WO2003082310A1 - Composition et methodes permettant le traitement ou la prevention des troubles induits par il1 - Google Patents

Composition et methodes permettant le traitement ou la prevention des troubles induits par il1 Download PDF

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Publication number
WO2003082310A1
WO2003082310A1 PCT/NL2003/000250 NL0300250W WO03082310A1 WO 2003082310 A1 WO2003082310 A1 WO 2003082310A1 NL 0300250 W NL0300250 W NL 0300250W WO 03082310 A1 WO03082310 A1 WO 03082310A1
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Prior art keywords
celery
isolate
unsaponifiables
vegetable oil
composition
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PCT/NL2003/000250
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English (en)
Inventor
Hobbe Friso Smit
Yvo Maria Franciscus Graus
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General Nutrition Investment Company
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Priority to AU2003225430A priority Critical patent/AU2003225430A1/en
Publication of WO2003082310A1 publication Critical patent/WO2003082310A1/fr

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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)
    • A61K36/185—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)
    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • 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

  • This invention relates to compositions that contain a celery material.
  • the present composition is particularly suitable for use in a method for the prophylactic and/or curative treatment of interleukin-l mediated diseases, in particular for the treatment or prevention of damage to the connective tissue and for reducing inflammation and inflammation associated complaints.
  • Inflammatory conditions of a joint are chronic joint diseases that afflict and disable, to varying degrees, millions of people worldwide. Arthritis is one of the most common disabling diseases. It has been estimated that about 10 percent of the Western population suffers from one or many forms of arthritis.
  • Rheumatoid arthritis is a disease of articular joints in which the cartilage and bone are slowly eroded away by a proliferative, invasive connective tissue called pannus, which is derived from the synovial membrane.
  • Subjects suffering from rheumatoid arthritis often have insufficient or abnormal cartilage in the joints due to a chronic inflammation reaction.
  • Osteoarthritis is a common joint disease characterized by degenerative changes in articular cartilage and reactive proliferation of bone and cartilage called osteophytes.
  • Degenerative changes in joint cartilage are for example caused by reduced synthesis of matrix molecules and increased degradation of articular cartilage. In order to counteract these phenomena it is essential that the cartilage formation is stimulated.
  • Most arthritic complaints relate to decreased mobility, pain, stiffness that develops during sleep and other discomforts due to insufficient cartilage in the joints.
  • interleukin-l The involvement of interleukin-l in arthritis has been implicated by two distinct lines of evidence.
  • IL-1 interleukin-l
  • IL-1 interleukin-l
  • IL-1 the interleukin-l
  • IL-1 causes proteoglycan loss, which can prevent proper maintenance of the cartilage.
  • IL-1 has been shown to inhibit collagen synthesis, which prevents proper matrix formation with collagen and makes the cartilage matrix vulnerable to more damage.
  • IL -1 stimulates production of inflammatory components which have adverse effects on the integrity of the joint, such as prostaglandin E2 (PGE2), nitric oxide (NO), matrix metalloproteases (MMPs), and cyclooxygenase-2 (COX-2).
  • PGE2 prostaglandin E2
  • NO nitric oxide
  • MMPs matrix metalloproteases
  • COX-2 cyclooxygenase-2
  • NSAIDs non-steroidal anti-inflammatory drugs
  • most of the currently available methods solely treat or prevent the symptoms of the arthritic complaints, such as joint swelling and pain.
  • drugs used today have side effects, e.g. gastrointestinal complaints.
  • herbal preparations mostly have limited side effects.
  • medicinal compositions containing herbal preparations often provide only a limited medicinal effect.
  • research directed towards the unraveling of the effects of the herbal preparations on the disease specific mechanism is extremely cumbersome.
  • Celery extract has been reported to have an anti-inflammatory effect.
  • EP708651 describes a therapeutic agent containing celery seed concentrate for the treatment of inflammatory complaints.
  • celery seed extract is often combined with other components in the hope to improve its effects.
  • WO0040258 describes the combined use of biologically active extracts of celery seed and non-steroidal anti-inflammatory drugs (NSAIDS) for the treatment and prevention of acute and chronic pain, inflammation and gastrointestinal irritation.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • US5916565 describes a composition for the treatment of arthritis, joint stiffness, joint mobility and joint pain in vertebrates, consisting essentially of a palatability agent (e.g. hydrogenated vegetable oils), cayenne, ginger, turmeric, yucca, Devils Claw, nettle leaf, Black Cohosh, alfalfa, celery seeds, D-glucosamine HC1 and mucopolysacchrides.
  • a palatability agent e.g. hydrogenated vegetable oils
  • CN1212128 describes a vegetable oil composition for eliminating bad breath.
  • the oil mixture comprises celery seed oil, sunflower seed oil and peppermint camphor.
  • Joint & Ligament Support FormulaTM includes Curcumin (Curcuma longa), Boswellia serrata, Bromelain, Cat's Claw's Root (Uncaria tomentosa), Ginger ( Zingiber officinale), Devil's Claw (Harpagophytum procumbens), Ascorbic acid, Methyl-sulfonyl-methane, Magnesium (citrate), Green Lipped Mussel (Perna canaliculus), Celery Seed extract (Apii/rMctu.?
  • Interleukin-l is one of the most potent inflammatory cytokines yet discovered and a cytokine, which is thought to be a key mediator in many diseases and medical conditions, termed "interleukin-l mediated diseases".
  • a disease or medical condition is considered to be an "interleukin-l mediated disorder” if the disease or medical condition is associated with elevated levels of IL-1 in bodily fluids or tissue or if cells or tissues taken from the body of a patient suffering from the disease or medical condition, produce elevated levels of IL-1 in culture.
  • the present inventors have surprisingly found that celery material is capable of mildly reducing IL-1 release in lipopolysaccharide (LPS) activated human peripheral blood monocytes (hPBMC). This result indicates that celery material can be used by mammals for reduction of IL-1 release in vivo. However, since celery material was found to be only capable of mildly reducing IL-1 release, these results show that additional agents are needed to enhance the IL-1 inhibitory effect of celery material.
  • LPS lipopolysaccharide
  • hPBMC human peripheral blood monocytes
  • the present invention provides novel compositions, comprising celery material and an isolate from vegetable oil enriched in unsaponifiables.
  • the combination of celery material and an isolate from vegetable oil enriched in unsaponifiables produces a synergistic effect, which can be explained from the individual actions of these compositions on the effects of IL- 1.
  • Celery material mildly inhibits the release of IL- 1
  • an isolate from vegetable oil enriched in unsaponifiables decreases the deleterious effects of IL-1 on synoviocytes and chondrocytes.
  • Deleterious effects of IL-1 on synoviocytes and chondrocytes include for example, reduction of proteoglycan synthesis (Mauviel, A. et al. 1991, Rev. Phum. Mai.
  • the present invention provides a method for the treatment or prevention of IL-1 mediated disorders, preferably a method for the repair, treatment or prevention of connective tissue damage, said method comprising the enteral, topical or transdermal administration of celery material and an isolate from vegetable oil enriched in unsaponifiables.
  • Unsaponifiable fractions of vegetable oil have been described to stimulate chondrocyte expression of transforming growth factor (TGF) beta 1, beta 2 and plasminogen activator inhibitor 1. (Boumediene K., 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)).
  • TGF transforming growth factor
  • the present invention provides a composition suitable for use in a method for the treatment or prevention of IL-1 mediated diseases, particularly the repair, treatment and prevention of damage to the connective tissue, the composition comprising celery material and an isolate from vegetable oil enriched in unsaponifiables.
  • the celery (Apium graveolens) material used in the present invention can be obtained from a variety of celery species, however is preferably obtained from one or more species selected from the group of A. graveolens var. dulce, A. graveolens var. rapaceum, A. graveolens var. graveolens and A. graveolens var. secalinum, more preferably the celery material is obtained from A. graveolens var. graveolens.
  • the celery material can be obtained from whole plants or from one or more parts thereof, for example stems, stalks, roots, shoots, rhizomes, tubers, fruits, foliage, kernels, husks, hulls, seeds or mixtures thereof. According to a preferred embodiment the celery material is obtained from the seeds of celery.
  • the celery material is a celery isolate.
  • the term "isolate" as referred to in here preferably encompasses any fraction that can be obtained from a plant material by means of isolation techniques known in the art, e.g. extraction, distillation, squeezing etc. and that displays the desired functional properties described herein before.
  • the celery isolate is preferably prepared by subjecting the celery plant or part thereof to one or more isolation processes selected from the group of solvent extraction, cold pressing, hot pressing, distillation, chromatography and filtering.
  • the celery isolate is suitably prepared using steam distillation, solvent extraction or essential oil distillation.
  • the celery material is preferably provided in the form of a celery extract.
  • extract refers to an isolate that has been obtained by means of solvent extraction.
  • the celery extract is preferably prepared by the following procedure:
  • Reduction of the celery material can be achieved by a variety of methods of commuting well known in the art, including crushing or grinding in a mill.
  • the celery particular matter is contacted with a suitable solvent.
  • the solvent is capable of solubilising the lipophilic components present in celery.
  • Preferred solvents include acetone, ethanol, chloroform, hexane, mixtures thereof and mixtures of any one of the previous mentioned solvents with water.
  • solvents used in supercritical extraction processes such as carbondioxide and nitrogen.
  • celery particulate matter is suspended in 80 - 100% ethanol, or a solvent used in supercritical extraction procedure. Suitable methods for the preparations of supercritical fluid celery extracts are given in WO0040258, the entire content of which is hereby incorporated by reference.
  • the weight ratio solvent to celery particulate matter is preferably between 0.1 and 100, more preferably between 1 and 50, even more preferably between 2 and 25.
  • the celery particulate matter is preferably suspended in the solvent for a sufficiently long time to extract soluble components therefrom, preferably for at least 5 minutes.
  • the suspension of the solvent and particulate matter may for example be subjected to agitation.
  • the non-dissolved particulate matter is removed from the suspension, for example by centrifugation or filtration.
  • the extract may, for example, be filtered with one or more filters having a pore size between 0.2-10 microns.
  • the liquid phase is concentrated by removal of a part or all of the solvent. According to a preferred embodiment, at least 95% of the solvent is removed from the preparation.
  • the solvent may for example be removed through distillation and/or by applying heat or vacuum.
  • the concentration ratio of the celery extract used in accordance with the present invention is preferably 0.002 and 0.6, more preferably between 0.01 and 0.25, even more preferably between 0.013 and 0.2, especially between 0.02 and 0.1.
  • the celery isolate preferably contains phthalides.
  • the amount of phthalides in the isolate exceeds 4%, more preferably 7%, even more preferably 10% by weight of dry matter.
  • celery isolate may consist essentially of phthalides, preferably the content of phthalides does not exceed 60 % by weight of dry matter, more preferably is below 40% by weight of dry matter.
  • the celery isolate comprises at least 0.5%, preferably at least 1% by weight of dry celery isolate of at least three phthalides selected form the group of butylphthalides3-n-butyl, phthalide3- n-butylidenephthalide, 3-iso-butylidene phthalide, 3-n-butyl-4,5-dihydrophthalide (also referred to as sedanenolide or senkyunolide), 3-n-butylidene-4,5-dihydrophthalide (also referred to as ligustilide), 3-isobutylidene-3a, 4-dihydrophthalide, 3-isoval(er)idene phthalide, 3-isoval(er)idene-3a,4-dihydrophthalide, sedanolide and sedanonic anhydride.
  • phthalides selected form the group of butylphthalides3-n-butyl, phthalide3- n-butylidenephthalide, 3-iso-butylidene
  • the celery isolate preferably contains terpenes, which may include monoterpenes and sesquiterpenes.
  • terpenes which may include monoterpenes and sesquiterpenes.
  • the amount of terpenes in the isolate exceeds 2%, more preferably exceeds 4%, even more preferably exceeds 5% by weight of dry matter.
  • celery isolate may comprises high weight percentages of terpenes, preferably the content of terpenes does not exceed 90%, more preferably it is below 50 % by weight of dry matter.
  • the celery isolate comprises at least 0.5 % by weight of dry matter of at least three terpenes selected from the group consisting of the monoterpenes beta-caryophyllene, p-cymene, D-carvone, caryophyllene oxide, beta-elemene, limonene, limonen-oxide, linalool, myrcene, alpha-pinene, beta-pinene and the sesquiterpenes alpha-selinene and beta-selinene.
  • the celery isolate preferably contains coumarins.
  • the amount of coumarins in the isolate exceeds 0.2 %, more preferably 1 %, even more preferably 3 % by weight of dry matter.
  • the celery isolate comprises at least 0.1%), preferably at least 0.5% by weight of dry matter of at least two coumarins selected form the group of nodakenetin, rutaretin, celereoin and celerin.
  • a celery material is used which significantly reduces IL-1 production in hPBMC.
  • the celery isolate is capable of reducing the IL-1 production of LPS activated hPBMC by 50% at a concentration of below 12.5 ⁇ g dry celery material/ml, even more preferably at a concentration below 10 ⁇ g/ml, most preferably at a concentration below 5 ⁇ g/ml.
  • the inhibition of IL-1 production in LPS activated hPBMC by celery isolate can be determined according to the method as given in example 1.
  • a suitable celery material showing an inhibition of IL-1 production in LPS activated hPBMC of 50%) at a concentration of below 5 ⁇ g/ml can be obtained by extracting celery seed with wate ⁇ ethanol mixture (weight ratio 2:98), wherein the weight ratio celery seed to dry celery seed extract is about 16. Dosages of celery material
  • the celery material needs to be administered in a sufficient quantity to inhibit the release of IL-1 in vivo.
  • Celery material is preferably administered in a daily amount between 0.5 and 250 mg, based on dry weight, of celery material per kg body weight. More preferably, a daily dosage comprises an amount between 1 and 150 mg, even more preferably between 1.5 and 100 mg, most preferably between 2 and 25 mg, based on dry weight, of celery material per kg of body weight.
  • a daily dose of the composition according to the invention preferably provides an amount between 25 mg and 3 g, more preferably between 50 mg and 2 g, even more preferably between 100 mg and 1.5 g, based on dry weight, of celery seed isolate on a daily basis.
  • the present invention provides a discrete dosage unit containing celery material and unsaponifiables from vegetable oil.
  • the term "discrete dosage unit” refers to a dosage unit suitable for unitary administration to human subjects and other mammals, and wherein the unit contains a predetermined quantity of the present active principles and optionally, a pharmaceutically acceptable carrier.
  • the discrete dosage unit according to the invention may. for example, comprise one or more tablets that are to be administered together, i.e. within a brief time interval (e.g. of less 15 minutes, more particularly of less than 5 minutes).
  • the dosage unit is an enteral dosage unit, more preferably a solid or semi-solid dosage unit.
  • the dosage unit is designed for oral administration.
  • the discrete unit dosage preferably contains between 10 mg and 4 g, more preferably between 50 mg and 1 gram, even more preferably between 100 mg and 750 mg celery seed material, preferably celery isolate, even more preferably celery seed isolate.
  • Unsaponifiable fraction of vegetable oil is a measure of the proportion of vegetable lipid material which does not react with alkali to form soap.
  • the unsaponifiables employed in the present invention are non- volatile at 100°C to 105°C.
  • the unsaponifiable matter content of vegetable oil enriched in unsaponifiables can be suitably determined according to the method described in "European Pharmacopoeia - Supplement 2001 (page 56).
  • the unsaponifiable organic materials may include sterols, tocopherols, carotenoids, higher aliphatic hydrocarbons, squalene and lipidic furans.
  • the vegetable oil enriched in unsaponifiables comprises a mixture of at least 3 of the aforementioned components. Even more preferably the vegetable oil enriched in unsaponifiables is enriched in at least three of the aforementioned components when compared to the crude, unfiltered vegetable oil from which it is obtained.
  • the unsaponifiable matter content is usually expressed as a percentage of the total sample. Compositions from vegetable oil enriched in unsaponifiables have an increased percentage of unsaponifiable matter compared to the filtered crude oil.
  • Vegetable oil generally contains below 3.5 % unsaponifiables, e.g.
  • soy oil contains 0.7 % unsaponifiables and avocado oil contains 3 % unsaponifiables (Thiers, M. H., 1972 J. Med. Lyon 53 (222): 195-8).
  • Suitable methods for the isolation of unsaponifiables from vegetable oil are well known to the art and have been already been described in the 1960's. Suitable methods are for example described in GB1142804, WO0151596 and WOO 170046, which are herein incorporated by reference.
  • the isolate from vegetable oil enriched in unsaponifiables comprises at least 10 wt.% unsaponifiables based on the total weight of the vegetable oil isolate, more preferably at least 25 wt.%>, more preferably at least 50 wt.%, even more preferably at least 90 wt.%.
  • the content of unsaponifiables in the vegetable oil enriched therein preferably is below 100 wt.%, more preferably below 98 wt.%, even more preferably below 95 wt.%.
  • the present composition preferably contains between 1 and 99 wt.%, more preferably between 2 and 75 wt.%, even more preferably between 5 and 50 wt.%, most preferably between 10 and 50 wt.% unsaponifiables based on the total dry weight of the composition. Sources of unsaponifiables
  • the isolate from vegetable oil enriched in unsaponifiables is obtained from a vegetable oil selected from the group consisting of avocado oil, soy oil, palm oil, corn germ oil, sunflower oil, canola oil and mixtures thereof. More preferably the unsaponifiables of avocado oil, soy oil or a mixture of these unsaponifiables are used, even more preferably the unsaponifiables of avocado oil are used, most preferably a mixture of unsaponifiables from soy oil and avocado oil is used.
  • the weight ratio soy oil unsaponifiables to avocado oil unsaponifiables is preferably between 1:10 and 10:1, more preferably between 5:1 and 1:1.
  • the vegetable oil enriched in unsaponifiable matter needs to be administered in an amount sufficient to decrease the effects of IL-1 in vivo.
  • the isolate from vegetable oil enriched in unsaponifiables is administered in a daily amount equivalent to between 0.1 and 250 mg unsaponifiables per kg body weight on a daily base. More preferably, a daily dosage comprises an amount between 0.5 and 150 mg, even more preferably between 1 and 100 mg, most preferably between 2 and 25 mg unsaponifiables per kg of body weight.
  • a daily dose of the composition according to the present invention preferably contains between 10 and 5000 mg, more preferably between 50 and 4000mg, even more preferably between 200 and 2000 mg unsaponifiables from vegetable oil.
  • the unsaponifiables are provided by oil enriched in unsaponifiables from vegetable oil.
  • the aforementioned discrete unit dosage preferably contains between 10 and 2500 mg, more preferably between 50 and 1000 mg, even more preferably between 100 mg and 1000 mg unsaponifiables from vegetable oil, preferably unsaponifiables from avocado oil.
  • the unsaponifiables from vegetable oil used in the discrete unit dosage is a mixture of at least 3, preferably at least 4 unsaponifiables. More preferably it is a mixture of at least 3, more preferably at least 4 unsaponifiables selected from the group consisting of sterols, tocopherols, carotenoids, higher aliphatic hydrocarbons, squalene and lipidic furans
  • Further components may be coadministered in the method according to the present invention.
  • these components contribute to the repair, treatment and/or prevention of connective tissue damage.
  • these components are selected from the group consisting of glucosamine, chondroitin, collagen type II, S- adenosylmethionine, methylsulfonylmethane (MSM), hydroxyproline and mixtures thereof, more preferably form the group consisting of glucosamine and chondroitin.
  • Glucosamine is a building block for glycosaminoglycans in cartilage and other connective tissue. When supplied exogenously, glucosamine stimulates connective tissue repair and synthesis.
  • Glucosamine can thus be used advantageously in the present method, i.e. both celery and the composition enriched in unsaponifiable matter from vegetable oil reduce the effects caused by IL-1, while glucosamine provides the building blocks for the repair and/or maintenance of a healthy cartilage.
  • the composition used in the present method can thus be advantageously combined with glucosamine, which can have a synergistic effect on the repair, treatment or prevention of connective tissue damage.
  • Glucosamine and/or salts thereof are preferably administered in an amount equivalent to between 1 and 100 mg glucosamine per kg body weight on a daily basis, even more preferably in an amount equivalent to between 2 and 25 mg glucosamine.
  • Chondroitine similar to glucosamine, also provides building blocks for the in vivo production of cartilage and/or other connective tissue.
  • the composition used in the present method can advantageously be combined with chondroitine, which is deemed to have a synergistic effect on the treatment or prevention of connective tissue damage.
  • Chondroitine and/or a salt thereof is preferably administered in a daily amount equivalent to between 1 and 100 mg chondroitine per kg body weight , even more preferably in an amount equivalent to between 2 and 25 mg chondroitine per kg body weight.
  • the present composition includes glucosamine and chondroitine, making use of the synergistic effects provided by the combination of glucosamine and chondroitine.
  • the composition may be administered enterally, topically or transdermally, however is preferably administered enterally in the form of an edible composition, more preferably in the form of a pharmaceutical composition or a nutritional supplement.
  • pharmaceutical composition and nutritional supplement within the spirit of the present invention refer to compositions that include a pharmaceutically acceptable carrier.
  • Pharmaceutical acceptable carriers are well known and described in the art.
  • compositions suitable for use with transdermal patches are encompassed.
  • the topical product should contain between 0.1 wt.% and 80 wt.% of the combination of celery material and unsaponifiable matter from vegetable oil to achieve adequate pharmacological action.
  • the present method comprises the enteral administration of a composition comprising celery material and an isolate from vegetable oil enriched in unsaponifiables.
  • compositions suitable for enteral administration, and particularly oral administration include meals, bars, pills, capsules, gels, biscuits, drinks etc.
  • the present method comprises the administration of the composition in a solid or semisolid dosage form, more preferably in the form of one or more pills, capsules, tablets, caplets, microparticles and microspheres.
  • the single solid or semisolid dosage unit form preferably has a weight between 0.1 and 30 grams, more preferably between 0.2 and 10 gram.
  • a daily dosage may include one or more pills, however, preferably a daily dosage consists of 1 to 10 pills.
  • the preparation according to the present invention is used in a method for the treatment of a interleukin-l mediated disorders selected from the group of: inflammatory conditions of a joint, including osteoarthritis, psoriatic arthritis and rheumatoid arthritis; pain and joint inflammatory condition resulting from strain, sprain, cartilage damage, trauma, orthopedic surgery, infection or other disease processes, more preferably from the group consisting of inflammatory conditions of a joint.
  • the composition is especially useful in a method for the treatment, repair or prevention of damage to the connective tissue.
  • the present invention thus makes available effective therapeutic and prophylactic methods for restoring cartilage function and integrity. Such methods are useful, in particular for the repair of defects or lesions in cartilage tissue which are the result of degenerative wear such as observed in osteoarthritis, as well as other mechanical derangements which may be caused by trauma to the tissue.
  • the present method for the treatment, repair or prevention of damage to the connective tissue may be manifested in the form of products, such as nutritional supplements, advertised to treat or prevent undesirable conditions of the joint and/or the treatment or prevention of symptoms thereof.
  • Nutritional supplements labeled with terminology pointing to the above method are encompassed by the present method.
  • Such terminology includes for example “joint health”, “mobility”, “cartilage plus”, “artri-cure”, “joint pain”, “flexibility”, “joint-repair”, “cartila”, “osteobiflex” or “joint-flex”.
  • the term “symptoms” includes pain, tenderness of the joints, swelling, stiffness, morning stiffness and loss of cartilage.
  • Example 1 Inhibition of IL-1 release by Celery seed extract.
  • PBMCs from human donors stored in liquid nitrogen were thawed, washed and counted. In parallel a visual viability check is performed using trypan blue. 20 ⁇ l celery seed extract solutions (Celery seed ext dry cone 1:10, Mediherb, Warwick, Australia), with concentrations of 0; 3.5; 17.5; 35; and 70 ⁇ g celery seed extract/ml were added to the wells of a 96-well culture plate (Falcon-BD, Franklin Lakes, NJ, USA). Subsequently 150 ⁇ l hPBMC suspension was pipetted into the wells, 1.5 x 10 5 cells per well.
  • biotinylated antibody 50 ⁇ l biotinylated antibody was added (1:1250) and the plates were incubated at room temperature on a shaker for 2 hours. Plates were washed 5 times and 100 ⁇ l streptavidine-HRP was added (1 :20000) and incubated at room temperature for 30 minutes. Subsequently the plates were washed 5 times. 3,3',5,5'-tetramethylbenzidine substrate solution was added. The color reaction was stopped by adding 100 ⁇ l 10% H 2 SO 4 and the plates were measured at 450nm in a microplate reader.
  • celery seed extract comprising 10 wt.%> phtalides (Celery seed ext dry cone 1:10, Mediherb, Warwick, Australia)
  • Example 3 Composition preventing damage to the connective tissue Nutritional supplement in the form of a soft gel providing on a daily base:
  • celery seed extract containing 10 wt.% phtalides (Celery seed ext dry cone 1:10, Mediherb, Warwick, Australia) • 250 mg avocado soy unsaponifiable material (PiascledineTM, Pharmascience, Courbevoie, France)
  • Excipients soybean oil, gelatin, glycerin, soya lecithin, yellow beeswax, Red 40 and titanium dioxide.

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Abstract

Un aspect de la présente invention concerne une composition comprenant : a. un composant à base de céleri, b. un isolat d'huile végétale enrichi en insaponifiables et c. éventuellement un excipient pharmaceutiquement acceptable. L'utilisation de cette composition est particulièrement indiquée dans une méthode destinée au traitement préventif et/ou curatif des troubles induits par l'interleukine-1, en particulier pour le traitement ou la prévention des lésions du tissu conjonctif et pour réduire l'inflammation et les symptômes associés aux inflammations. Un autre aspect de l'invention concerne une méthode de traitement curatif ou préventif des troubles induits par l'interleukine-1 chez les mammifères, cette méthode comprenant l'administration de la composition décrite à un mammifère par voie digestive, topique ou transdermique.
PCT/NL2003/000250 2002-04-03 2003-04-03 Composition et methodes permettant le traitement ou la prevention des troubles induits par il1 WO2003082310A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003225430A AU2003225430A1 (en) 2002-04-03 2003-04-03 Composition and method for the treatment or prevention of il-1 mediated disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP02076322 2002-04-03
EP02076322.3 2002-04-03

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US11604026B2 (en) 2019-03-14 2023-03-14 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11634257B2 (en) 2017-10-09 2023-04-25 Terumo Bct Biotechnologies, Llc Lyophilization container and method of using same

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
US11634257B2 (en) 2017-10-09 2023-04-25 Terumo Bct Biotechnologies, Llc Lyophilization container and method of using same
US11604026B2 (en) 2019-03-14 2023-03-14 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11609042B2 (en) 2019-03-14 2023-03-21 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use
US11609043B2 (en) 2019-03-14 2023-03-21 Terumo Bct Biotechnologies, Llc Lyophilization container fill fixture, system and method of use
US11740019B2 (en) 2019-03-14 2023-08-29 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11747082B2 (en) 2019-03-14 2023-09-05 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use
US11815311B2 (en) 2019-03-14 2023-11-14 Terumo Bct Biotechnologies, Llc Lyophilization container fill fixture, system and method of use
US11994343B2 (en) 2019-03-14 2024-05-28 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use

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