WO2008139314A1 - Compositions et procédés de traitement de troubles articulaires - Google Patents

Compositions et procédés de traitement de troubles articulaires Download PDF

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WO2008139314A1
WO2008139314A1 PCT/IB2008/001182 IB2008001182W WO2008139314A1 WO 2008139314 A1 WO2008139314 A1 WO 2008139314A1 IB 2008001182 W IB2008001182 W IB 2008001182W WO 2008139314 A1 WO2008139314 A1 WO 2008139314A1
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composition
proanthocyanidins
proline
lysine
hydroxyproline
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PCT/IB2008/001182
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Peter Rohdewald
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Horphag Research (Luxembourg) Holding Sa
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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K36/13—Coniferophyta (gymnosperms)
    • A61K36/15—Pinaceae (Pine family), e.g. pine or cedar
    • 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)
    • A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
    • 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
    • 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)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • 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)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • 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)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • 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)
    • A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • 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

Definitions

  • the present invention relates to methods and compositions for treating joint disorders in vertebrates.
  • Arthritis is a collective term for a number of different conditions that cause pain, swelling and limited movement in joints and connective tissue throughout the body. The condition is usually chronic and progressive. The main symptoms of arthritis are joint pain, joint stiffness or inability to move a joint normally, and sometimes swelling that lasts more than two weeks. Most treatment programs include a combination of medication, exercise, rest, use of heat and cold, joint protection techniques, and sometimes surgery. The two most prevalent forms of arthritis are osteoarthritis (OA), and rheumatoid arthritis (RA).
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • Osteoarthritis (OA, also known as degenerative arthritis or degenerative joint disease, and sometimes referred to as “arthrosis” or “osteoarthrosis”) is a degenerative joint disease characterized by a breakdown of the joint's cartilage. Cartilage functions to cushion the ends of the bones at each joint. A breakdown of the cartilage causes the bones to rub against each other, causing pain and loss of movement. Osteoarthritis primarily affects hands and weight-bearing joints, such as the knee, hips, feet and back. Risk factors for osteoarthritis include advanced age, obesity, joint injury, and genetic disposition. Causes for osteoarthritis include an abnormal release of destructive enzymes from the cartilage cells themselves, and inherent defects in the way joints fit together.
  • Medications include aspirin, acetaminophen, ibuprofen and nonsteroidal anti-inflammatory drugs (hereinafter NSAEDs) for pain relief and inflammation reduction.
  • NSAEDs nonsteroidal anti-inflammatory drugs
  • Corticosteriod injection directly into affected joints in acute cases is also employed.
  • Other noninvasive techniques commonly used to control osteoarthritis include heat/cold treatment, exercise, joint protection and weight control.
  • Rheumatoid arthritis is an inflammatory disease having many components, including an autoimmune disorder aspect.
  • the autoimmune disorder aspect is generally characterized by inflammation of the membrane lining the joint resulting from an attack upon the joint by the body's own immune system.
  • the inflammation causes pain, stiffness, warmth, redness and swelling.
  • the inflamed joint lining, called the synovium can invade and damage surrounding bone and cartilage.
  • the involved joint can lose shape and alignment, resulting in pain, loss of movement and possible destruction of the joint.
  • Early symptoms of the disease include general fatigue, soreness, stiffness and aching. Pain usually occurs in the same joints on both sides of the body and will usually start in the hands or feet.
  • Rheumatoid arthritis can also affect wrists, elbows, shoulders, neck, knees, hips and ankles. Other symptoms include lumps, called rheumatoid nodules, under the skin in areas subjected to pressure, such as the back of elbows.
  • Conventional treatment of rheumatoid arthritis focuses on reducing swelling, relieving pain and stiffness, and maintaining normal joint function.
  • Medications include NSAIDs for controlling inflammation, joint pain, stiffness and swelling.
  • Disease-modifying drugs include low doses of prednisone, methotrexate, hydroxychloroquine, azulfidine, gold salt and cyclosporin, used alone or in combination. Some combination of exercise, rest, medication, joint protection, physical and occupational therapy, and surgery is also used to treat rheumatoid arthritis patients.
  • Synovial joints are the most common and most moveable type of joints in the body and are the joints most afflicted in arthritis sufferers. As with all other joints in the body, synovial joints achieve movement at the point of contact of the articulating bones by encasing the ends of the articulating bones with a cavity and the occupation of a fluid in that cavity which aids movement. The surfaces of the two articulating bones at the joint are covered in cartilage. The thickness of the cartilage varies with each joint, and sometimes may be of uneven thickness. Articular cartilage is multi- layered. A thin superficial layer provides a smooth surface for the two bones to slide against each other.
  • the synovium is a membrane that covers all the non-cartilaginous surfaces within the joint capsule. It secretes synovial fluid into the joint, which nourishes and lubricates the articular cartilage. The synovium is separated from the capsule by a layer of cellular tissue that contains blood vessels and nerves.
  • Synovial fluid is a thick, stringy fluid found in the cavities of synovial joints. With its egg-like consistency (synovial comes from Latin for "egg"), synovial fluid reduces friction between the articular cartilage and other tissues in joints to lubricate and cushion them during movement.
  • synovial membrane The inner membrane of synovial joints is called the synovial membrane, which secretes synovial fluid into the joint cavity.
  • This fluid forms a thin layer (approximately 50 micrometers) at the surface of cartilage, but also seeps into microcavities and irregularities in the articular cartilage surface, filling any empty space.
  • the fluid within articular cartilage effectively serves as a synovial fluid reserve.
  • weeping lubrication mechanically (so-called weeping lubrication) to maintain a layer of fluid on the cartilage surface.
  • hyaluronan a polymer of disaccharides composed of D-glucuronic acid and D-N-acetylglucosamine joined by alternating beta- 1,4 and beta- 1,3 glycosidic bonds.
  • Hyaluronan is synthesized by the synovial membrane and secreted into the joint cavity to increase the viscosity and elasticity of articular cartilages and to lubricate the surfaces between synovium and cartilage.
  • Synovial fluid also contains lubricin secreted by synovial cells. It is chiefly responsible for so-called boundary-layer lubrication, which reduces friction between opposing surfaces of cartilage. There is also some evidence that it helps regulate synovial cell growth.
  • MMP matrix metallproteinases
  • MMP plays an important part in the degradation of the joint matrix in many forms of arthritis.
  • a selected subgroup within MMP is formed, for example, by collagenases. Only collagenases are able to degrade native collagen, which exercises an important supporting function in the joints.
  • a large number of different inhibitors of MMPs and of collagenases are known (EP 0 606 046; WO94/28889; WO96/27583). Unfortunately, these inhibitors are known for causing substantial side effects, which are manifested as musculoskeletal pain or arthralgias.
  • glucosamine has been used for the treatment of osteoarthritis. It is thought that since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of joint cartilage, supplemental glucosamine may help to rebuild cartilage and treat arthritis. Glucosamine is often sold in combination with other supplements such as chondroitin sulfate and methylsulfonylmethane as being beneficial for arthritis sufferers.
  • glucosamine and chondroitin sulfates have several disadvantages.
  • Glucosamine and N-acetylglucosamine are currently produced by extraction and acid hydrolysis of chitin from shellfish waste.
  • Shellfish derived glucosamine could be limited by the amount of raw material available and the product potentially carries the risk of shellfish protein contamination and potential adverse reaction in people who are allergic to shellfish.
  • Another more significant concern has been that the extra glucosamine could contribute to diabetes by interfering with the normal regulation of the hexosamine biosynthesis pathway (Buse MG.
  • One aspect of the present invention provides methods for treating a joint disorder (e.g., joint inflammation or arthritis, including osteoarthritis and rheumatoid arthritis) in a patient, preferably a human patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a proteolytic enzyme inhibitor, preferably proanthocyanidins, lysine, and one or more components selected from proline, hydroxyproline, collagen, collagen derivatives (e.g., collagen hydrolysates) and combinations thereof.
  • a joint disorder e.g., joint inflammation or arthritis, including osteoarthritis and rheumatoid arthritis
  • a patient preferably a human patient
  • a therapeutically effective amount of a composition comprising a proteolytic enzyme inhibitor, preferably proanthocyanidins, lysine, and one or more components selected from proline, hydroxyproline, collagen, collagen derivatives (e.g., collagen hydrolysates) and combinations thereof.
  • the present invention provides compositions for treating or preventing a joint disorder (e.g., joint inflammation or arthritis, including osteoarthritis and rheumatoid arthritis) in a vertebrate, preferably a human, comprising a proteolytic enzyme inhibitor, preferably proanthocyanidins, lysine, and one or more components selected from proline, hydroxyproline, collagen, collagen derivatives (e.g., collagen hydrolysates) and combinations thereof.
  • a joint disorder e.g., joint inflammation or arthritis, including osteoarthritis and rheumatoid arthritis
  • a joint disorder e.g., joint inflammation or arthritis, including osteoarthritis and rheumatoid arthritis
  • a joint disorder e.g., joint inflammation or arthritis, including osteoarthritis and rheumatoid arthritis
  • a joint disorder e.g., joint inflammation or arthritis, including osteoarthritis and rheumatoid arthritis
  • a joint disorder e.g
  • the compositions do not contain any additional amino acids other than proline, hydroxyproline and lysine. In other embodiments of the invention, the compositions do not contain any additional amino acids other than proline and lysine. Further, some embodiments of the invention are directed to oral and topical compositions which contain only three active ingredients: (1) proanthocyanidins, preferably in the form of Pycnogenol ® , (2) proline and (3) lysine. It is contemplated that whenever appropriate, any embodiment of the present invention can be combined with one or more other embodiments of the present invention, even though the embodiments are described under different aspects of the present invention.
  • compositions of the present invention are orally administered compositions of protease inhibitors and amino acids which can serve as metabolic precursors for the therapy of joint and connective tissue disorders in vertebrates.
  • the components of these compositions act synergistically to promote the repair and maintenance of connective tissue and to reduce inflammation in these tissues so that the degradation process in the joint tissues, including in the synovial joint and synovial fluid, is halted and repair may be initiated. Further these compositions suppress the autoimmune response which creates the inflammatory response and which further degrades tissue in the affected area.
  • compositions for treating joint disorders in vertebrates comprise proanthocyanidins, proline/hydroxyproline and lysine - three ingredients that act synergistically to treat joint disorders, prevent degradation of joint tissue and to promote the natural repair of joint tissues.
  • Proanthocyanidins represent a group of plant polyphenols found in roots, barks and fruits with an astringent taste.
  • Proanthocyanidins include the subgroups of procyanidins, prodelphinidins and propelargonidins.
  • Proanthocyanidins are biopolymers composed of flavan subunits. Since the biopolymers are a mixture of different sizes comprising different amounts of subunits, the term is usually used in the plural form (proanthocyanidins) but it is also used in the singular form (proanthocyanidin).
  • Procyanidins are composed of catechin and epicatechin units, also called monomeric procyanidins.
  • Proanthocyanidins are homogeneous or heterogeneous polymers consisting of the monomer units catechin or epicatechin, which are connected either by 4-8 or 4-6 linkages, to the effect that a great number of proanthocyanidin isomers exist.
  • the procyanidin oligomers have a chain length of 2-12 monomer units.
  • Proanthocyanidins are extracted from plant material by conventional methods using solvents like water, ethanol or acetone or fluid carbon dioxide. The extracts are purified by solvent/solvent extraction, ultra filtration or chromatographic procedures. The purified extracts are concentrated by solvent evaporation, freeze drying or spray drying.
  • Proanthocyanidins may be derived from herbal sources or produced by synthesis. Common sources of proanthocyanidins can be found in vegetable extracts, as for example in extracts of the bark of the maritime pine, cones of cypresses, cocoa beans, and grape seeds. It follows that proanthocyanidins-rich extracts may be prepared from these materials.
  • the Pycnogenol ® food supplement contains approximately 70-80% (such as, for example, 70% to 75%) of proanthocyanidins and is a complex mixture of phenolic substances which includes other flavanols such as catechin, epicatechin and taxifolin.
  • Pycnogenol ® is the preferred protease inhibitor of the claimed invention because of the superior results obtained from Pycnogenol ® when used in our clinical studies. While we do not know the reasons for the superior results when using Pycnogenol ® , it is possible that the result is attributable to the unique combination (ratios) of proanthocyanidins, catechin and epicatechin in Pycnogenol ® .
  • Proanthocyanidins possess a multitude of interesting and useful biochemical and pharmacological qualities. In particular, they are well known for their protective effect against aging associated chronic diseases, such as atherosclerosis and related cardiovascular events such as stroke or heart infarction.
  • Pycnogenol ® pine bark extract has been shown to stimulate endothelial nitric oxide synthase and to induce vasodilation (Fitzpatrick, D. F., Bing, B., Rohdewald, P., 1998).
  • Pycnogenol ® food supplement contains taxifolin and a wide range of phenolic acids, e.g., free acids like p-hydroxybenzoic acid, protoacatechic acid, vanillic acid, caffeic acid and ferulic acid as well as glucosides and glucose esters.
  • phenolic acids e.g., free acids like p-hydroxybenzoic acid, protoacatechic acid, vanillic acid, caffeic acid and ferulic acid as well as glucosides and glucose esters.
  • Pycnogenol ® extracts containing proanthocyanidins, scavenge free radicals in vitro and in vivo.
  • MMPs matrix metal loproteases
  • proanthocyanidins function as a protease inhibitor to stabilize degrading joint tissue, including synovial joint tissue and synovial fluids. Proanthocyanidins achieve this function through a number of mechanisms.
  • proteolytic enzymes are an enzyme (e.g., protease) that breaks down non-living tissue.
  • protease an enzyme that breaks down non-living tissue.
  • These enzymes include, at least, collagenase, elastase, glycosidases, hyaluronidase, and ⁇ -glycuronidase. These enzymes are involved in the destruction of the main structural components of joint tissue such as: collagen, elastin, and hyaluronic acid (Facino, et al, Arzneischaria. 1994 May; 44(5):592-601).
  • the pine bark extract also inhibits in vitro the activation of NF- ⁇ B, the key element of inflammation.
  • Plasma taken from volunteers following intake of Pycnogenol ® inhibits significantly the activation of NF- ⁇ B in inflammatory cells ex vivo, blocking subsequent steps of the inflammatory reactions.
  • Cyclooxygenases initiate the production of pain-producing prostaglandins.
  • Plasma from human volunteers inhibits cyclooxygenases I and II following intake of Pycnogenol ® . The sum of these antiinflammatory effects suggests that this special pine bark extract could have a positive effect in reducing symptoms of mild to moderate osteoarthritis.
  • L-Proline is an amino acid that is essential for collagen synthesis.
  • Collagen contains about 9% proline (Pro).
  • Multiple prolines and/or hydroxyprolines in a row can create a polyproline helix, the predominant secondary structure in collagen.
  • the hydroxylation of proline (or other additions of electron-withdrawing substituents such as fluorine) increases the conformational stability of collagen significantly.
  • the hydroxylation of proline is a critical biochemical process for maintaining the connective tissue of higher organisms. Severe diseases such as scurvy can result from defects in this hydroxylation.
  • proline is an amino acid in many proteins
  • the proline of compositions of the present invention should preferably be in amino acid form (i.e., not part of a protein or a protein hydrolysate).
  • Proline, in amino acid form provides superior absorption when used topically or orally.
  • Lysine is an essential amino acid, which means that it is essential to human health but cannot be manufactured by the body. For this reason, lysine must be obtained from food.
  • Lysine appears to help the body absorb and conserve calcium and it also plays an important role in the formation of collagen, a substance important for bones and connective tissues including skin, tendon, and cartilage. Conversely, lysine deficiency negatively affects calcium absorption and cartilage formation, other symptoms of lysine deficiency include kidney stones, fatigue, nausea, dizziness, loss of appetite, agitation, bloodshot eyes, slow growth, anemia, and reproductive disorders.
  • lysine makes up only 3 or 4% of the total amino acid in collagen, it nevertheless serves an important function in the constitution of the cross-links between the molecules to build the fibrils and the fibers of collagen. Defects of lysine metabolism are responsible for heritable diseases of the connective tissue as types FV and IX of the Ehlers- Danlos syndrome, lathyrism, the Menkes kinky hair syndrome, Cutis-Laxa or the type II of osteogenesis imperfecta.
  • lysine is an amino acid in many proteins
  • the lysine of compositions of the present invention should preferably be in amino acid form (i.e., not part of a protein or a protein hydrolysate). Lysine, in amino acid form, provides superior absorption when used topically or orally.
  • compositions of the present invention are provided.
  • proanthocyanidins proline/hydroxyproline and lysine is superior to the direct use of chondroitin sulfate or glucosamine for a number of reasons.
  • chondroitin sulfate or glucosamine there is a high rate of allergic reactions when chondroitin sulfate or glucosamine is used, which causes undesirable immune reactions in a patients including redness, swelling, and discomfort.
  • Disadvantages of chondroitin sulfate and glucosamine are discussed in the background section of this application.
  • compositions of the invention present a number of advantages over the prior art including (1) the compositions are substantially free of glucosamine and thus are free from the side effects of glucosamine, (2) the compositions are substantially free of chondroitin sulfate or other products derived from shark cartilage.
  • the compositions do not contain any additional amino acids other than proline/hydroxyproline and lysine. It is our observation that compositions of the present invention are suitable for oral and/or topical administration when only two amino acids (lysine and proline — in either or both the hydroxylated or unhydroxylated forms) are added to proanthocyanidins.
  • some embodiments of the invention are directed to oral and topical compositions which contain only three active ingredients: (1) proanthocyanidins, preferably in the form of Pycnogenol ® , (2) proline and/or hydroxyproline and (3) lysine.
  • Some embodiments of the invention are directed to oral and topical compositions which contain only three active ingredients: (1) Pycnogenol ® , (2) proline and (3) lysine.
  • the dosages listed in this specification are for the average person of about 80 kg, such as between 50 to 100 kilograms. For patients weighing more or less than the foregoing, it may be necessary to adjust the dosage accordingly, as is well known to one of skill in the art.
  • an “effective” amount or a “therapeutically effective amount” of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect, e.g., reduction of a symptom associated with a joint disorder.
  • An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • extract includes any preparation obtained from plants, fruits or vegetables using an extraction method.
  • One aspect of the present invention is a method for treating a joint disorder in a patient, preferably a human patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a proteolytic enzyme inhibitor, lysine and one or more components selected from proline, hydroxyproline, collagen, collagen derivatives, such as collagen hydrolysates, or combinations thereof.
  • a composition comprising a proteolytic enzyme inhibitor, lysine and one or more components selected from proline, hydroxyproline, collagen, collagen derivatives, such as collagen hydrolysates, or combinations thereof.
  • examples of the joint disorder include, but is not limited to, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, ankylosing spondylitis, Sjogren's syndrome and osteoporosis.
  • the joint disorder is joint inflammation.
  • the joint disorder is arthritis, such as osteoarthritis or rheumatoid arthritis.
  • the degradation of synovial joint proteins is diminished.
  • the therapeutically effective amount of the composition is administered orally.
  • the proteolytic enzyme inhibitor inhibits the action of a proteolytic enzyme selected from the group consisting of collagenase, elastase, glycosidases, hyaluronidase, ⁇ -glucuronidase and combinations thereof.
  • a proteolytic enzyme selected from the group consisting of collagenase, elastase, glycosidases, hyaluronidase, ⁇ -glucuronidase and combinations thereof.
  • the one or more components selected from proline, hydroxyproline, collagen, collagen derivatives is selected from proline, hydroxyproline and combinations thereof.
  • the proteolytic enzyme inhibitor comprises proanthocyanidins.
  • the proanthocyanidins are an extract from a plant material or are synthesized.
  • the plant material is selected from the group consisting of grape seeds, grape skin, cinnamon bark, cypress cones, pine barks, ginkgo leaves, cocoa beans, tamarind, tomato, peanut, almond, apple, cranberry, blueberry and tea leaves.
  • the proanthocyanidins are from a pine bark extract, e.g., a pine bark extract from a pine of the P inus pinaster species.
  • about 20 mg to about 10 grams per day of proanthocyanidins are administered. In some preferred embodiments, about 50 mg to about 500 milligrams per day of proanthocyanidins are administered. According to some embodiments of this method, about 12 mg/kg/day to about 9 g/kg/day of lysine is administered. According to some embodiments of this method, about 12 mg/kg/day to about 9 g/kg/day of proline and/or hydroxyproline is administered.
  • the therapeutically effective amount of the composition is substantially free of glycosaminoglycans. According to some embodiments of this method, the therapeutically effective amount of the composition is substantially free of chondroitin sulfate and/or glucosamine.
  • the therapeutically effective amount of the composition consists essentially of a proteolytic enzyme inhibitor, lysine and either or both of proline and hydroxyproline. According to some embodiments of this method, the therapeutically effective amount of the composition consists essentially of proanthocyanidins, proline/hydroxyproline and lysine. According to some embodiments of this method, the therapeutically effective amount of the composition is administered in the absence of glycosaminoglycans. According to some embodiments of this method, the therapeutically effective amount of the composition is administered in the absence of chondroitin sulfate and/or glucosamine.
  • compositions for treating or preventing a joint disorder in a vertebrate comprising a proteolytic enzyme inhibitor, lysine and one or more components selected from proline, hydroxyproline, collagen, collagen derivatives, such as collagen hydrolysates, or combinations thereof.
  • this composition is for oral administration.
  • this composition diminishes the degradation of synovial joint proteins.
  • the composition is for a joint disorder that includes, but is not limited to, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, ankylosing spondylitis, Sjogren's syndrome and osteoporosis.
  • the joint disorder is joint inflammation.
  • the joint disorder is arthritis, such as osteoarthritis or rheumatoid arthritis.
  • the proteolytic enzyme inhibitor of this composition inhibits the action of a proteolytic enzyme selected from the group consisting of collagenase, elastase, glycosidases, hyaluronidase, ⁇ -glucuronidase and combinations thereof.
  • a proteolytic enzyme selected from the group consisting of collagenase, elastase, glycosidases, hyaluronidase, ⁇ -glucuronidase and combinations thereof.
  • the one or more components selected from proline, hydroxyproline, collagen, collagen derivatives is selected from proline, hydroxyproline and combinations thereof.
  • the proteolytic enzyme inhibitor of this composition comprises proanthocyanidins.
  • the proanthocyanidins are an extract from a plant material or are synthesized.
  • the plant material is selected from the group consisting of grape seeds, grape skin, cinnamon bark, cypress cones, pine barks, ginkgo leaves, cocoa beans, tamarind, tomato, peanut, almond, apple, cranberry, blueberry and tea leaves.
  • the proanthocyanidins are from a pine bark extract, e.g., a pine bark extract from a pine of the P inus pinaster species.
  • a unit dosage of this composition contains about 20 mg to about 10 grams of proanthocyanidins. In some preferred embodiments, a unit dosage of this composition contains about 50 mg to about 500 milligrams of proanthocyanidins. According to some embodiments, a unit dosage of this composition contains about 12 milligrams to about 9 grams of lysine. According to some embodiments, a unit dosage of this composition contains about 12 milligrams to about 9 grams of proline and/or hydroxyproline. According to some embodiments, this composition is a unit dosage for consumption for a person of between 40 to 100 kg weight.
  • this composition contains between 1% proanthocyanidins to 80% proanthocyanidins by weight. According to some embodiments, this composition contains between 1% to 50% proline and/or hydroxyproline by weight. According to some embodiments, this composition contains between 1% lysine to 50% lysine by weight. In some preferred embodiments, this composition contains between 50% to 80% proanthocyanidins by weight, between 1% proline and/or hydroxyproline to 25% proline and/or hydroxyproline by weight, and between 1% lysine to 25% lysine by weight. According to some embodiments, the composition is substantially free of glycosaminoglycans.
  • the composition is substantially free of chondroitin sulfate and/or glucosamine.
  • the composition consists essentially of proanthocyanidins, lysine and either or both of proline and hydroxyproline.
  • the composition consists essentially of proanthocyanidins, proline and lysine.
  • the WOMAC osteoarthritis Index composite score measured no statistically significant difference between the placebo and Pycnogenol+Lys/Pro supplemented groups prior to and after 1 month of treatment based upon self-reported pain, stiffness, and physical function (Table 1). Significant reductions in self-reported pain, physical function and WOMAC composite scores occurred in the Pycnogenol+Lys/Pro treated group after 2 months of supplementation compared to patients treated with placebo (Table 1).
  • proanthocyanidins and lysine and proline administered as the only active ingredients, are able to induce a beneficial effect on patients suffering from osteoarthritis.
  • proanthocyanidins had significant activity in lowering nitric oxide production by activated macrophages (Virgili F et al.; 1998. In: Flavonoids in health and disease. Rice- Evans CA, Packer LM, eds. Marcel Dekker: New York. 421-36.), resulting from inhibition of NF- ⁇ B controlled inducible nitric oxide synthetase (iNOS) expression and demonstrated to lower generation of peroxides from activated macrophages ("oxidative burst").
  • iNOS NF- ⁇ B controlled inducible nitric oxide synthetase
  • Nitric oxide is a major catabolic factor produced by chondrocytes in response to proinflammatory cytokines (Pelletier J.P., Arthritis Rheum, 2001, 44: 1237-47). Overproduction of nitric oxide by chondrocytes plays a major role in the perpetuation of cartilage destruction in osteoarthritis (Pelletier J.P. et al., Osteoarthritis Cartilage, 1996, 4: 77-84; Grabowski P. S., et al., Br. J. Rheumatol, 1997, 36: 651-55).
  • Osteoarthritic chondrocytes release matrix metalloproteinases (MMP) which promote cleavage of articular collagen and gelatin. Excessive MMP expression exacerbates articular connective tissue and cartilage degradation and plays a critical role in the development of inflammatory joint disease.
  • MMP matrix metalloproteinases
  • a broad spectrum of MMP species are expressed in osteoarthritic cartilage and these contribute significantly to tissue damage, pain and stiffness (Sholpov B. V. et al., Arthritis Rheum, 40: 2065-74; Imai K. et al., Am J Pathol, 1997, 151 : 245-56; Mohtai M. et al., Lab Invest, 1992, 66: 680-90; Ohta S. et al., Lab Invest, 1998, 78 :79-87; Mitchell P.G. et al., J Clin Invest, 1996, 97: 761-68).
  • proanthocyanidin metabolites were as potent as hydrocortisone for inhibition of MMP-9 released from activated macrophages.
  • the pronounced MMP inhibitory activity of proanthocyanidin and its metabolites should provide significant help for allowing recovery of articular tissue. From our experiments it was striking that all clinical symptoms improved gradually during the three months treatment course. It may be speculated that anti-inflammatory and MMP-inhibitory activity of proanthocyanidins allowed for progressive articular tissue recovery which resulted in significant symptom improvement only after 2 of months treatment.

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Abstract

L'invention concerne des procédés et des compositions pour le traitement d'un trouble articulaire, en particulier chez l'homme. En particulier, l'invention concerne des compositions qui contiennent un inhibiteur d'enzyme protéolytique, de préférence des proanthocyanidines, de la lysine et une ou plusieurs parmi la proline, l'hydroxyproline, le collagène et des dérivés du collagène. Les compositions sont utiles pour traiter un trouble articulaire, tel qu'une inflammation articulaire ou une arthrite, dont l'ostéoarthrite et la polyarthrite rhumatoïde.
PCT/IB2008/001182 2007-05-11 2008-05-12 Compositions et procédés de traitement de troubles articulaires WO2008139314A1 (fr)

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JP2012206983A (ja) * 2011-03-30 2012-10-25 Kao Corp アグリカン分解抑制剤
JP2016185941A (ja) * 2015-03-27 2016-10-27 株式会社東洋新薬 松樹皮抽出物含有組成物
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012206983A (ja) * 2011-03-30 2012-10-25 Kao Corp アグリカン分解抑制剤
JP2016185941A (ja) * 2015-03-27 2016-10-27 株式会社東洋新薬 松樹皮抽出物含有組成物
US20200030349A1 (en) * 2017-03-28 2020-01-30 Natural Products & Drugs Gmbh Physiologically active preparation comprising n-acetyl-glucosamine for the treatment of back pain

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