and processes in favor for joint repair.
  • Curcumin/turmeric is an anti-inflammatory polyphenol. Oral administration of curcumin/tumeric not only eases typical osteoarthritic pain within a couple of weeks, but also reduce or stop cartilage destructions by down-regulating pro-inflammatory cytokines.
  • NF- kappaB is chronically active in many inflammatory diseases such as osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, and cancer.
  • Curcumin inhibits transcription factor NF- kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) which regulates a variety of genes encoding pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6), chemokines (IL-8, MlPI-alpha), and inducible enzymes (iNOS, COX-2).
  • NF- kappaB nuclear factor kappa-light-chain-enhancer of activated B cells
  • NF-kappaB down-regulates the production of phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitrix oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, TNF-alpha, and IL-12. And there is plenty of evidence that curcumin/tumeric is safe for long-term use.
  • MSCs pluri potent mesenchymal stem cells
  • osteoblasts & chondrocytes Takada et al 2009; Viccica et al 2010.
  • OPG osteoprotegrin
  • Curcumin/turmeric suppresses pain and inflammation but that is not enough for cartilage repair. It appears that cartilage repair depends on the newly-activated chondroblasts which bind damaged extracellular matrix (ECM), secret the precursor molecules and amend damaged ECM when destructive cytokines are down-regulated. Without the newly-activated ECM
  • cartilage repair may not occur even if plenty of cartilage precursor molecules such as glucosamine, chondoitin, collagen UC-II and hyaluronan are orally provided.
  • Osteoarthritis is the result of mechanical and biological events that destabilize the balance between the synthesis and breakdown of cartilage. This imbalance can be caused by multiple factors: genetic, metabolic, traumatic, or wear and tear. Osteoarthritis affects all bones and tissues of the joints and manifests itself by biochemical, molecular and
  • cartilage destruction is not always linear but can be interrupted with phases of restoration of the damages and the joint space.
  • the consequences of this disease also vary.
  • the cartilage supporting the body weight and motion breaks down and the cartilage loses thickness.
  • the cartilage loses thickness.
  • reshaping of the bone with the appearance of osteoporosis and areas of bone condensation begins.
  • the inhomogeneous bone tissues can cause pain in surrounding tissues and also induce severe brittleness of bone tissue; then, tissue debris can form and accumulate within the joint. This causes joint inflammation and enhances further joint degeneration.
  • the synovial joints contain a variety of pro-inflammatory mediators, but at the same time they also contain proteinase inhibitors (TIMP1, TIMP2) and a variety of mitogenic growth factors (transforming growth factors (TGF), bone morphogenic protein (BMP), insulin-like growth factor-1 (IGF-1), and epidermal growth factor (EDGF)).
  • TGF transforming growth factors
  • BMP bone morphogenic protein
  • IGF-1 insulin-like growth factor-1
  • EDGF epidermal growth factor
  • Pro-inflammatory mediators include cytokines, chemokines, methalloproteinases (MMP), other proteinases, tumor necrosis factor-alpha (TNF-alpha), and interleukins (IL-1, IL-6, IL-8).
  • MMP methalloproteinases
  • TNF-alpha tumor necrosis factor-alpha
  • IL-1, IL-6, IL-8 Primary cytokines IL-1 and TNF-alpha and secondary cytokines IL-6 and IL-8 cause inflammation in synovial membrane and cartilage.
  • IL-8 stimulates production of prostaglandin 2 (PGE2) and PGE2 stimulates breakdown of extracellular matrix.
  • IL-6 decreases the production of type II collagen.
  • Collagenases breakdown the collagen type II scaffolding in cartilage.
  • Levels of collagenase-1 (MMP-1) and collagenase-3 (MMP-13) correlate with the severity of cartilage destruction.
  • Aggrecanases degrade aggrecan, the major component of proteoglycans in cartilage.
  • Major aggrecanases, ADAMTS-4 and ADAMTS-11 contain the disintegrin and metalloprotease with thrombospondin motif.
  • Stromelysins and gelatinase-A (MMP-2) and gelatinase-B (MMP-9) are also involved.
  • Stromelysin levels also correlate with the severity of osteoarthritis.
  • Other proteolytic enzymes include elastases and hyaluronidases.
  • NO Free radical nitric oxide
  • iNOS Inducible NO synthetase
  • NF- kappaB The activation of NF- kappaBproduces COX-2 and inducible NO synthetase.
  • Kealey et al disclose cocoa extracts and polyphenols enriched procyanidins in treating periodontal disease. These compounds act as antioxidants, COX- and lipooxygenase modulator, NO synthetase modular, inhibitor of ROS (reactive oxygen species), platelet aggregator modulator, apoptosis modulator, and anti-cancer agents.
  • Cyclooxygenase catalyzes the metabolism of arachidonic acid to prostaglandin H.sub.2 (PGH.sub.2), which is further metabolized to various prostaglandins (PGs), prostacyclins and thromboxane A2.
  • PGs are ubiquitous hormones that functions as paracrine and autocrine mediators to affect a myriad of physiological changes in the immediate cellular environment.
  • the varied physiological effects of PGs include inflammatory reactions such as rheumatoid arthritis and osteoarthritis, blood pressure control, platelet aggregation, induction of labor and aggravation of pain and fever.
  • COX exists in two isoforms, COX-1 and COX-2.
  • PGs produced by COX-1 and COX-2 are identical molecules, however, COX-1 and COX-2 generate a unique pattern and various amounts of eicosanoids in different tissues; therefore, relative differences in the activation of these enzymes may result in quite dissimilar biological responses.
  • COX-1 is expressed constitutively in most tissues whereas COX-2 is induced by pro-inflammatory stimuli including cytokines, mitogens, and bacterial lipopolysaccharide.
  • Non-steroidal anti-inflammatory drugs are COX inhibitors used in the control of pain and inflammation of osteoarthritis.
  • COX-1 is believed to be responsible for PG synthesis in normal gastric mucosa, but it now appears that both COX-1 and COX-2 have important physiological roles in normal gastric mucosa.
  • selective COX-2 inhibitors which do not down-regulate PGE.sub.2 in gastric mucosa
  • the drugs thus developed, Celebrex ® and Vioxx ® showed gastric toxicity inducing spontaneous bleeding and delaying gastric ulcer healing. Vioxx ® was withdrawn from the market and Celebrex ® has been used under a black box warning for the elevated risk of cardiovascular disease.
  • Patent Application US 20120207827 disclose the oral and topical use of dimethylsulfoxide (DMSO) and methylsulfornylmethane (MSM) in treating osteoarthritis.
  • DMSO dimethylsulfoxide
  • MSM methylsulfornylmethane
  • Patent Application US 20120201781 Kamath RV discloses the use of antibody against IL-1 in treating osteoarthritis.
  • Patent Application US 20090280081 Vasios G discloses JAK3-specific inhibitors (hymenialdisine, debromohymenialdisine, and their derivatives) in treating osteoarthritis; JAK3-specific inhibitors down-regulate steady state mRNA levels of key cellular components involved in cartilage degradation.
  • TNF-alpha inhibitor, Enbrel ® has been successfully used in treating rheumatoid arthritis.
  • Krumhar KC discloses the compositions and methods that include boswellic acid, curcuminoids, gingerols, capsaincinoid, quercetin, genistein, daidzein, vitamin C, and linoleic acid.
  • curcuminoids include boswellic acid, curcuminoids, gingerols, capsaincinoid, quercetin, genistein, daidzein, vitamin C, and linoleic acid.
  • compositions in alleviating inflammation and oxidative stress comprising
  • compositions for inflammatory disorders comprised of an extract of flowering and fruiting heads of the plant, Sphaeranthusindicus; the compositions are intended to inhibit tumor necrosis factor (TNF-alpha), interleukin (IL-1, IL-6, IL-8), the expression of intercellular adhension molecule-1 (ICAM-1), vascular-cell adhension molecule-1 (VCAM-1), and E-Selectin.
  • TNF-alpha tumor necrosis factor
  • IL-1, IL-6, IL-8 interleukin
  • IAM-1 intercellular adhension molecule-1
  • VCAM-1 vascular-cell adhension molecule-1
  • E-Selectin E-Selectin.
  • Dushenkov et al disclose compositions containing theaflavin (black tea extract) and glucosamine; they claim that theaflavin inhibits NF- kappaB activation and COX-2 gene expression and suppresses inflammation.
  • Patent No. US 8,192,768 Gokaraju et al disclose anti-inflammatory and antioxidant supplement compositions comprising boswellic acid, curcumoids, glucosamine, chondroitin, garlic extract, bromelain, quercetin, gallic acid, caffeic acid, green tea, resveratrol, MSM, and serratiopeptidase.
  • the compositions are used to inhibit COX-2 and 5-LOX enzymes and inflammation.
  • Boswellic acid is pentacyclictriterpene isolated from the resin of Boswelliserrata.
  • Boswelli acid shows anti-inflammatory effects since it inhibits the synthesis of leukotriene (cytokine modulator) and the action of 5-lipoxygenase (5-LO) that is involved in prostaglandin synthesis (Ammon et a 1, 1993).
  • Boswelli extracts are now seen in many supplement products made for inflammatory diseases including osteoarthritis. Boswelli extracts are also shown to have anti-cancer activities against brain tumor, leukemia, and colon cancer. A high dose is hepatotoxic while a low dose is hepatoprotective. Dosage guidelines have now been developed for safe uses (SalGenecists, Inc., Boswellia Information).
  • Curcumin/tumeric is another popular component in therapeutic products made to prevent and/or treat inflammatory diseases and cancer (Aggarwal et al, 2007).Curcumin inhibits the activation of a transcription factor NF-kappaB which regulates a variety of genes encoding pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6), chemokines (IL-8, MlPI-alpha), inducible enzymes (iNOS, COX-2), and other molecules (Shakibaei et a I, 2007; Chainani-Wu, 2003).
  • NF-kappaB which regulates a variety of genes encoding pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6), chemokines (IL-8, MlPI-alpha), inducible enzymes (iNOS, COX-2), and other molecules (Shakibaei et a I, 2007; Chainani-Wu, 2003).
  • NF-kappaB down-regulates the production of phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitrix oxide (NO), collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, TNF-alpha, and IL-12.
  • NO nitrix oxide
  • MCP-1 monocyte chemoattractant protein-1
  • NF-kappaB is a "rapid-acting" primary transcription factor involved in cellular responses to stimuli such as stress, cytokines, free radicals, bacterial and viral antigens.
  • stimuli such as stress, cytokines, free radicals, bacterial and viral antigens.
  • IkappaB dimmers are sequestered in an inactive state in the cytoplasm bound to inhibitor (IkappaB).
  • IKK kinase
  • Eukaryotic cells widely use NF-kappaB as a regulator of genes that control cell proliferation and cell death (apoptosis); and NF-kappaB plays a key role in regulating the immune response to infection.
  • NF-kappaB is activated by TNF-alpha, I L-1, bacterial
  • LPS lipopolysaccharides
  • ROS reactive oxygen species
  • ionizing radiation and others.
  • NF-kappaB The activation of the NF-kappaB leads to many chronic inflammatory diseases including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, asthma, and atherosclerosis. Uncontrolled NF-kappaB production increases the risk of developing cardiovascular diseases.
  • N F-kappa is constitutively active; and uncontrolled NF-kappaB leads to proliferation. Blocking NF-kappaB has thus been a strategy to control cancer. Natural and synthetic NF-kappaB inhibitors have been explored for therapeutics of cancer and inflammation.
  • NF-kappaB is also activated via RAN K (receptor activator of NF-kappaB) bound on the surface membrane of osteoclasts (boneresorption cells).
  • Osteoprotegrin (OPG) inhibits this activation by binding RANKL bound on the surface membrane of osteoblasts (bone forming cells).
  • OPG down-regulates activities of osteoclasts and NF-ka ppaB, and plays a major role on the activities of osteoblasts and bone formation.
  • Estrogen and phytoestrogen stimulate the production of OPG, and down-regulate activities of osteoclasts and NF-kappaB: This prevents bone loss and inflammation.
  • TNF-alpha is a pleiotropic pro-inflammatory cytokine, produced mainly by macrophages, but by other types of cells as well.
  • TN F-alpha initiates a cytokines cascade and increases vascular permeability, thereby recruiting macrophages and neutrophils to a site of infection or inflammation.
  • TNF-alpha causes blood clotting. Prolonged overproduction of TNF-alpha harms cells and tissues and may result in a condition known as cachexia.
  • TNF-alpha demonstrates beneficial as well as pathological activities; it has both growth stimulating and growth inhibitory effects; it is self-regulated.
  • the beneficial functions include maintaining homeostasis by regulating the body's circadian rhythm, replacing injured tissue by stimulating fibroblast growth, mounting an immune response and killing bacterial, viral, fungal, and parasitic infections, and certain tumors.
  • inappropriate productions of TN F-alpha cause chronic inflammation and tissue damages.
  • TNF-alpha is shown to play critical roles in bowel disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, osteoporosis, coronary heart disease, vasculitis, ulcerative colitis, psoriasis, diabetes, Alzheimer's disease, and others.
  • the human digestive system hardly absorbs many of naturally-occurring bioactive polyphenols,isoflavones, and flavonoids: only less than 2% of orally-administered plant compounds could be found in the blood stream. Because of the low bioavailability, many positive results obtained using these bioactive compounds in vitro and in animal systems have often suffered from being reproduced when applied to human. Low and varying bioavailability also makes accurate dosing difficult. Now, however, the bioavailability problems seem to have found a number of solutions.
  • Birbara PJ Patent Application US 20120213842
  • Edgar KJ et al Patent Application US 20130237609 describe cellulose derivatives for enhancing
  • MSCs Mesenchymal stem cells
  • adipocytes fat cells
  • osteoblasts bone cells
  • chondrocytes cartilage cells
  • myocytes muscle cells
  • neurons neurons
  • MSCs are found in a variety of tissues but among them adipose tissue is one of the richest sources of MSCs. Compared to bone marrow, there are more than 500 times more mesenchymal stem cells in adipose tissue than bone marrow. Since MSCsgrow vigorously in vitro while maintaining their multipotency, and human MSCs avoid allorecognition, MSCs have tremendous potentials in tissue engineering (Chanda 2010).
  • Isoflavones (daidzin, genistin), flavonoids(quercetin, kaempferol, agigenin), and/or estrogendownregulate PPAR-gamma and direct differentiation of MSCs toward osteoblasts and chondrocytes from adipocytes
  • ZDs Anti- diabetes drugsthiazolidinediones
  • TGF-beta morphogenic transforming growth factor-beta
  • IGF-l Insulin-like growth factor-1
  • BMP-2, BMP-4, and BMP-7 all TGF-beta family
  • ECM three-dimentionalextracellurmatrix
  • synovial fluid is a viscous fluid found in the cavities of synovial joints.
  • the principal role of synovial fluid is to reduce friction between cartilages of synovial joints during movement.
  • the inner membrane of synovial joints is called the synovial membrane and secretes synovial fluid into the joint cavity.
  • the fluid contains viscous hyaluronic acid (anionic, nonsulfated
  • glycosaminoglycan secreted by fibroblast-like cells in the synovial membrane and interstitial fluid filtered from the blood plasma.
  • This fluid forms a thin layer (roughly 50 microns) at the surface of the cartilage and also seeps into microcavities and irregularities in the articular cartilage surface, filling all empty space.
  • the synovial fluid held in the cartilage is squeezed in and out to reduce friction and absorb shock.
  • a meniscus, made of fibrocartilage also reduces friction and disperses gravitational stress during movement.
  • Synovial fluid of osteoarthritis patients contains MSCs which have chodrogenic potential (Kurth et al 2007; Fan et al 2009).
  • synovial fluid also contains, at varying quantities, growth factors (BMPs, IGF-1), Type II collagen, and exposed extracellular matrix (ECM).
  • BMPs growth factors
  • IGF-1 growth factors
  • Type II collagen Type II collagen
  • ECM exposed extracellular matrix
  • synovial fluid looks isolated, without blood supply, from the rest of the body, but it isn't.
  • the inside of the joint is connected with outside cells and tissues through the flowing interstitial fluid; and the inside cells and tissues communicate with the outside cells and tissues via various modulators, e.g., cytokines and chemokines.
  • modulators e.g., cytokines and chemokines.
  • certain levels ofpro-inflammatory modulators should be present within synovial fluid for communication and to stimulate proliferation of cells and tissues. Moderate pain thus could beconstructive rather than destructive.
  • Chondrogenesis during embryogenesis.
  • the skeletal system is derived from the mesoderm germ layer. Chondrogenesis is the process by which cartilage is formed from condensed mesenchymal tissues, which differentiate into chondrocytes and begin secreting the molecules that form the extracellular matrix (ECM).
  • ECM extracellular matrix
  • the greater part of the skeleton is cartilaginous. This temporary cartilage is gradually replaced by bone
  • Articular cartilage thus formed is free of blood, lymphatic vessels and nerve structures, particularly at knee joints. Within the joint, cartilage is in contact by its deepest layer with subchondral bone and its most superficial layer with synovial fluid.
  • the extracellular matrix In the articular cartilage, the extracellular matrix (ECM) is primarily composed of water, proteoglycans (major components are aggrecans), type II collagen, and hyaluronic acid; and chondrocytes occupy roughly 5% of the tissue volume.
  • chondrocytes are metabolically active and consume (take up) great quantities of oxygen, glucose, glutamine and other nutrients from the synovial fluid and synthesize glucosamine, one of the major components of proteoglycans; the synovial fluid then removes carbon dioxide and metabolic wastes through the interstitial fluid. It is not known, however, whether these chondrocytes within articular cartilage are capable of proliferating and engaging in cartilage repair. [0052] It is historically said that cartilage, once damaged, has limited repair capabilities because chondrocytes are bound in lacunae and cannot migrate to the damaged area (the surface area of articular cartilage); and because articular (hyaline) cartilage has no blood supply.
  • Load-bearing cartilages must have visoelastic properties manifested from its
  • ECM extracellular matrix
  • glycosaminoglycan 15-30%). This composition provides cartilage with compressive, tensile, and frictional properties (Huey et al., 2012). Attempts to reconstruct a cartilage ex vivo with various growth factors (such as fibroblast growth factor-18, TGF-beta) tend to produce a weak fibrocartilage since reconstructions occur under no load or mechanical stress. Mechanical and gravitational stimulation during in vitro reconstruction increases the percentage of
  • Osteoporosis is a bone disease that leads to an increased risk of bone fracture.
  • Osteoporosis a disease that results in over 1.5 million bone fractures a year. Most bone fractures involve lumber vertebrae (the lower back), hip, thigh and wrist. Osteoporosis affects 55% of Americans after age 50. Of these about 80% are women. Osteoporosis is the most common in women after menopause because reduced estrogen levels enhance osteoclast's bone resorption activities. Estrogen (as well as testosterone) also affects calcium absorption and bone mineralization. Osteoporosis is caused by imbalance between bone resorption and bone formation. Age-related bone loss is believed to parallel to the accumulation of adipose tissues in bone marrow.
  • the skeletal (muscle) system is in constant renewal. Newly-born babies renew almost all of their bones in the first year, while adults renew them at a rate of about 10% a year.
  • the remodeling process takes place in bone multicellular units. Bone is resorbed byosteoclast cells after which new bone is deposited by osteoblast cells. Excessive bone resorption and inadequate bone formation develops fragile bone tissue which leads to osteoporosis.
  • Bone remodeling is under hormonal control (estrogen, testosterone, thyroid hormone calcitonin, parathyroid hormone PTH); utilizes cytokines and growth hormones (TGF- beta, IGF-1) (Reddi 1997);and is affected by the calcium metabolism (skeletal bones are calcium storage sites), vitamin D, and steroids.
  • TGF- beta, IGF-1 cytokines and growth hormones
  • the body must maintain proper levels of calcium within the body.
  • Vitamin D becomes calcitriol (1,25-dihydroxyvitamin D), an active form of vitamin D, inside the body and helps calcium absorption.
  • Calcium metabolism is also influenced by the level of phosphate, magnesium, and vitamin K (menaquinone-7).
  • Osteoblasts (bone forming cells) are derived from mesenchymal stem cells while osteoclasts (bone resorpting cells) are derived from monocytes/macrophages. Osteoblasts and osteoclasts cross-talk and coordinate in bone remodeling. Osteoblasts produce RANKL
  • osteoclast differentiation factor RANKL binds to cell surface receptor RANK on osteoclasts and activates osteoclasts. Osteoclasts resorb tipped, cracked, or broken bones, and osteoblasts lay out new bones being helped by growth hormones BMPs and IGF-1. Osteoprotegrin (OPG) guards the skeleton from excessive bone resorption. OPG, by competitively binding to RANKL, down-regulates the activation of osteoclasts. Estrogen (or phytoestrogen) stimulates the production of OPG and down-regulates bone resorption as well as NF-kappaB.
  • OPG osteoprotegrin
  • Denosumab Prolia ® ; Amgen
  • RANKL overactive osteoclasts
  • PPAR-gamma peroxisome proliferator-activated receptor-gamma
  • PPAR-gamma is a nuclear hormone receptor transcription factor. PPAR-gamma plays an important role in the decision of bilateral differentiation of mesenchymal stem cells to adipocytes or osteoblasts/chondrocytes.
  • Natural ligands of the PPAR-gamma receptors are fatty acids such as lauric acid, petroselenic acid, linolenic acid, linoleinic acid, arachidonic acid, and fatty acid metabolites such as 15-deoxy-delta 12, 14-prostaglandin J2.
  • the synthetic ligands comprise the group of TZDs (Troglitazone, Rosiglitazone, Pioglitazone), the non-TZDs (GW1929, GW7845), and the nonsteroidal anti-inflammatory drugs (flufenamic acid, fenoprofen).
  • Anti-diabetes drugs TZDs agonize (activate) PPAR-gamma this reduces the secretion of unestrified fatty acids and adipokines TNF-alpha and other inflammatory cytokines resistin and plasminogen-activator inhibitor-1 (PAI-l);enhances the secretion of adiponectin; and regulates the glucose transporter protein GLUT-4 in the cell membrane.
  • PAI-l plasminogen-activator inhibitor-1
  • the net result of these changes is to reduce insulin resistance in muscle and liver and to mitigate prothrombotic and pro-inflammatory states.
  • the activation of PPAR- gamma with TZDs increases adipocytes in bone marrow and decreases osteoblasts, resulting in bone loss. Both pre- and post-menopausal women treated with TZDs are reported to have an increased risk of bone fracture (Grey 2008).
  • Isoflavones are widely distributed in the plant kingdom and over 700 different isoflavones are described.
  • the isoflavones which display estrogenic activity belong to a small sub-group and restricted almost exclusively to the Leguminosae family.
  • the best known estrogenic isoflavones are daidzein (PPAR-gamma inhibitor), genistein (tyrosine kinase inhibitor), glycitin, formononetin, and biochanin A, which are found most abundantly in soybean, lentil, Puerarialobata (kudzu), alfalfa, red clover, chickpeas,peanut and other beans.
  • isoflavones principally occur as water-soluble glycosides or molonates. Glycosylated or molonatedisoflavones are hardly absorbed by the digestive system in human. Glucosidase (of gastrointestinal microbes), fermentation, or hydrolysis converts glycosides to water-insoluble aglycones which are absorbed through lumens of the lower intestines and colons.
  • the root extract of perennial leguminous vine Puerarialobata contains coumarins, isoflavonoids (puerarin, daidzin, daidzein) and saponins (kudzusaponins).
  • Kudzu and its extracts have been used for many disorders such as fevers, gastrointestinal disorders, muscle aches, allergies, respiratory problems, skin problems, high blood pressure, migraine headache, lowering cholesterol, and treating alcoholism (Keung 1996).
  • Reppert et al (2008) prepared radiolabeled daidzein to monitor absorption, metabolic distribution, kinetics and accumulation of daidzein and its metabolites in various organs over time.
  • Phytochemicals and phytonutrients are a group of plant secondary metabolites with a diphenylpropane structure. They are widely distributed in the plant kingdom and are common constituents of fruits and vegetables such as: parsley, artichoke, basil, celery, grapefruit, blueberries, teas, citrus, wine, cacao, capers, apples, onions, ginkgobiloba, hypericumperforatum (St. Jogn's wart), lyciumbarbarum (goji berries), and morindacitrifolia (Indian mulberry).
  • Flavanoids also can positively influence the bone remodeling process as well as chondrogenesis. Quercetin, kaempferol, myricetin, and apigenin are a potent anti-inflammatory agent (Kim et al., 2004; Wang et al., 2006). These flavonoids inhibit NF-kappaB, down-regulate many pro-inflammatory responses, and relieve pain just like curcumin/turmeric described above.
  • Quercetin and kaempferol functioning as phytoestrogen, down-regulate activities of osteoclast cells just as isoflavones (genistein, daidzein); and as a PPAR-gamma inhibitor, inhibit adipogenesis and stimulate bone formation andchondrogenesis.
  • flavonoids are also known for their preventive activitiesin cancer, microbial infection, Alzheimer's disease and Parkinson disease.
  • Watanabe et al (Patent No. US 5,650,433 & Patent JP 07-025761) showed a number of synthetic flavonoids (apigenin, luteolin, acacetin, linarin, diosmetin, baicalein, fisetin, kaempferol, quercetin, hesperetin, hesperidin, etc.) were chondroprotective when cultured chondrocytes were challenged by the proteoglycan depleting agent, PMA (phorbolmyristate acetate).
  • PMA proteoglycan depleting agent
  • compositions containing apigenin not only prevented further cartilage destructions but also promoted the proliferation of chondrocytes and was capable of restoring artificially-damaged cartilage in rabbit.
  • the present invention extended these observations and demonstrated that kudzu extract
  • ginkgobiloba extract containingquercetin and kaempferol
  • curcumin inhibited PPAR-gamma
  • synergistically stimulate bone- formation &chondrogenesis and repaired cartilage in human.
  • proliferating chodrocytes might be newly derived from fibroblast-like cells on synovial membrane, synovial fluid MSCs, or bone marrow MSCs.
  • Apigenin, quercetin and kaempferol are a potent inhibitor of cytochrome P450 2C9 (CYC2C9) and may thus interfere with the actions of numerous drugs including cyclosporine.
  • Patent No. US 6,436,446 disclose compositions for increasing bone density, comprising isoflavone, inulin, oligosaccharide, calcium, and organic acid.
  • Patent No. US 6,638,540 discloses plant extracts of onions, parsley, cabbage, arugula or roquette to prevent increased bone resorption and treat osteoporosis.
  • Patent No. US 6,391,309 teaches
  • compositions comprising isoflavones, lignana, saponins, sapogenins, catechins, phenolic acids.
  • Patent No. US 6,340,703 discloses soy isoflavonesformononetin and daidzein.
  • Patent No. US 5,830,887 discloses genistin, diadzein, formononetin, and biochanin A.
  • Patent Application No. 20090304823 disclose compositions comprising rosemary extracts that promote bone growth and maintenance.
  • Patent No. US 8,242,100 Pan discloses compositions comprising isoflavones or isoflavone metabolites for inducing bone growth or inhibiting bone loss.
  • US 8,227,013 discloses nutritional supplements comprising fermented soy (HEALAN 951TM; Healan Products, Inc.), sweetener, and Curcumin C3 ComplexTM with Bioperine ® (Sabinsa Co.).
  • the nutritional supplements are intended for: antioxidant support, Alzheimer's disease support, cardiovascular support, immune support and supports for wound healing, arthritis, cancer, and antiviral effects.
  • Patent No. US 5,612,074 discloses nutrient fortified food bars containing proteins, fibers, polyunsaturated fatty acids, carbohydrates, flavones, minerals and others.
  • the adult skeleton contains about 1,200 gm of calcium, 99% of which is stored in the bones and teeth; the remaining 1% of calcium (10 - 12 gm) circulates in a soluble form within the body.
  • the role of calcium in maintaining strong bones and teeth is well known.
  • Calcitonin The parafollicular cells (C-cells) of the thyroid produce a small polypeptide hormone calcitonin. Calcitonin acts to reduce blood calcium, opposing the effects of parathyroid hormone (PTH), and protects against calcium loss from skeleton during the periods of calcium mobilization such as pregnancy and lactation. Calcitonin inhibits calcium absorption by the intestines and renal tubular cell's reabsorption of calcium and allowing calcium to be secreted in the urine. Calcitonin receptors are found on osteoclasts and calcitonin inhibits osteoclasts. Calcitonin also participates in phosphate metabolism. It inhibits phosphate reabsorption by the kidney tubules.
  • PTH parathyroid hormone
  • Parathyroid hormone boosts the level of calcium in the blood; if PTH is low, bone releases calcium into the bloodstream.
  • the hormone and vitamin B) enhances the absorption of calcium from the intestine and decreases the amount that is lost through urine.
  • Low circulating vitamin D which is common among the elderly, increases parathyroid hormone; this leads to bone resorption and bone loss.
  • Osteoporosis drugs Strontium ranelate (Ranelic acid) stimulates OPG production as estrogen.
  • Denosumab Prolia ® ; human monoclonal antibody; Amgen
  • This drug is used to treat osteoporosis, bone metastasis, rheumatoid arthritis, multiple myeloma and giant cell tumor of bone.
  • Raloxifene (Evista ® ; Eli Lilly) is a selective estrogen receptor modulator.
  • Biphosphates Feosamax ® , Boniva ® , Acetonel ® ) force osteoclasts to apoptosis.
  • TABLE 1 explains the timing when curcumin and/or kudzu extract (daidzin) was started being taken or stopped as indicated by the numbered arrows in Figure 1.
  • Theimprovement in the walking or jogging ability reflectscumulative improvements in the conditions and functions of bones and joints(at knee, hip, ankle, in particular). Curcumin orisoflavonesalone did not produce the observed improvement; and improvement was seen only curcumin and isoflavones were taken together. Curcumin and isoflavones (daidzin, in particular) work synergistically. Isoflavone (daidzin) appears towork dose-dependently.
  • Osteoarthritis products were made as follows. Kudzu extract (containing daidzin), or ginkgo biloba extract (containing quercetin, kaempferol) was subjected to acid hydrolysis to make them aglycons. To enhance bioavailability, isoflavone and flavonoid aglycons along with turmeric extract (curcumin) were mixed separately with gumghatti and ground using wet mill to make nanoparticles (size ⁇ 1 nm) according to Patent Application US 20120195949.
  • Product I contains turmeric extract (curcumin 30 mg) and kudzu extract (daidzein 30 mg).
  • Product II contains turmeric extract (curcumin 30 mg) and ginkgo biloba extract (flavonoids 30 mg).
  • Product III contains turmeric extract (30 mg curcumin), kudzu extract (daidzein 30 mg), and ginkgo biloba extract (flavonoids 30 mg). These products may be taken one to three times a day.
  • Eighty volunteers are recruited who have been at least 45 years of age and sufferfrom knee pain (with grade 2 or 3 osteoarthritis) for at least six months and on the majority of days.
  • Group A (20 people) are given product I;
  • Group B (20 people) Product II,
  • Group C (20 people) Product III, and
  • Group D (20 people) placebo, respectively, each twice a day. All are encouraged to do moderate exercise.
  • the primary outcome over the trial period of 12 weeks measure an increase in mobility as the distance or the speed patients can travel (walk or jog).
  • the secondoutcome measure changes in pain, stiffness, flexibility, jointfunctions, and swelling. Patient's equol-producer status is also determined.
  • a test is planned in which the effects of the products listed in [0077] on osteoarthritis are enhanced with systematic exercise or taking protein (amino acids).
  • Exercise stress
  • Amino acids are precursors for glucosamine and chondrotin sulfate, key structural components of cartilage.
  • Zhao G et al. Effects of solid dispersion and self-emulsifying formulations on the solubility, dissolution, permeability and pharmacokinetics of isorhamnetin, quercetin and kaempferol in total flavones of Hippophaerhamnoides L. Drug Devlnd Pharm 2013 Jul; 39(7): 1037-45.

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Abstract

L'invention concerne une composition pour le traitement de l'arthrose, comprenant un agent anti-inflammatoire et un agent qui améliore la formation osseuse et la chondrogenèse en combinaison. L'utilisation combinée de l'agent anti-inflammatoire et de l'agent qui améliore la formation osseuse et la chondrogenèse peut faciliter et inverser la progression de l'arthrose de façon synergique. Des exemples de l'agent anti-inflammatoire comprennent un inhibiteur de NF-kappaB qui est de la curcumine ou un extrait de curcuma. Des exemples de l'agent qui améliore la formation osseuse et la chondrogenèse comprennent un phytonutriment qui comprend un inhibiteur de PPAR-gamma et/ou de phyto-œstrogène. Le phytonutriment peut être choisi dans le groupe consistant en un extrait de soja, un extrait de kudzu, un extrait de ginkgo et un extrait de graines de céleri. L'inhibiteur de PPAR-gamma et/ou le phyto-œstrogène peut être choisi dans le groupe consistant en la génistéine, la daidzéine, la quercétine, le kaempférol et l'apigénine hautement absorbables.
PCT/US2014/021139 2013-03-06 2014-03-06 Composition et méthode de traitement de l'arthrose Ceased WO2014138372A1 (fr)

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RU2712027C2 (ru) * 2014-10-10 2020-01-27 Лиминал Байосайенсиз Лимитед Соединения фенилкетонкарбоксилата и фармацевтические композиции для предотвращения и лечения остеопороза
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RU2712027C2 (ru) * 2014-10-10 2020-01-27 Лиминал Байосайенсиз Лимитед Соединения фенилкетонкарбоксилата и фармацевтические композиции для предотвращения и лечения остеопороза
WO2019045677A1 (fr) * 2017-08-28 2019-03-07 Global Biolife Inc. Méthode et composition destinées à prévenir et à traiter des infections virales
JP2021500308A (ja) * 2017-08-28 2021-01-07 グローバル バイオライフ インコーポレーテッドＧｌｏｂａｌ Ｂｉｏｌｉｆｅ Ｉｎｃ． ウイルス感染を予防および治療するための方法および組成物
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US11311563B2 (en) 2017-08-28 2022-04-26 Global Biolife Inc. Method and composition for preventing and treating viral infections
JP7216714B2 (ja) 2017-08-28 2023-02-01 グローバル バイオライフ インコーポレーテッド ウイルス感染を予防および治療するための方法および組成物
CN114206330A (zh) * 2019-08-02 2022-03-18 三得利控股株式会社 软骨再生促进用组合物
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IT202100032921A1 (it) * 2021-12-29 2023-06-29 Mivell S R L S Composizione per il trattamento di osteopenia e osteoporosi
EP4205733A1 (fr) * 2021-12-29 2023-07-05 Mivell S.r.l.s. Composition pour le traitement de l'ostéopénie et de l'ostéoporose
CN114903961A (zh) * 2022-05-16 2022-08-16 大闽食品（漳州）有限公司 一种治疗骨关节病的组合物及其应用

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