+

WO2003043576A2 - Compositions osteogeniques et chondrogeniques fluentes - Google Patents

Compositions osteogeniques et chondrogeniques fluentes Download PDF

Info

Publication number
WO2003043576A2
WO2003043576A2 PCT/US2002/036973 US0236973W WO03043576A2 WO 2003043576 A2 WO2003043576 A2 WO 2003043576A2 US 0236973 W US0236973 W US 0236973W WO 03043576 A2 WO03043576 A2 WO 03043576A2
Authority
WO
WIPO (PCT)
Prior art keywords
bone
composition
agent
cartilage
agents
Prior art date
Application number
PCT/US2002/036973
Other languages
English (en)
Other versions
WO2003043576A3 (fr
Inventor
Pamela Lynn Plouhar
Scott Bruder
Rhonda Clarke
Hugo Pedrozo
Original Assignee
Depuy Products, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Depuy Products, Inc. filed Critical Depuy Products, Inc.
Priority to AU2002365969A priority Critical patent/AU2002365969A1/en
Publication of WO2003043576A2 publication Critical patent/WO2003043576A2/fr
Publication of WO2003043576A3 publication Critical patent/WO2003043576A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
    • 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
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1858—Platelet-derived growth factor [PDGF]
    • A61K38/1866—Vascular endothelial growth factor [VEGF]
    • 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
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4833—Thrombin (3.4.21.5)
    • 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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/112—Phosphorus-containing compounds, e.g. phosphates, phosphonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/428—Vitamins, e.g. tocopherol, riboflavin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43—Hormones, e.g. dexamethasone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/64—Animal cells

Definitions

  • the present invention relates to the repair of cartilage and bone.
  • the present invention relates to the repair of cartilage and bone using a flowable composition comprising an osteogenic agent or a chondrogenic agent and a suitable carrier.
  • the body typically reacts quickly to defects in bone, such as those resulting from injury, infection, malignancy, or developmental malformation.
  • defects in bone such as those resulting from injury, infection, malignancy, or developmental malformation.
  • the processes of bone repair work well under normal circumstances.
  • a good repair may be still achieved using simple methods of immobilization.
  • fractures at risk of delayed union, nonunion, or malunion often fail to heal correctly.
  • a fracture that takes longer to heal than expected is a delayed union, while a fracture that fails to heal in a reasonable amount of time, usually greater than 6 to 12 months, is termed a nonunion.
  • a malunion may occur when a fracture does not heal with a normal alignment.
  • such fractures may either fail to ever heal, or fail to provide sufficient bone quality allowing the resumption of normal activities.
  • bone defects such as step defects, pits, surface abnormalities, and the like, that are not associated with fractures may also fail to heal correctly. Since movement within a bone defect, such as a fracture, may serve to stimulate the processes of repair, defects in bone not arising from a fracture, like step defects, pits, and surface abnormalities, may also require an undesirable length of time to heal.
  • defects in cartilage arising from injury, infection, malignancy, or developmental malformation often fail to heal with normal cartilage tissue.
  • defects include Grade III and Grade IN (osteochondral) cartilage lesions that can be caused by traumatic injury to a joint or upon the removal of graft tissue used to treat other sites, such as donor sites in osteochondral grafting.
  • lesions or defects can be created during the treatment of tumors involving articular surfaces, or during the removal of cysts.
  • the failure to repair bone and cartilage defects often results in pain, instability, and an associated loss of function of the involved limb. Fractures occurring in young, productive individuals that fail to heal or fail to heal properly can result in permanent life-altering disabilities, diminishing the quality of life.
  • fracture and other types of defects occurring in the elderly can cause chronic pain and lead to instability having exacerbated consequences to an already physically-challenged group.
  • inco orating techniques of internal fixation are often performed.
  • Existing bone may be supplemented with bone autografts, as well as bone allografts or other synthetic materials, to provide the necessary internal fixation.
  • Such bone supplementation may also be performed in conjunction with other artificial prostheses and implants.
  • These artificial prostheses for internal fixation may provide structural stability and may be fabricated from many materials, for example metals such as stainless steel, cobalt- chromium-molybdenum alloys, titanium, and the like.
  • the simultaneous stimulation of new bone formation may be performed using various agents, including bioceramics, polymers, such as poly(lactic acid)/poly(glycolic acid) copolymers, and natural substances, such as collagen and hydroxyapatite, as described in U.S. Patent Nos. 6,071,530, 5,385,887, 4,578,384, 4,563,489, 4,637,931, 4,578,384, 6,162,225, 5,181,926, and 5,084,051.
  • Semi-solid materials such as gels and pastes, have also been used.
  • DYNAGRAFTTM (GenSci Regeneration Laboratories, Inc., Irvine, CA), incorporates demineralized bone matrix (DBM), cancellous bone chips, or mineralized bone into a poloxamer.
  • DBM demineralized bone matrix
  • cancellous bone chips or mineralized bone into a poloxamer.
  • graft materials and prostheses like those described typically involves a surgical operation.
  • specialized materials can be introduced into the defect site using less invasive procedures, such as introduction by injection.
  • injectable compositions are the non-sintered bioceramics found in U.S. Patent Nos. 6,214,368, 6,165,486, and 5,782,971, allograft demineralized bone paste formulations, and the collagen compositions described in U.S.
  • U.S. Patent No. 4,645,503 discloses production of a moldable bone implant material containing approximately 65-95% hard filler particles and a binder composed of approximately 35-50% of a biocompatible, biodegradable thermoplastic polymer which has fluid flow properties at about 60 °C.
  • agents which are free from a support structure may be introduced locally to the defect site by injection, or alternatively administered systemically.
  • systemic administration can be limited by the ability to selectively target the therapeutic substance to a particular site.
  • a non-operative, minimally invasive introduction or administration of a composition capable of promoting bone or cartilage repair, that will also exhibit a desirable residence time at the defect site is desired.
  • a flowable composition for introduction to a bone or cartilage defect comprising an osteogenic agent or chondrogenic agent, where the osteogenic agent or chondrogenic is an inhibitor of bone resorption or a bone anabolic agent, and a biocompatible carrier that is more fluid at ambient temperature than at an elevated temperature.
  • a flowable composition for introduction to a bone or cartilage defect comprising an osteogenic agent or chondrogenic agent, where the osteogenic agent or chondrogenic is a protein, a non-native protein, a protein fragment, or a peptide, and a biocompatible carrier that is more fluid at ambient temperature than at an elevated temperature.
  • a flowable composition for introduction to a bone or cartilage defect comprising an osteogenic agent or chondrogenic agent, where the agent is a bone marrow cell, a genetically-modified cell, or a population of bone marrow cells or genetically-modified cells, and a biocompatible carrier that is more fluid at ambient temperature than at an elevated temperature.
  • the agent is an inhibitor of bone resorption, such as estrogen, selective estrogen receptor modifiers, bisphosphonates, ⁇ src-tyrosine kinase inhibitors, cathepsin K inhibitors, vacuolar-ATPase inhibitors, or analogs or derivatives thereof.
  • the agent is a bone anabolic agent, such as statins, fluprostenol, vitamin D, prostaglandins, or analogs or derivatives thereof.
  • the agent is a bone cell stimulating factor (BCSF), chrysalin, KRX-167, MP52, or an analog or derivative thereof.
  • the composition is substantially free of the bone morphogenetic protein-2 (BMP-2).
  • Carriers useful with the above agents include poloxamers, hydrogels, and block copolymers, including pluronic F127, as known as poloxamer 407, pluronic F108, pluronic F98, and the like.
  • the carriers may be block copolymers of poly(propylene oxide) and poly(ethylene oxide), including block copolymers having a poly(propylene oxide) fragment having a molecular weight in the range from about 900 to about 4000.
  • the block copolymer may have poly(ethylene oxide) fragments comprising from about 70% to about 80% by weight of the block copolymer.
  • the carrier may comprise from about 5% to about 99% of the composition.
  • compositions may also include a bioactive component such as collagen, collagen lattices and insoluble collagen derivatives, hydroxyapatite, tricalcium phosphate, calcium phosphate, radio-opacifying agents, carboxymethylcellulose, hydroxyethylcellulose, sodium alginate, xanthan gum, and hyaluronic acid or salts thereof.
  • a bioactive component such as collagen, collagen lattices and insoluble collagen derivatives, hydroxyapatite, tricalcium phosphate, calcium phosphate, radio-opacifying agents, carboxymethylcellulose, hydroxyethylcellulose, sodium alginate, xanthan gum, and hyaluronic acid or salts thereof.
  • bioactive components are salicylic acid, acetaminophen, ibuprofen, naproxen, piroxicam, flurbiprofen, morphine, cocaine, lidocaine, bupivacaine, xylocaine, and benzocaine.
  • bioactive components include amino acids, peptides, vitamins, inorganic elements, co-factors for protein synthesis, hormones, enzymes, nerve growth promoting substances, fibronectin, growth hormones, colony stimulating factors, cytokines, interleukin-1, angiogenic drugs and polymeric carriers containing such drugs, biocompatible surface active agents, anti-thrombotic drugs, cytoskeletal agents, natural extracts, bioadhesives, antitumor agents, antineoplastic agents, tumor-specific antibodies conjugated to toxins, tumor necrosis factor, cellular attractants and attachment agents, immuno-suppressants, penneation and penetration enhancers, blood, blood cells, and nucleic acids.
  • a flowable composition for introduction to a bone or cartilage defect comprising an osteogenic agent or chondrogenic agent that is substantially free of the bone morphogenetic protein BMP-2, and a biocompatible carrier that is more fluid at ambient temperature than at an elevated temperature.
  • a method for repairing a bone or cartilage defect comprising administering a composition described herein in an amount effective to enhance the repair of the bone or cartilage defect.
  • the compounds may be administered by injection.
  • defects include fractures, fractures at risk of non-union, defects in bone or cartilage caused by the removal of a tumor or cyst, defects in bone or cartilage associated with a joint prosthesis, osteotomy defects associated with treatment of a mal-alignment or a deformation, defects in bone or cartilage cased by trauma or degeneration, defects in bone or cartilage associated with a spinal alignment or spinal fusion procedure, and oral-maxillofacial, cranio-facial, and periodontal defects.
  • osteoogenic agent refers to agents that promote, induce, stimulate, generate, or otherwise effect the production of bone or the repair of bone.
  • the presence of an osteogenic agent in the defect site may elicit an effect on the repair of the defect in terms of shortening the time required to repair the bone, by improving the overall quality of the repair, where such a repair is improved over situations in which such osteogenic agents are omitted, or may achieve contemporaneously both shortened repair times and improved bone quality. It is appreciated that osteogenic agents may effect bone production or repair by exploiting native or endogenous systems, such as by the inhibition of bone resorption.
  • chondrogenic agent refers to agents that promote, induce, stimulate, generate, or otherwise effect the production of cartilage or the repair of cartilage.
  • the presence of a chondrogenic agent in the defect site may elicit an effect on the repair of the defect in terms of shortening the time required to repair the cartilage, by improving the overall quality of the repair, where such a repair is improved over situations in which such chondrogenic agents are omitted, or may achieve contemporaneously both shortened repair times and improved cartilage quality. It is appreciated that chondrogenic agents may effect cartilage production or repair by exploiting native or endogenous systems, such as by the inhibition of cartilage breakdown.
  • flowable refers to the ability of a material to flow either of its own accord or under the influence of a mechanical force, such as may be exerted by the plunger element of a syringe.
  • Compositions of paste-like or putty-like consistency as well as those of liquid or runny consistency are properly referred to as flowable.
  • the term also applies to compositions whose consistencies allow a shape-sustaining character, but are still readily deformable. Specific forms of flowable compositions include cakes, pastes, putties, creams, fillers, and liquids.
  • Osteogenic agents may promote bone growth by acting as bone anabolic agents, or bone antiresorptive agents.
  • Chondrogenic agents may promote cartilage growth by acting as cartilage anabolic agents, or cartilage antiresorptive agents.
  • Compositions of the present invention may also effect repair of the bone or cartilage defect by stabilizing the defect to promote healing.
  • the ramifications of using such osteogenic or chondrogenic agents include increased healing rates, effecting a more rapid new bone or cartilage ingrowth, improved repair quality or improved overall quality of the resulting bone or cartilage.
  • Cartilage repairing compositions employing one or more small molecules, one or more large molecules, a cell or a population of one or more cells or cell-types exhibiting a chondrogenic capability are described herein.
  • chondrogenic agents comprising a combination of such small molecules, large molecules, and cell populations are also contemplated.
  • Bone repairing compositions employing one or more small molecules, one or more large molecules, a cell or a population of one or more cells or cell-types exhibiting an osteogenic capability are described herein.
  • osteogenic agents comprising a combination of such small molecules, large molecules, and cell populations are also contemplated.
  • the osteogenic agent or chondrogenic agent is a "small molecule" such as a synthetic molecule, drug, or pharmaceutical involved in or important to bone or cartilage biology, including statins, such as lovastatin, simvastatin, atorvastatm, and the like, fluprostenol, vitamin D, estrogen, a selective estrogen receptor modifier, a bisphosphonate, such as allendronate, ibandronate, and the like, a src-tyrosine kinase inhibitor, a cathepsin K inhibitor, a vacuolar-ATPase inhibitor, a prostaglandin, such as PGE-2, hydroxyapatite, tricalcium phosphate, and analogs and derivatives thereof. Combinations of such small molecules in providing the osteogenic or chondrogenic agent are contemplated herein.
  • statins such as lovastatin, simvastatin, atorvastatm, and the like
  • fluprostenol such as lovastatin, si
  • the small molecule, drug, or pharmaceutical is a compound that slows the resorption of bone or cartilage by metabolic or physiological processes. Such compounds may be bone or cartilage resorption inhibitors or other anti-resorptive agents.
  • the small molecule, drug, or pharmaceutical is a compound that induces the proliferation of bone or cartilage, or induces or conducts bone or cartilage ingrowth. Such agents may be bone or cartilage anabolic agents.
  • the osteogenic agents are compounds active at the nicotine acetylcholine receptor (ACR), such as the nicotmic ACR present in endothelial cells.
  • ACR nicotine acetylcholine receptor
  • the nicotinic ACR is involved in the neovascularization of the implanted composition.
  • the promotion of vascular tissue may be a precursor event to the induction of new bone formation.
  • Such neovascularization may be accomplished by including nicotinic ACR agonists.
  • Known nicotinic agonists in combination with the herein described carriers are contemplated as illustrative osteogenic compositions.
  • the osteogenic agent or chondrogenic agent is a
  • large molecule such as protein, an enzyme, a peptide, a receptor ligand, a peptide hormone, lipid, or carbohydrate involved in, or important to, bone or cartilage physiology, including chrysalin, osteogenic growth peptide (OGP), bone cell stimulating factor (BCSF), KRX-167, MP52, gastric decapeptide, parathyroid hormone (PTH), a fragment of parathyroid hormone, osteopontin, osteocalcin, a f ⁇ broblast growth factor (FGF), such as basic f ⁇ broblast growth factor (bFGF) and FGF-1, osteoprotegerin ligand (OPGL), platelet-derived growth factor (PDGF), an insulin-like growth factor (IGF), such as IGF-1 and IGF-2, vascular endothelial growth factor (NEGF), transforming growth factor (TGF), such as TGF-alpha and TGF-beta, epidermal growth factor (EGF), growth and differentiation factor (GDF), such as GDF-5
  • the bone morphogenic proteins, or BMPs comprise a subset of prteins from the TGF-beta super family of proteins.
  • BMPs have been implicated in bone and cartilage physiology, including BMP-1, BMP-2, BMP-3, BMP-4, BMPS, BMP-6 and BMP-1, disclosed in U.S. Pat. ⁇ os.
  • the osteogenic agents and chondrogenic agents described herein are non-native proteins, enzymes, or peptides.
  • Such non-native proteins include proteins produced in exogenous systems, such as genetically-modified cells, and recombinant proteins, like MP52, also known as BMP-14 or rh.GDF-5, or other proteins isolated from genetically-modified cells and tissues. Proteins that have been modified by chemical synthesis are also included.
  • non-native proteins include proteins that are prepared by chemical synthesis.
  • the osteogenic agents and chondrogenic agents described herein are protein fragments or peptides that are prepared by chemical synthesis or by proteolysis of other proteins. Such proteolysis may be either chemical or enzymatic.
  • these protein fragments or peptides may be compounds that do not typically occur as a result of typically-encountered or normal metabolic and physiological processes.
  • the thrombin fragment TP508, also known as chrysalin is representative of such protein fragments and peptides.
  • the osteogenic agents and chondrogenic agents are nuclear transcription factors or inhibitors of nuclear transcription factor binding in combination with cells, especially cells from the host or subject. Such nuclear transcription factors regulate the transcription of certain genes.
  • the osteogenic agents and chondrogenic agents are inhibitors of the binding of peroxisome proliferator-activated receptors (PPAR), such as PPAR- ⁇ , PPAR- ⁇ , and PPAR- ⁇ .
  • PPAR peroxisome proliferator-activated receptors
  • PPAR- ⁇ is thought to be required for recruitment of mesenchymal cells into the adipocyte lineage.
  • PPAR binding is involved in, and may be required for adipogenesis. As PPAR binding is blocked, more precursor cells will mature into osteoblasts.
  • compounds that bind directly to transcription factors or transcription regulators implicated in recruiting precursor or mesenchymal cells are also contemplated as osteogenic and chondrogenic agents to be included in the compositions described herein. Examples include, but are not limited to SOX-9, SOX-5, CBFA-1 (RUNX-2), and the like. Such binders of transcription factors or transcription regulators are capable of modulating or stimulating the expression of certain genes.
  • Osteogenic agents and chondrogenic agents described herein may also be substantially free of the bone morphogenetic protein BMP-2. It is well-known that BMP-2 causes osteoprogenitor cells to differentiate into osteoblast-like cells, the cells that deposit and mineralize new bone. As used herein in conjunction with the presence of the bone morphogenetic protein BMP-2, the term “substantially free” refers to levels of BMP-2 so reduced that effects on the bone or cartilage defect following the introduction of the osteogenic or chondrogenic agents described herein are likely not attributable to BMP-2. However, it is appreciated that the complete preclusion of BMP-2 from the osteogenic or chondrogenic agent may not be accomplished in certain circumstances, or when using certain sources of the osteogenic or chondrogenic agent.
  • the osteogenic agent or chondrogenic agent is a cell or population of cells involved in, or important to, bone or cartilage biology, such as pluripotent stem cells, autologous, allogenic, or xenogeneic progenitor cells, osteoblasts, chondrocytes, adipose-derived stem cells, bone marrow cells, mesenchymal stem cells, homogenized or comminuted tissue transplants, genetically transformed cells, and the like. Combinations of such cell populations in providing the osteogenic or chondrogenic agent are also contemplated herein.
  • Carriers of the present invention are desirably bio-compatible, bio- absorbable materials with low host toxicity, low irritative properties, and have a low potential for antigenicity.
  • Suitable carriers include, but are not limited to, poly(ethylene oxide), poly(propylene oxide), polyoxyalkylenes, poloxamers, hydrogels, block copolymers, including reverse-phase block copolymers, such as poly(ethylene oxide)- poly(propylene oxide) copolymers and the like.
  • Illustrative block copolymers are of the following general structure: HO(C 2 H 4 O) a (C 3 H 6 0) b (C 2 H 4 0) c H where a, b, and c are integers.
  • Typical values for the integers a, b, and c may be selected to provide block copolymers where the poly(ethylene oxide) fragment comprises a particular percent range of the total molecular weight, or alternatively, the integers a, b, and c may be selected to provide a particular range of total molecular weight of the block copolymer, such as those resulting in a molecular weight in the range from about 4700 to about 14600 g/mol.
  • Illustrative examples include block copolymers according to the above formula where the integer a is in the range from about 75 to about 125, the integer b is in the range from about 55 to about 85, and the integer c is in the range from about 75 to about 125.
  • Block copolymers of poly(ethylene oxide)-poly(propylene oxide) refer generically to non-ionic surface active agents of a polymer type having a relatively hydrophobic poly(propylene oxide) fragment bracketed or blocked by a pair of relatively hydrophilic poly(ethylene oxide) fragments. Block copolymers are distinguished by this bracketed arrangement of the homopolymer components. It may be feasible to prepare surface active agents having various properties by changing either the molecular weight of the block copolymer or the relative molecular weight of the polypropylene oxide) fragment, thereby altering the corresponding mixing ratio thereof, to the ethylene oxide.
  • the poly(ethylene oxide) fragments illustratively may comprise from about 70% to about 80% of the total weight of the carrier.
  • Block copolymers such as the PLURONIC ® block copolymers, including but not limited to F127, F108, and F98, often exhibit reverse-phase properties, such as reversible temperature-dependent sol-gel transitions. Such block copolymers form gels at body temperature, while remaining liquid or substantially fluid at ambient temperature.
  • block copolymers include those where the molecular weight of the poly(propylene oxide) fragment is in the range from about 900 to about 4000, or in the range from about 1500 to about 4000, and where the percent by weight of the ethylene oxide fragment in the total block copolymer molecule is about 70%.
  • the poly(ethylene oxide)-poly(propylene oxide) block copolymer PLURONIC ® -F127 (BASF Corp., Mt. Olive, NJ), also known as poloxamer 407, with a molecular weight of about 12,600 g/mol, is a suitable carrier composed mostly (70% by weight) of poly(ethylene oxide).
  • the flowable carrier may be made up of one or more liquid polyhydroxy compounds or derivatives in solution with one or more solid polyhydroxy compounds or derivatives.
  • Carriers may further include physiologically relevant solvents such as water, physiological saline, ethanol, glycerol, or glucose.
  • carriers may include additives such as propylene glycol, polypropylene glycol, ethylene glycol, polyethylene glycol, or mixtures thereof, to adjust the flowable properties of the composition.
  • additional carrier components include other F-series PLURONICTM block copolymers. Functionally, the carrier component of the composition serves to provide a flowable material of widely varying consistency.
  • the carrier may comprise from about 5% to about 99%, or from about 16% to about 40% of the composition, depending on the application in which it is used and the choice of the carrier. In other illustrative embodiments the carrier comprises about 5% to about 90%, about 10% to about 90%, or about 10%) to about 50% of the composition. It is appreciated that the level of carrier component may be adjusted to maintain the flowable nature of the composition at ambient temperature and the corresponding decrease on flowability at elevated temperatures. Components that provide additional structure to or generally reduce the fluidity of the flowable composition are also contemplated.
  • Such components include collagen, collagen lattices and insoluble collagen derivatives, hydroxyapatite, cartilage fragments, calcium phosphate, radio-opacifying agents, carboxymethylcellulose, hydroxyethylcellulose, sodium alginate, xanthan gum, hyaluronic acid or a salt thereof, and the like.
  • additional components may be added in conjunction with other ingredients described herein in order to balance an increase in the flowability of the osteogenic or chondrogenic composition upon the addition of other ingredients in variations of the herein-described compositions.
  • the flowable osteogenic and chondrogenic compositions described herein are capable of being introduced to the defect site via multiple formats. Such flowable formats are advantageously delivered, applied, or otherwise introduced to the defect site without necessarily requiring surgery. It is appreciated that in some cases surgery is desirable to introduce the composition in variations of the process of the present invention. In particular, arthroscopic surgery and other minimally invasive surgical techniques are suitable means for delivering the flowable osteogenic agents and chondrogenic agents described herein. Delivery of flowable formats may be accomplished by a variety of known means, such as by injection via a cannula, catheter, syringe, syringe with a needle, pressure applicator, pump, and the like, or via a combination thereof.
  • Such modes of delivery allow positioning of the osteogenic composition or chondrogenic composition even in defect sites in challenging locations or situations.
  • Such compositions further allow a sustained disposition or sustained residence time of the accompanying osteogenic agent or chondrogenic agent within the defect site.
  • sustained times in the defect site may be due to a degree of protection provided to the osteogenic agent or chondrogenic agent by the biocompatible carrier.
  • Such protection may minimize exposure of the agent to routes of excretion, degradation via metabolism, non-target organs or tissues, or other processes that tend to reduce the effective concentration of the agent at the defect site.
  • Such residence times are conveniently chosen in an end-use dependent manner, illustratively to allow sufficient time for the osteogenic agent or chondrogenic agent to effectively enhance bone or cartilage repair.
  • An embodiment includes an injectable format of such an osteogenic composition or chondrogenic composition.
  • Particularly illustrative are carriers that undergo a temperature dependent sol-gel phase transition.
  • Compositions employing carriers that are substantially liquid at ambient temperatures and semi-solid at body temperature are contemplated.
  • Such carriers may especially serve to promote the achievement of prolonged residence times of the osteogenic agent or chondrogenic agent in the defect site, as described herein.
  • ambient temperature refers to a temperature range from about 1 °C to about 30 °C, or a range from about 4 °C to about 25 °C. Elevated temperatures include “body temperature.”
  • body temperature refers to the normal temperature range observed in various mammalian species, typically in the range from about 30 °C to about 40 °C, or illustratively about 37 °C.
  • Illustrative compositions may be injectable liquids or gels at ambient temperatures at the time of administration and may form gels, solids, or semi-solids at body temperatures within short periods of time after administration.
  • the moldability of the composition prior to gel, solid, or semi-solid formation allows the composition to conform to irregularities, crevices, cracks, holes, and the like, in the implant site.
  • the osteogenic composition or chondrogenic composition exhibits the ability to maintain its cohesiveness and resist erosion subsequent to being applied or introduced to an osseus or cartilaginous defect site.
  • desirable bioerosion can take place within a time-frame in an end-use dependent manner consistent with effective bone or cartilage repair. It is appreciated that such relative ranges of bioerosion may be selected in an end-use dependent manner with routine experimentation.
  • any of a variety of medically or surgically useful substances can also be incorporated into the flowable osteogenic or chondrogenic compositions described herein.
  • additional bioactive substances, agents, or components may be added to the osteogenic agent or chondrogenic agent component, added to the carrier component, or added to the osteogenic or chondrogenic composition once formed. It is contemplated that such additives may serve to reduce barriers to repair and thus maximize the potential of the osteogenic or chondrogenic agent.
  • bioactive agents such as hydrocortisone, prednisone, and the like
  • agents include anti-inflammatory agents, such as hydrocortisone, prednisone, and the like, NSAIDS, such as acetaminophen, salicylic acid, ibuprofen, and the like, selective COX-2 enzyme inhibitors, antibacterial agents, such as penicillin, erytliromycin, polymyxin B, viomycin, chloromycetin, streptomycins, cefazolin, ampicillin, azactam, tobramycin, cephalosporins, bacitracin, tetracycline, doxycycline, gentamycin, quinolines, neomycin, clindamycin, kanamycin, metronidazole, and the like, antiparasitic agents such as quinacrine, chloroquine, vidarabine, and the like, antiparasitic agents such as quinacrine, chloroquine, vidarabine,
  • Systemic analgesic agents such as salicylic acid, acetaminophen, ibuprofen, naproxen, piroxicam, flurbiprofen, morphine, and the like, and local anesthetics such as cocaine, lidocaine, bupivacaine, xylocaine, benzocaine, and the like, are also contemplated as bioactive components suitable as additives.
  • bioactive components that may enhance the overall effectiveness of the osteogenic or chondrogenic agent include amino acids, peptides, including peptide fragments of the various bone morphogenetic proteins, vitamins, inorganic elements, co-factors for protein synthesis, hormones, enzymes such as collagenase, peptidases, oxidases, and the like, angiogenic drugs and polymeric carriers containing such drugs, biocompatible surface active agents, anti-thrombotic drugs, cytoskeletal agents, natural extracts, bioadhesives, antitumor agents, antineoplastic agents, such as methotrexate, 5-fluorouracil, adriamycin, vinblastine, cisplatin, and the like, tumor-specific antibodies conjugated to toxins, tumor necrosis factor, cellular attractants and attachment agents; immuno-suppressants, permeation and penetration enhancers, such as fatty acid polyethylene glycol monoesters of laureate, myristate, stearate, and the like, and nucleic acids
  • bioactive components capable of promoting growth and survival of cells and tissues, or augmenting the functioning of cells, are contemplated, and include nerve growth promoting substances, such as a ganglioside, nerve growth factor, and the like, fibronectin (FN), growth hormones, such as somatotropin, human growth honnone (HGH), and the like, colony stimulating factors, cytokines, and interleukin-1 (IL-1).
  • nerve growth promoting substances such as a ganglioside, nerve growth factor, and the like, fibronectin (FN), growth hormones, such as somatotropin, human growth honnone (HGH), and the like, colony stimulating factors, cytokines, and interleukin-1 (IL-1).
  • nerve growth promoting substances such as a ganglioside, nerve growth factor, and the like, fibronectin (FN), growth hormones, such as somatotropin, human growth honnone (HGH), and the like, colony stimulating factors, cytokines, and
  • Such methods comprise the step of introducing to the cartilage or bone defect site a flowable composition, as described herein, comprising an effective amount of an osteogenic agent or chondrogenic agent incorporated in a biocompatible carrier, to promote, induce, stimulate, repair, or otherwise generate new bone or new cartilage growth at the site, or at sites proximal to the site of administration.
  • the amount of the osteogenic agent used in the methods described herein should be an amount effective to elicit bone-inducing, bone-promoting, bone-stimulating, or bone-generating properties.
  • the amount of chondrogenic agent used in the methods described herein should be an amount effective to elicit cartilage-inducing, cartilage-promoting, cartilage-stimulating, or cartilage-generating properties. Amounts of osteogenic agent or chondrogenic agent conforming to ultimate doses from about 1 ng to about 15 mg per unit volume carrier are not unusual.
  • osteogenic compositions or chondrogenic compositions to the site of a bone or cartilage defect, resulting from injury, infection, malignancy, developmental malformation, and the like, desirably leads to the repair of the defect by promoting new bone or new cartilage growth.
  • defect sites of introduction include acute fractures, especially fractures at risk of forming non-unions, mal-unions, delayed unions, step defects, and other tissue defects, such as tissue regeneration sites, sites of tumor or cyst removal, osteotomies used to treat mal-alignment or other deformations, and defects created by osteolysis around total joint replacements.
  • Such bone defects may be treated anywhere in the skeleton.
  • Illustrative treatment sites include sites of long bone defects and fractures, sites of knee, hip, shoulder, and other joint prostheses, sites of spinal repair, such as spinal fusion, and other alignment defects, and oral-maxillofacial, cranio-facial, and periodontal defects.
  • the osteogenic composition can be utilized for a variety of orthopedic, neurosurgical, and oral or maxillofacial surgical procedures such as the repair of simple and compound fractures, non-unions requiring external or internal fixation, joint reconstructions such as arthrodesis, general arthroplasty, cup arthroplasty of the hip, femoral and humeral head replacement, femoral head surface replacement and total joint replacements, repairs of the vertebral column including spinal fusion and internal fixation, tumor surgery, such as deficit filling, disectomy, laminectomy, anterior cervical and thoracic operations, repair of spinal injuries, and spinal deformities, such as scoliosis, lordosis, and kyphosis treatments, intramedullary fixation of fractures, mentoplasty, temporomandibular joint replacement, alveolar ridge augmentation and reconstruction, inlay bone grafts, implant placement and revision, sinus lifts, and the like.
  • joint reconstructions such as arthrodesis, general arthroplasty, cup arthr
  • the osteogenic compositions and chondrogenic compositions described herein can be readily prepared when and as needed, preferably with the components of the composition, the means for their combination to provide the composition, and the means for applying the composition to a bone defect site being provided in the form of a unitary kit.
  • the osteogenic compositions and chondrogenic compositions can be prepared before immediate use and may be stored in a sterile condition for later use, optionally within the means which will be used to introduce the osteogenic composition or chondrogenic composition to the bone or cartilage defect site.
  • osteogenic compositions and chondrogenic compositions and methods of using such compositions described herein may be combined for use in conjunction with conventional methods for repairing bone and cartilage defects, such as prostheses, and the like.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Biomedical Technology (AREA)
  • Surgery (AREA)
  • Materials Engineering (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un procédé de réparation d'une anomalie cartilagineuse ou osseuse au moyen d'une composition fluente contenant un agent chondrogénique ou un agent ostéogénique ainsi qu'un excipient biocompatible présentant une plus grande fluidité à des températures ambientes qu'à des températures élevées.
PCT/US2002/036973 2001-11-20 2002-11-15 Compositions osteogeniques et chondrogeniques fluentes WO2003043576A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002365969A AU2002365969A1 (en) 2001-11-20 2002-11-15 Flowable osteogenic and chondrogenic compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33161001P 2001-11-20 2001-11-20
US60/331,610 2001-11-20

Publications (2)

Publication Number Publication Date
WO2003043576A2 true WO2003043576A2 (fr) 2003-05-30
WO2003043576A3 WO2003043576A3 (fr) 2004-02-19

Family

ID=23294655

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/036973 WO2003043576A2 (fr) 2001-11-20 2002-11-15 Compositions osteogeniques et chondrogeniques fluentes

Country Status (2)

Country Link
AU (1) AU2002365969A1 (fr)
WO (1) WO2003043576A2 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005009496A1 (fr) * 2003-07-31 2005-02-03 Bioretec Oy Dispositif d'implant multifonctionnel
US7473678B2 (en) 2004-10-14 2009-01-06 Biomimetic Therapeutics, Inc. Platelet-derived growth factor compositions and methods of use thereof
WO2010033862A2 (fr) * 2008-09-19 2010-03-25 The Board Of Regents, The University Of Texas System Procédés de traitement du cancer
US7799754B2 (en) 2004-10-14 2010-09-21 Biomimetic Therapeutics, Inc. Compositions and methods for treating bone
CN102020777A (zh) * 2010-11-29 2011-04-20 同济大学 一种纳米羟基磷灰石海藻酸钙可注射型水凝胶的制备方法及其应用
US7951880B2 (en) 2004-12-10 2011-05-31 University Of Iowa Research Foundation Compositions for breast implant filling and methods of use
US20110166417A1 (en) * 2008-01-18 2011-07-07 The Regents Of University Of Michigan Method and device for repair of degenerative cartilage
US8114841B2 (en) 2004-10-14 2012-02-14 Biomimetic Therapeutics, Inc. Maxillofacial bone augmentation using rhPDGF-BB and a biocompatible matrix
US8870954B2 (en) 2008-09-09 2014-10-28 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendon and ligament injuries
US8940311B2 (en) 2004-10-21 2015-01-27 Tae-Hong Lim In situ controlled release drug delivery system
WO2015135822A1 (fr) 2014-03-14 2015-09-17 Ecole Polytechnique Federale De Lausanne (Epfl) Combinaison agent actif-particule favorisant la régénération osseuse
US9161967B2 (en) 2006-06-30 2015-10-20 Biomimetic Therapeutics, Llc Compositions and methods for treating the vertebral column
CN105209484A (zh) * 2013-03-14 2015-12-30 建新公司 温敏性骨生长组合物
CN105251048A (zh) * 2015-10-16 2016-01-20 山东福瑞达医药集团公司 一种含黄原胶的可注射型软骨组织保护及修复材料
US9642891B2 (en) 2006-06-30 2017-05-09 Biomimetic Therapeutics, Llc Compositions and methods for treating rotator cuff injuries
US10279079B2 (en) 2011-07-05 2019-05-07 The Research Foundation For The State University Of New York Compositions and methods for spinal disc repair and other surgical and non-surgical indications
US20200390869A1 (en) * 2019-04-12 2020-12-17 Affirmed Pharma, Llc Rusalatide acetate compositions
US11235030B2 (en) 2010-02-22 2022-02-01 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendinopathies

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113521386A (zh) * 2020-04-17 2021-10-22 南京宁宇医疗器材有限公司 一种可注射型含rhBMP-2的骨修复水凝胶及其制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5290558A (en) * 1989-09-21 1994-03-01 Osteotech, Inc. Flowable demineralized bone powder composition and its use in bone repair
WO1998034655A1 (fr) * 1997-02-07 1998-08-13 Stryker Corporation Dispositif osteogeniques sans matrice, implants et methodes d'utilisation associees
UA67754C2 (uk) * 1997-10-10 2004-07-15 Пфайзер, Інк. Агоністи простагландину, фармацевтична композиція на їх основі (варіанти), спосіб нарощення та збереження кісткової маси у хребетних та спосіб лікування (варіанти)

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005009496A1 (fr) * 2003-07-31 2005-02-03 Bioretec Oy Dispositif d'implant multifonctionnel
US7473678B2 (en) 2004-10-14 2009-01-06 Biomimetic Therapeutics, Inc. Platelet-derived growth factor compositions and methods of use thereof
US11571497B2 (en) 2004-10-14 2023-02-07 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods of use thereof
US11364325B2 (en) 2004-10-14 2022-06-21 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods of use thereof
US7799754B2 (en) 2004-10-14 2010-09-21 Biomimetic Therapeutics, Inc. Compositions and methods for treating bone
US11318230B2 (en) 2004-10-14 2022-05-03 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods of use thereof
US9545377B2 (en) 2004-10-14 2017-01-17 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods of use thereof
US8114841B2 (en) 2004-10-14 2012-02-14 Biomimetic Therapeutics, Inc. Maxillofacial bone augmentation using rhPDGF-BB and a biocompatible matrix
US10258566B2 (en) 2004-10-14 2019-04-16 Biomimetic Therapeutics, Llc Compositions and methods for treating bone
US8940311B2 (en) 2004-10-21 2015-01-27 Tae-Hong Lim In situ controlled release drug delivery system
US7951880B2 (en) 2004-12-10 2011-05-31 University Of Iowa Research Foundation Compositions for breast implant filling and methods of use
US10456450B2 (en) 2006-06-30 2019-10-29 Biomimetic Therapeutics, Llc Compositions and methods for treating rotator cuff injuries
US9161967B2 (en) 2006-06-30 2015-10-20 Biomimetic Therapeutics, Llc Compositions and methods for treating the vertebral column
US11058801B2 (en) 2006-06-30 2021-07-13 Biomimetic Therapeutics, Llc Compositions and methods for treating the vertebral column
US9642891B2 (en) 2006-06-30 2017-05-09 Biomimetic Therapeutics, Llc Compositions and methods for treating rotator cuff injuries
US20110166417A1 (en) * 2008-01-18 2011-07-07 The Regents Of University Of Michigan Method and device for repair of degenerative cartilage
US8870954B2 (en) 2008-09-09 2014-10-28 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendon and ligament injuries
US11135341B2 (en) 2008-09-09 2021-10-05 Biomimetic Therapeutics, Llc Platelet-derived growth factor composition and methods for the treatment of tendon and ligament injuries
WO2010033862A2 (fr) * 2008-09-19 2010-03-25 The Board Of Regents, The University Of Texas System Procédés de traitement du cancer
WO2010033862A3 (fr) * 2008-09-19 2010-08-19 The Board Of Regents, The University Of Texas System Procédés de traitement du cancer
US11235030B2 (en) 2010-02-22 2022-02-01 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendinopathies
CN102020777A (zh) * 2010-11-29 2011-04-20 同济大学 一种纳米羟基磷灰石海藻酸钙可注射型水凝胶的制备方法及其应用
US10279079B2 (en) 2011-07-05 2019-05-07 The Research Foundation For The State University Of New York Compositions and methods for spinal disc repair and other surgical and non-surgical indications
CN105209484A (zh) * 2013-03-14 2015-12-30 建新公司 温敏性骨生长组合物
EP2970421A4 (fr) * 2013-03-14 2016-11-02 Genzyme Corp Compositions de croissance osseuse thermosensibles
JP2016514030A (ja) * 2013-03-14 2016-05-19 ジェンザイム・コーポレーション 感熱性骨成長組成物
WO2015135822A1 (fr) 2014-03-14 2015-09-17 Ecole Polytechnique Federale De Lausanne (Epfl) Combinaison agent actif-particule favorisant la régénération osseuse
CN105251048A (zh) * 2015-10-16 2016-01-20 山东福瑞达医药集团公司 一种含黄原胶的可注射型软骨组织保护及修复材料
US20200390869A1 (en) * 2019-04-12 2020-12-17 Affirmed Pharma, Llc Rusalatide acetate compositions
US11883472B2 (en) * 2019-04-12 2024-01-30 Affirmed Pharma, Llc Rusalatide acetate compositions

Also Published As

Publication number Publication date
AU2002365969A1 (en) 2003-06-10
AU2002365969A8 (en) 2003-06-10
WO2003043576A3 (fr) 2004-02-19

Similar Documents

Publication Publication Date Title
WO2003043576A2 (fr) Compositions osteogeniques et chondrogeniques fluentes
JP6324653B2 (ja) リン酸カルシウム配合骨セメントを用いる脊椎骨の最小侵襲治療（ｍｉｔｖ）
US9138509B2 (en) Composition for filling bone defects
Schnettler et al. Bone ingrowth in bFGF-coated hydroxyapatite ceramic implants
US7019192B2 (en) Composition for filling bone defects
AU770196B2 (en) Osteogenic paste compositions and uses thereof
US8048857B2 (en) Flowable carrier compositions and methods of use
US6437018B1 (en) Malleable paste with high molecular weight buffered carrier for filling bone defects
US8747899B2 (en) Injectable in situ self-forming mineral-polymer hybrid composition and uses thereof
Kim et al. A comparative study of the effectiveness of sinus bone grafting with recombinant human bone morphogenetic protein 2–coated tricalcium phosphate and platelet-rich fibrin–mixed tricalcium phosphate in rabbits
EP1477176B1 (fr) Composition osseuse malléable pour remplir de défauts osseux
JP2007533376A (ja) 遅延凝固リン酸カルシウムペースト
NZ533008A (en) Complex mixture of a partially demineralised bone matrix (DBM) mixed with a gelatin and saline phosphate buffer acting as a carrier for the agent, DBM
WO2008021795A2 (fr) Matrice de support fluide
EP1255576A1 (fr) Composition hybride mineral polymere
JP2013155204A (ja) 生体再吸収性ポリマーマトリックス、ならびにその作製および使用方法
CN101264340A (zh) 用于填充骨缺损的陶瓷组合物
JP2016209599A (ja) リン酸カルシウム配合骨セメントを用いる脊椎骨の最小侵襲治療（ｍｉｔｖ）
US20060198863A1 (en) Ceramic composition for filling bone defects
WO2006088866A2 (fr) Support porteur biodegradable pour regeneration osseuse
Gromov et al. Recombinant human bone growth factor BMP-2 synthesized in Escherichia coli cells. Part 2: from combined use with other protein factors in animal models to application in medicine
AU2015215892B2 (en) Minimally invasive treatment of vertebra (mitv) using a calcium phosphate combination bone cement
US20210121428A1 (en) Compositions for treatment of annular spinal disc injury
AU2008200841A1 (en) Composition For Filling Bone Defects

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载