WO2005020955A1 - Compositions pour prevenir les cicatrices et les fibroses apres blessure ou chirurgie - Google Patents

Compositions pour prevenir les cicatrices et les fibroses apres blessure ou chirurgie Download PDF

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Publication number
WO2005020955A1
WO2005020955A1 PCT/EP2004/009867 EP2004009867W WO2005020955A1 WO 2005020955 A1 WO2005020955 A1 WO 2005020955A1 EP 2004009867 W EP2004009867 W EP 2004009867W WO 2005020955 A1 WO2005020955 A1 WO 2005020955A1
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Prior art keywords
fibrosis
gel
lesion
antineoplastic agent
resorbable
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PCT/EP2004/009867
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English (en)
Inventor
Norfrid Klug
Jin-Yul Lee
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Cell Center Cologne Gmbh
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Publication of WO2005020955A1 publication Critical patent/WO2005020955A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • compositions for preventing scars and fibrosis after injury or surgery are provided.
  • the present invention relates to the use of an antineoplastic agent and a resorbable, viscous substance for the preparation of a pharmaceutical composition for the inhibition or prevention of fibrosis and/or scarring of a lesion in a mammal.
  • the present invention further concerns said pharmaceutical compositions as well as surgical gels comprising an antineoplastic agent for preventing scars and fibrosis after injury or surgery.
  • peridural fibrosis is common after back surgery known as either lumbar diskectomy or laminectomy.
  • Peridural fibrosis may cause recurring low back pain or leg pain after surgery. Operating again to remove the scar tissue often leads to more scarring.
  • an antiadhesion barrier gel ADCON-L ® (Gliatec, Inc., Cleveland, OH), consisting of a carbohydrate polymer that prevents the invasion of fibroblasts as disclosed in European patent application EP 0 586 535 A1, and a collagen-based gel GAO (Gel Amidon Oxyde) have been demonstrated to decrease the peridural fibrosis in animal experiments (Liu et al., J. Neurosurg. (Spine 1) 94 (2001), 61-67; Einhaus et al, Spine 22 (1997), 1440-1446; Wujek et al., Exp. Neurol.
  • Epidural hematoma in the path of surgical dissection might also play an important role for the formation of peridural fibrosis (Songer et al., Spine 20 (1995), 571-580). Collagen in combination with tissue adhesive, too, has demonstrated only moderate success in the inhibition of peridural fibrosis.
  • TachoComb ® a local hemostyptic agent consisting of a patch of collagen, which is covered with a fixed layer of the solid coagulation factors fibrinogen and thrombin and the fibrinolysis inhibitor aprotinin, was more effective in reducing the epidural fibrosis than other hemostyptic materials.
  • complete prevention of epidural scar formation and dural adhesion has not been achieved (Lee et al., Minim. Invasive Neurosurg. 46 (2003), 106-109).
  • the present invention is directed to a method for the inhibition or prevention of fibrosis and/or scarring of a lesion in a mammal comprising administering to a subject in need thereof a therapeutic amount of an antineoplastic agent, preferably in combination with a resorbable, viscous substance.
  • antineoplastic agent is an antineoplastic antibiotic, most preferably Mitomycin-C or a derivative thereof.
  • the present invention relates to a surgical gel comprising an antineoplastic agent, most preferably an antibiotic such as Mitomycin-C.
  • antineoplastic agent in accordance with the present invention may be accompanied by the use of further therapeutic agents such as a local analgesic or anesthetic and/or anti- inflammatory agent.
  • further therapeutic agents such as a local analgesic or anesthetic and/or anti- inflammatory agent.
  • the compositions and gels of the invention are preferably designed to release the therapeutic agents over time.
  • the present invention also concerns a device designed for the application of a composition or gel as defined above into a surgical lesion, wherein, for example, the antineoplastic agent and resorbable, viscous substance are mixed upon application.
  • Fig. 1 Laminectomy site treated with MMC (0.1 mg/ml): laminectomy defect (arrowheads) showing the light epidural fibrous tissue (asterisk) clearly separated through an empty layer from dura mater (arrow) (HE, x2.5).
  • Fig. 2 Laminectomy site treated with MMC (0.05 mg/ml): moderate epidural fibrosis (arrowhead) without dura (arrow) adherence. Note the more prominent fibrosis near the bone defect (asterisk) (HE, xlO).
  • Fig. 3 Laminectomy site treated with MMC (0.01 mg/ml): moderate to dense epidural fibrosis with adhesion to dura (arrow) (HE, xlO).
  • Fig. 4 Control site without MMC: dense epidural fibrosis with marked dura (arrow) adherence (HE, x 10) .
  • the present invention relates to the use of an antineoplastic agent and a viscous, preferably resorbable substance for the preparation of a pharmaceutical composition for the inhibition or pre- vention of fibrosis and/or scarring of a lesion in a mammal.
  • the present invention is based on the observation that the combination of a resorbable, viscous substance with an antineoplastic agent prevents the ingrowth of fibroblasts into the epidural space and their attachment, thereby inhibiting the scarring of lesions with their detrimental effect on the surgery outcome.
  • Preliminary experiments suggest a surprising synergistic effect of the physical barrier provided by the viscous substance and the antiproliferative effect provided by the antineoplastic agent.
  • mice and rats are used as animal models for various reasons.
  • the laminotomy defects the animals are subjected to are usually smaller than those suffered by humans.
  • the mass of paravertebral muscles is much lower in mice and rats.
  • the extent of the laminotomy defect as well as the mass of surrounding muscle to which fibrosis may form attachments play a decisive role in epidural fibrosis and other surgical adhesions.
  • treatments that appear to be effective in the animal model cannot always be transferred to humans.
  • an antineoplastic agent refers to substances inhibiting or preventing the growth of neoplasms, inhibiting the maturation and reducing the proliferation of cells.
  • antineoplastic agents are used as chemotherapeutics for the treatment of malignant tumors and include, but are not limited to, e.g., 5-fluorouracil, arabinocytosine, taxol and methodextrate as well as the antineoplastic antibiotics Mithramycin, Daunorubicin, Bleomycin and Mitomycin-C. Those skilled in the art will readily be able to identify suitable antineoplastic agents and their respective effective concentration range.
  • a "resorbable, viscous substance” refers to a substance capable of forming a gel matrix or viscous fluid when in the body of a living subject.
  • the substance may be made from both naturally derived materials as well as non-naturally derived materials.
  • the viscosity of said substance is preferably low enough such that it can be readily injected through a conventional application device. However, the viscosity of the liquid or viscous fluid should not be too low, lest the substance will be dislocated from the surgical site by normal movement of the mammal.
  • viscosity of said substance will range from about 100 to about 300 000 cps, but might be lower or higher depending on the particular requirements at the site of lesion and/or the prop- erties of the antineoplastic agent.
  • compositions of the present invention does not substantially adversely affect any desired characteristics of the cells or tissues at the lesion site of said mammal other than preventing or inhibiting fibrosis. It is also preferred that the material used does not cause any substantially medically undesirable effect in any other areas of the mammal.
  • the term "resorbable” refers to substances that are degradable or absorbable, and will be gradually degraded and/or absorbed after the substance has been delivered to the site of lesion. Such degradation should preferably be in a controlled fashion. Preferably substantial degradation takes place only after a time sufficient to prevent or inhibit fibrosis during wound healing. Typically, the resorbable substance is substantially degraded (i.e., at least 50 % of the biocompatible substance is degraded into smaller molecules, or absorbed or excreted from the body) within one year after the injection of the composition into the lesion of a mammal
  • suitable degradable or absorbable biocompatible substances include, but are not limited to polylactide, chondroitin sulfate (a proteoglycan component), polyesters, polyethylene glycols, polycarbonates, polyvinyl alcohols, polyacrylamides, polyamides, polyacrylates, polyesters, polyetheresters, polymethacrylates, polyurethanes, polycaprolactones, polyphosphazenes, polyorthoesters, polyglycolides, copolymers of lysine and lactic acid, copolymers of lysine-RGD and lactic acid, and the like, and copolymers of the same.
  • polylactide chondroitin sulfate (a proteoglycan component)
  • polyesters polyethylene glycols, polycarbonates, polyvinyl alcohols, polyacrylamides, polyamides, polyacrylates, polyesters, polyetheresters, polymethacrylates, polyurethanes, polycaprolactones, polyphospha
  • suitable biodegradable or absorbable naturally derived biocompatible materials for the constructs include, but are not limited to chitosan, agarose, alginate, hyaluronic acid, and carrageenan (a carboxylated seaweed polysaccharide), demineralized bone matrix, and the like, and copolymers of the same as well as collagen.
  • Collagens can also be prepared by conventional methods such as those disclosed in US Patents Nos. 3,934,852; 3,121,049; 3,131,130; 3,314,861; 3,530,037; 3,949,073; 4,233,360 and 4,488,911.
  • surgical gels like, e.g., GELFOAM ® , HYSKON-70, INTERCEED ® , ADCON-L ® will provide a suitable resorbable, viscous substance.
  • antineoplastic antibiotic as said antineoplastic agent in the preparation of a pharmaceutical composition of the invention is preferred.
  • the anti- biotic properties will additionally provide a protection from infections during wound healing, another cause for fibrosis and scarring.
  • said antineoplastic antibiotic is selected from the group consisting of Mithramycin, Daunorubicin, Bleomycin and Mitomycin-C or derivatives including prodrugs thereof, wherein Mitomycin-C is most preferred since it has been shown to be the most effective one of this group.
  • Mitomycin-C MMC is an alkylating antibiotic substance isolated from Streptomyces caespitosus that potentially supresses fibroblast proliferation after surgery (Gilman et al., 1992, The Pharmacological Basis of Therapeutics, ed. 8. New York: McGraw Hill, vol 2, 1247-1248).
  • MMC Mitomycin-C
  • the appropriate concentration of the antineoplastic agent might be dependent on the particular agent.
  • concentration range in which it is efficient in the inhibition of cell proliferation has to be compared with the toxic concentrations; the clearance rate as well as the metabolic products play a role as do the solubility and the formulation.
  • Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50 % of the population) and LD50 (the dose lethal to 50 % of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
  • Mitomycin-C is the preferred antineoplastic agent.
  • Mitomycin-C is an aziridine antibiotic produced by Streptomyces caespitosus, variants of which are designated Mitomycin-A, Mitomycin-B, etc.
  • Mitomycin-C is an antineoplastic agent and a bacteriocide, and inhibits DNA synthesis by cross-linking the strands.
  • Mitomycin-C is available from, e.g., Roche Applied Science, Wako Chemicals USA Inc., BioAge Pharmaceuticals Inc., Merck Ltd., Sigma- Aldrich and others. Synthesis and evaluation of macromolecular prodrugs of Mitomycin-C are described in De Marre et al, J. Control Release 36 (1995), 87-97. Formulations for the sustained release of Mitomycin-C from poly(DL-lactide)/poly(DL-lactide-co-glycolide) films are described, for example, by Gumusderelioglu and Deniz, J. Biomater. Sci. Polym. Ed. 11 (2000), 1039-1050.
  • the antineoplastic agent preferably Mitomycin-C or a derivative thereof or prodrug is present in an concentration between 0.025 and 2 mg/ml, preferably about 0.05 mg/ml to about 0.1 mg/ml; see also the Example.
  • said lesion is a surgical lesion.
  • the uses and methods of the present invention can be applied to any condition that causes scar tissue formation such as after laminectomies and laminotomies for disk excision or decompressive laminectomy for spinal stenosis.
  • Laminectomies and laminotomies frequently remove bone tissue and leave the dura exposed.
  • Post-laminectomy scar tissue also termed epidural fibrosis, is primarily formed from fibrous connective tissue and develops in the postoperative hematoma that forms between the paraspinous muscles and the dura.
  • the dura is relatively thin and can easily be injured during surgery.
  • the dura is susceptible to damage during revision surgery when scar tissue adheres to the dura making it difficult for the surgeon to perform an adequate neurolysis.
  • the surgical lesion to be treated results from laminectomy, diskectomy, joint surgery, abdominal surgery, surgery of the hand or foot or corresponding extremities, or thoracic surgery.
  • Fibrotic joint lesions often result from traumata due to physical exertion or contact associated with athletics, such as fall or collision.
  • Scar tissue will form in the traumatized area after tendon or muscle damage and renders the injured joint stiff and painful. Removal of the fibrous adhesions by surgery or arthroscopy can induce further fibrosis during wound healing rendering the therapy unsuccessful similar to failed back surgery.
  • compositions of the present invention include prevention of scarring following transplantation, implantation of temporary prosthetics, and adhesions after surgery between the brain and the dura.
  • the inhibition or prevention of fibrosis after laminectomy or diskectomy in a mammal is a preferred embodiment of the present invention, particularly if the mammal is a human.
  • the uses, methods, compositions, gels and devices disclosed herein are preferably applied to humans.
  • the treatment of other mammals is envisaged as well, in particular the treatment of big animals, in particular domestic animals such as horses, cows, sheep, dogs, but also other mammals such as elephants and other animals comparable in size.
  • the resorbable, viscous substance is a gel.
  • the term "gel” refers to a colloid in which the disperse phase has been combined with the continuous phase to produce a viscous semisolid jelly-like or a semi-fluid product.
  • the gelling may entirely or partially occur prior to delivery to the mammal, and in the latter case completely gel after delivery or the gelling may occur entirely after delivery.
  • a gelling agent may be used or other gelling may be caused to occur because of shifts in pH or temperature (thus, a composition may be ungelled at room temperature, but when injected, due to the higher body temperature may gel).
  • gels or gels and fluids are possible.
  • the gelatin is a thermo-reversible gel that will return to the liquid state at a higher temperature.
  • the gel can be either of a semisolid type or semi-fluid. Examples for a semisolid gels are disclosed e.g. in US patent No. 6,565,842. It can also be a liquid material or a gel material having a viscosity or density that is lower than the above-described ranges, but is capable of forming a suitable gel in the physiological environment of a mammal, e.g., in a human body. For this purpose, many polymers known in the art can be used. For example, US patents Nos.
  • 4,474,751 and 4,474,752 disclose polymers known as Tetronic® polyols. Such polymers can be dissolved in an aqueous base with a desired pH, and the solution can be injected subcutaneously or intramuscularly. Upon injection into a physiological environment, the aqueous solution can form a semi-solid gel at body temperature.
  • compositions, wherein the resorbable, viscous substance is a semi-fluid gel are preferred.
  • suitable substances for the gel include, but are not limited to agarose, alginate, collagen, carrageenan (a carboxylated seaweed polysaccharide), chitosan and derivatives thereof.
  • polylactide chondroitin sulfate (a proteoglycan component)
  • polyesters polyethylene glycols, polycarbonates, polyvinyl alcohols, polyacrylamides, polyamides, polyacrylates, polyesters, polyetheresters, polymeth- acrylates, polyurethanes, polycaprolactones, polyphosphazenes, polyorthoesters, polyglycolides, copolymers of lysine and lactic acid, copolymers of lysine-RGD and lactic acid, dextran, dextrin, starch, cellulose, chitosan, demineralized bone matrix and the like and copolymers of the same.
  • the viscosity of the gel will be highly dependent on the amount of cross-linking within the polymer. Methods for decreasing or increasing the viscosity either by controlling the cross-linking or other suitable means are well known to those skilled in the art.
  • the resorbable, viscous substance is designed to be resorbed by the mammal during the wound healing process.
  • wound healing times may vary. Superficial cuts will heal within a few days while extensive back or knee surgery will take several weeks to months to heal completely.
  • the resorbable substance is preferably degraded or absorbed substantially within 6 months after application, more preferably within about 3 months after application.
  • said substance is completely degraded or absorbed within one year after application.
  • the antineoplastic agent is designed to be released in an active form over time.
  • General methods for the preparation of retard compositions, i.e compositions for controlled release of drugs are known in the art; see, e.g., Gupta et al, Drug Discov. Today 7 (2002), 569-579.
  • Controlled release can be achieved for example by chemical modification of the agent or application as a prodrug, whereby the prodrug is inactive and rendered active by a metabolic reaction at the site of application.
  • various formulations of agents are possible, tailoring the release according to needs.
  • the antineoplastic agent can be cross-linked with the resorbable substance such that it is released when the substance is degraded.
  • the present invention also concerns the pharmaceutical compositions as defined above as well as surgical gels comprising an antineoplastic agent according to the invention.
  • the composition or gel according to the invention further comprises a local analgesic or anesthetic and/or anti-inflammatory agent, preferably in a form to be released over time. That way the pain of wound healing is treated simultaneously and thereby reducing the stress to the mammal.
  • Local application requires usually a lower dose of analgesic or anesthetic, which is a further advantage of providing an analgesic or anesthetic with the composition or gel of the invention.
  • Suitable analgesics or anesthetics are well known to those skilled in the art and readily available.
  • the effective dosage of said analgesic or anesthetic can be readily determined or is provided by the manufacturer.
  • analgesics or anesthetics include, but are not limited to, Dilaudid, Hydrocodone meperidine, Morphine sulfate, Oxycodone, Oxy- codone/aspirin propoxyphene napsylate, Roxicet, Tramadol, Procaine, Tylenol/codeine, bupiva- caine, lidocaine, diazepam or morphine.
  • an anti-inflammatory agent can be added to the composition or gel according to the invention.
  • Inflammation is a cause for fibrosis and aggravates scarring as well as pain.
  • the antineoplastic agent might not inhibit inflammation sufficiently, even if it is effective in preventing or inhibiting fibrosis.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Aspirin Ibuprofen (Advil, Motrin, others), Ketoprofen (Orudis), Naproxen so- dium (Aleve), Diclofenac potassium (Cataflam), Diclofenac sodium (Voltaren), Etodolac (Lodine), Flurbiprofen (Ansaid), Indomethacin (Indocin), Ketorolac (Toradol, Acular), Nabu- metone (Relafen), Naproxen (Anaprox, Naprelan, Naprosyn), Oxaprozin (Daypro), Piroxicam (Feldene) or Sulindac (Clinoril).
  • steroidal anti-inflammatory drugs like, e.g., Corticosteroids or Prednisone.
  • the gel can contain local hemostypic agents, for example fibrin, thrombin or fibrinolysis inhibitor aprotinin, to improve the prevention of peridural fibrosis corresponding to the previous study described in Lee et al., Minim. Invasive Neurosurg. 46 (2003), 106-109.
  • local hemostypic agents for example fibrin, thrombin or fibrinolysis inhibitor aprotinin
  • aprotinin fibrinolysis inhibitor
  • a medicinal composition comprising a pain medication described above (whether time release or not) and the antineoplastic agent as described in this embodiment preferably will provide several beneficial functions, i.e. pain mitigation and scar tissue suppression at the surgical site.
  • a medicinal composition is of particular use following spine surgery, where the effects of postoperative pain and scar tissue formation all can be devastating and debilitating, whether acute or chronic.
  • the present invention is particularly useful when a patient is undergoing spinal or orthopedic surgery and will need a bone graft.
  • the present invention also encompasses the use of a resorbable, viscous substance and/or an antineoplastic agent for the preparation of the pharmaceutical composition or gel of the invention as well as a method for inhibiting or preventing fibrosis and/or scarring of a lesion in a mammal, wherein an antineoplastic agent is applied to the lesion in an amount that effectively reduces fibrosis.
  • the present invention relates to a sterile device, designed for the application of the pharmaceutical composition or gel according to the invention into a surgical lesion.
  • a sterile device designed for the application of the pharmaceutical composition or gel according to the invention into a surgical lesion.
  • the properties of the antineoplastic agent and the site of lesion different devices can be necessary, ranging from common syringes to specialized apparatuses as disclosed in international application WO02/055135.
  • the antineoplastic agent and the resorbable, viscous substance are mixed upon application. Examples for such two-barrelled syringe-like applicators are those commonly used to apply fibrinogen-based tissue sealants known as DUPLOJECT, PAN- TAJECT or HEMASEEL.
  • MMC Mitomycin-C
  • MMC was applied to the laminectomy sites in various concentrations. Alternately, MMC in concentrations of 0.01, 0.05 and 0.1 mg/ml was applied locally to the laminectomy sites. One laminectomy site per rat was left without any treatment, and served as a control. Pre- and postoperatively evoked potentials - sensible (SEP) and motor-evoked potentials (MEP) - were measured in addition to clinical evaluation. Mobility and any evidence of neurological deficit were recorded.
  • mice Five male Wistar rats, each weighing 400 - 450 g, were used in this study. On each of rats, three laminectomies were performed at cervical, thoracic and lumbar vertebrae. The animals were anesthesized with intraperitoneal application of Nembutal (7.5 mg/kg body weight). Using an aseptic technique, the dorsal skin and fascia were incised in the midline under a surgical microscope. After separation of the paraspinal muscles, the spinous processes were removed with a rongeur. A rectangular 5x2 mm laminectomy defect was created with a high speed drill, leaving the dura clean and fully exposed.
  • Nembutal 7.5 mg/kg body weight
  • SEP Stenor
  • MEP motor-evoked potentials
  • Histopathological evaluation was performed 8 weeks later. After sacrificing by an overdose of intraperitoneally pentobarbital, the animals were intracardially perfused with phosphate-buffered saline solution (0.1 M; pH 7.2) followed by 4 % paraformaldehyde solution. Afterwards, the spinal column including surrounding muscle tissue was removed en bloc. After 4 days of decalcifi- cation, formalin-fixed paraffin sections were histopathologically analyzed. Each bloc was completely cut in 10 ⁇ m sections to optimally visualize the laminectomy site. These sections were stained for hematoxylin and eosin (H&E) and Elastica van Gieson (EVG). The epidural fibrosis was graded for severity as absent, light, moderate or dense. The extent of fibrosis along the dura mater was examined.
  • H&E hematoxylin and eosin
  • EMG Elastica van Gieson
  • the epidural fibrous tissue was moderate in cases of MMC with concentration of 0.05 mg/ml, especially bilaterally near the bony defect (Fig. 2).
  • Fig. 3 In the laminectomy defects treated with MMC with concentration of 0.01 mg/ml, a wide-spread dural adhesion was observed (Fig. 3). No side effects on nervous tissue was noted. All control sites showed dense epidural fibrosis with marked dura adherence (Fig. 4).
  • this study shows that local application of MMC solution into the laminectomy defect is very effective in reducing edpidural scar formations and preventing dural adhesions in adult rats, respecting the integrity of adjacent nervous tissue.
  • the application of MMC solution over the dura mater and around the nerve roots is easily feasible. Because of the fluid state of MMC, a compression of nervous tissue like epidural implants did not occur. Furthermore, any chronic inflammatory reaction of the dura mater was prevented.
  • compositions comprising an antineoplastic agent, preferably an antibiotic such as Mitomycin-C in combination with a substance or matrix which is resorbable and viscous such as a semi-fluid gel is envisaged.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions comprenant un agent antinéoplasique et une substance visqueuse, résorbable, permettant d'inhiber ou de prévenir la fibrose et/ou la cicatrisation d'une lésion chez un mammifère. L'invention concerne également des compositions pharmaceutiques ainsi que des gels chirurgicaux comprenant un agent antinéoplasique permettant de prévenir les cicatrices et les fibroses après blessure ou chirurgie.
PCT/EP2004/009867 2003-09-03 2004-09-03 Compositions pour prevenir les cicatrices et les fibroses apres blessure ou chirurgie WO2005020955A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006113249A2 (fr) * 2005-04-12 2006-10-26 Warsaw Orthopedic, Inc. Procedes et dispositifs de protection de la mobilite d'un disque prothetique articulaire
WO2009016379A3 (fr) * 2007-08-01 2009-04-16 Renovo Ltd Médicaments et procédés permettant d'inhiber la cicatrisation non oculaire
EP2332591B2 (fr) † 2008-03-13 2018-02-28 KCI Licensing, Inc. Système de déchargement et de traitement de pression réduit

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WO1995009003A1 (fr) * 1993-09-29 1995-04-06 Alcon Laboratories, Inc. Compositions contenant des facteurs de croissance et des antimetabolites
EP0931548A2 (fr) * 1998-01-22 1999-07-28 Seikagaku Corporation Agent Antifibrotique

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WO1995009003A1 (fr) * 1993-09-29 1995-04-06 Alcon Laboratories, Inc. Compositions contenant des facteurs de croissance et des antimetabolites
EP0931548A2 (fr) * 1998-01-22 1999-07-28 Seikagaku Corporation Agent Antifibrotique

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006113249A2 (fr) * 2005-04-12 2006-10-26 Warsaw Orthopedic, Inc. Procedes et dispositifs de protection de la mobilite d'un disque prothetique articulaire
WO2006113249A3 (fr) * 2005-04-12 2007-08-02 Warsaw Orthopedic Inc Procedes et dispositifs de protection de la mobilite d'un disque prothetique articulaire
JP2008538315A (ja) * 2005-04-12 2008-10-23 ウォーソー・オーソペディック・インコーポレーテッド 関節形成性人工円板の運動能力を保存する方法およびデバイス
AU2006236849B2 (en) * 2005-04-12 2010-04-15 Warsaw Orthopedic, Inc. Methods and devices for preserving motion in an articulating prosthetic disc
US8257438B2 (en) 2005-04-12 2012-09-04 Warsaw Orthopedic, Inc. Methods and devices for preserving motion in an articulating prosthetic disc
WO2009016379A3 (fr) * 2007-08-01 2009-04-16 Renovo Ltd Médicaments et procédés permettant d'inhiber la cicatrisation non oculaire
EP2332591B2 (fr) † 2008-03-13 2018-02-28 KCI Licensing, Inc. Système de déchargement et de traitement de pression réduit

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