WO2006045183A1 - Compositions barrieres polymeres pour plaies chirurgicales - Google Patents

Compositions barrieres polymeres pour plaies chirurgicales Download PDF

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Publication number
WO2006045183A1
WO2006045183A1 PCT/CA2005/001631 CA2005001631W WO2006045183A1 WO 2006045183 A1 WO2006045183 A1 WO 2006045183A1 CA 2005001631 W CA2005001631 W CA 2005001631W WO 2006045183 A1 WO2006045183 A1 WO 2006045183A1
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WIPO (PCT)
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composition
film
agent
polymer
bone growth
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PCT/CA2005/001631
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English (en)
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John K. Jackson
Helen Burt
Gethin Owen
Donald Brunette
Babak Cheroudi
Karen Long
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The University Of British Columbia
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Publication of WO2006045183A1 publication Critical patent/WO2006045183A1/fr

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    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L31/127—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing fillers of phosphorus-containing inorganic materials
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/041—Mixtures of macromolecular compounds
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L31/129—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing macromolecular fillers

Definitions

  • This invention relates to the field of resorbable polymer barrier compositions for use in surgical applications.
  • Periodontal tissues that surround teeth are composed of bone, cementum (a bony substance covering the root of the tooth), periodontal ligaments and a sheath of gingiva.
  • Periodontitis is a disease condition caused by the accumulation of oral bacterial between the gingival and the apical portion of the tooth. If oral hygiene is not maintained the bacteria will replicate, and accumulate to form a 'biofilm'. Once the biofilm is established, the bacteria release toxins into surrounding tissues, invoking a host immune response, including degrading enzymes in attempts to confine the bacterial invasion.
  • Neutrophils at the site of inflammation attempt to destroy the bacteria by releasing proteolytic enzymes such as neutrophilic serinases, elastase, cathepsin and the matrix metalloproteinases including gelatinase and collagenase. In doing so, further damage to the gingival tissues results, periodontal ligaments (PDL) and crestal alveolar bone. Bone resorption is caused by the osteoblasts which are attracted to the site and stimulated by neutrophilic inflammatory mediators such as TNF-alpha and IL-1 (Potemba J et al. 2000. RpIe of bacterial proteinases in matrix destruction and modulation of host response. Periodontology 24:153-192. HaII 1 T and Chambers, T.
  • debridement In severe cases, surgical intervention is required to remove the inflamed tissue and bacteria from the periodontal pocket - this is known as debridement.
  • Poly(lactic-co-glycolic acid) is a synthetic, resorbable polymer with known applications in guided tissue regeneration. Without the inclusion of elasticizing agents, PLGA films are relatively stiff and inelastic, with a long degradation profile. Under normal physiological conditions, PLGA films degrade over a 3 to 6 month period and the inclusion of medicaments in the PLGA film had little effect on degradation rates ⁇ Andersen JM and Shive MS. 1997. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv. Drug. Del. Rev. 28:5-24; Webber WL et al, 1997. Characterization of soluble, salt-loaded degradable PLGA films and their release of tetracycline J Biomed Mater Res.
  • a polymeric barrier composition comprising a polymer of lactic acid and glycolic acid, an elasticizing agent and a bone growth enhancing agent for the preparation of a medicament for the treatment of a surgical wound.
  • the composition may be capable of forming a film, or may be a film.
  • a polymeric barrier composition comprising a polymer of lactic acid and glycolic acid, an elasticizing agent and a bone growth enhancing agent.
  • the composition may be capable of forming a film, or may be a film.
  • a method of preparing a polymeric barrier composition comprising combining a polymer of lactic acid and glycolic acid with an elasticizing agent and a bone growth enhancing agent in an organic solvent, to form a solution or suspension, casting said solution or suspension on a form or mould, and evaporating said organic solvent, causing a polymer film to remain on said form or mould.
  • a method for the treatment of a surgical wound comprising administering a polymeric barrier composition to a patient in need thereof, wherein the polymeric barrier composition comprises a polymer of lactic acid and glycolic acid, an elasticizing agent and a bone growth enhancing agent.
  • the composition may be capable of forming a film, or may be a film.
  • the elasticizing agent may be selected from the group consisting of MePEG, PEG, and an amphipathic diblock copolymer.
  • the elasticizing agent may be present in a range of concentrations, from about 1% (w/w) to about 40% (w/w).
  • the bone growth enhancing agent may be a bisphosphonate.
  • Bisphosphonates include alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate and zoledronate.
  • the bisphosphonate is present in a concentration from about 0.1% to about 5%.
  • said bone growth enhancing agent is selected from the group consisting of hydroxyapatite, calcium pyrophosphate, calcium triphosphate and demineralised bone.
  • Hydroxyapatite, calcium pyrophosphate and calcium triphosphate are examples of a more general group of calcium phosphates.
  • said bone growth enhancing agent is a calcium phosphate.
  • he bone growth enhancing agent is hydroxyapatite.
  • the bone growth enhancing agent is present in a concentration of about 20% to about 80%, or about 25%, or about 50%, or about 75%.
  • the ratio of lactic acid to glycolic acid in the polymer of lactic acid and glycolic acid is from about 50:50 (w/w) to about 95:5 (w/w).
  • the ratio of lactic acid to glycolic acid is about 50:50 (w/w), or about 85:15 (w/w) or about 95:5 (w/w).
  • the composition may further comprise an antibiotic, antiproliferative or anti- inflammatory medicament.
  • a kit for preparing a polymer barrier composition comprising a polymer of lactic acid and glycolic acid, an elasticizing agent, a bone growth enhancing agent and instructions for combining the polymer, the elasticizing agent and the bone growth enhancing agent.
  • the composition may be capable of forming a film, or may be a film.
  • the kit may further comprise a form or mould.
  • the polymer of lactic acid and glycolic acid and/or the elasticizing agent and/or the bone growth enhancing agent may be provided solubilised or suspended in an organic solvent.
  • Figure 1 shows a thermogram of PLGA (50/50) films containing 0%, 10%, 20%, 30% or 40% MePEG (w/w).
  • Figure 2 illustrates the change in the glass transition temperature (Tg) of a PLGA (50/50) film containing 0%, 10%, 20%, 30% or 40% MePEG.
  • the open circles show the theoretical drop as determined by the Fox equation, and the closed circles show the measured Tg values.
  • Figure 3 illustrates the change in the glass transition temperature (Tg) of a PLGA (85/15) film containing 0%, 10%, 20%, 30% or 40% MePEG.
  • FIG. 4 shows stressistrain curves for PLGA (85/15) films containing 0, 5%, 10%, 15% or 20% MePEG.
  • the star series show the results for a film containing 0% MePEG
  • the 'x' series show the results for a film containing 5% MePEG
  • the grey triangle series show the results for a film containing 10% MePEG
  • the solid square series show the results for a film containing 15% MePEG
  • the solid diamond series show the results for a film containing 20% MePEG.
  • Figure 5 shows a time course of MePEG loss from films of 50:50 PLGA containing 20% w/w MePEG, incubated in PBS, as determined by quantitative gel permeation chromatography.
  • Figure 6 shows the change in mass of a PLGA (85/15) film containing 10%
  • Figure 7 shows the change in area of a PLGA (85/15) containing 10% MePEG film over time as MePEG is solublized out of the film.
  • Figure 8 shows the cumulative release of tetracycline from PLGA (85/15) films including 0%, 10%, 20% or 30% MePEG.
  • Solid diamonds show the release of tetracycline from films containing 0% MePEG
  • solid squares show the release of tetracycline from films containing 10% MePEG
  • solid triangles show the release of tetracycline from films containing
  • Figure 9 shows a time course of the release of alendronate from PLGA (85/15) films including 10%, 20% or 30% of amphipathic diblock copolymer.
  • the Y axis is alendronate released in mg/mg film.
  • the hollow square shows the results of a film lacking alendronate.
  • the solid diamonds show the results of alendronate release in a film containing 10% amphipathic diblock copolymer
  • the solid squares show the results of alendronate release in a film containing 20% amphipathic diblock copolymer
  • the solid triangles show the results of alendronate release in a film containing 30% amphipathic diblock copolymer.
  • Figure 10 shows a bar graph illustrating the effect of alendronate on the growth of osteoblasts on PLGA (85/15)/10% amphipathic diblock copolymer films with varying concentrations of alendronate.
  • the Y axis is the number of cells per view.
  • the white bars show the count results on a film lacking alendronate, the black bars show the count results on a film containing 0.25% alendronate and the hatched bar shows the count results on a film containing 0.5% alendronate.
  • the invention provides, in part, a polymeric barrier composition for use in guided tissue regeneration.
  • the barrier composition includes a film containing of poly(lactic-co-glycolic acid), an elasticizing agent and a medicament, such as bone-growth enhancing agent.
  • the film may be precast on a template to a suitable size and configuration for the desired application, and may include a modified surface texture to encourage or inhibit migration and/or growth of specific cell types. Further embodiments of the invention may include the inclusion of antibiotics, anti-proliferative compositions or tissue regeneration or bone growth enhancing agents, such as bisphosphonates in the polymeric film.
  • a 'polymeric barrier composition' as used herein refers to a composition that is, or is capable of forming an impermeable or semi-permeable barrier.
  • the composition includes a polymer, for example a polymer of lactic acid and glycolic acid.
  • the composition may be formed into a barrier by moulding or casting in an appropriate shape.
  • the barrier may be a film.
  • a 'polymer of lactic acid and glycolic acid' as used herein refers to a polymer including repeating linked units of lactic acid and glycolic acid monomers.
  • a 'bisphosphonate' as used herein refers to a group of medicaments characterized by a geminal bisphosphonate bond.
  • Bisphosphonates may include alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zoledronate or pharmaceutically acceptable salts or derivatives thereof and mixtures thereof.
  • a therapeutically effective amount of a medicament as used herein refers to that amount of a medicament, for example, a bisphosphonate compound, that will elicit a desired therapeutic effect or response when administered in accordance with a desired treatment regimen.
  • a therapeutically effective amount of a bisphosphonate compound is an amount that, when administered to a patient or test subject, decreases the rate of bone resorption in a test animal or patient.
  • a therapeutically effective amount of a bisphosphonate when applied to cultured bone-regenerating cells, causes the cells to respond in a manner conducive to reducing resorption of bone.
  • a therapeutically effective amount of bisphosphonate when administered to a patient or test subject inhibits loss of bone mass at a site of periodontal surgery, or causes an increase in bone mass at a site of periodontal surgery.
  • treatment refers to the administration or application of a remedy or remedies to a patient or test subject for prevention or relief of disease or injury. Treatment may include medicinal applications or surgical management or therapy.
  • 'bone growth enhancing agent' refers to a composition that encourages or enhances the formation of bone or bone-like tissue.
  • bone growth enhancing agents include bisphosphonates, bone substitutes such as a calcium phosphate, demineralized bone or bioactive materials that act in a similar manner or have a similar effect.
  • a 'calcium phosphate' as used herein refers to a salt of calcium containing at least one phosphate group.
  • Examples of calcium phosphates include hydroxyapatite, calcium pyrophosphate and calcium triphosphate, Other examples of a calcium phosphate may include alpha-tricalcium phosphate (.alpha.-TCP), beta- tricalcium phosphate (.beta.-TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate hydrate, apatite, and fluorapatite.
  • a therapeutically effective amount of a bone growth enhancing agent is an amount that, when administered to a patient or test subject, inhibits further loss of bone mass, or increases bone mass.
  • the bone growth enhancing agent may be administered locally at a site of surgical intervention, for example a site of periodontal surgery.
  • a film may be impermeable or semipermeable, and may be, for example, a barrier.
  • a film may be opaque or transparent, or semi-transparent, and may be any desired colour, or have no colour (a 'clear' film).
  • a film may be homogeneous, or may have particulate components suspended in it.
  • a film may further have markings, patterns or other surface features on either or both sides. These surface features may result from the materials included in the film, or may result from the process by which the film is formed.
  • a film may be produced in a range of thicknesses depending on desired application.
  • a film may have a uniform thickness, or the thickness may vary in different areas.
  • 'plasticizer', 'plasticizing agent', 'elasticizer' or 'elasticizing agent' refer to a compound, for example an organic polymer, that, when combined with the parent material, confers elasticity or elastic properties such as stretching or flexibility.
  • elasticizing agents used herein may include methoxypolyethylene glycol (MePEG), polyethylene glycol (PEG) and amphipathic diblock copolymers.
  • the term 'elasticity' as used herein refers to the tendency of a body to return to its original shape after it has been deformed. Deformation may include stretching or compression.
  • the terms flexible, elastic, resilient or supple all refer in a literal sense to a body that is capable of withstanding stress without injury or damage.
  • a stress is an applied force or system of forces that may strain or deform a body.
  • To strain a structure or shape is to alter the relation between the parts of the structure or shape by applying an external force, which deforms the structure or shape.
  • the ratio of stress/strain is commonly referred to as Young's modulus. This is an established physical parameter of elasticity, and known in the art.
  • 'amphipathic diblock copolymer' refers to a polymer including two chains of differing polymers.
  • One polymer is hydrophobic, and the second is hydrophilic.
  • hydrophobic polymers may include but are not limited to polylactic acid, polylactic-co-glycolic acid, polycaprolactone, polyhydroxybutyrate and polymethylmethacrylate.
  • hydrophilic polymers may include but are not limited to methoxypolyethylene glycol (MePEG), polyethylene glycol (PEG), polyacrylic acid and polysaccharides.
  • Polymeric barrier compositions may include biocompatible polymers, elasticizing agents and bone-growth enhancing agents, and in select embodiments, medicaments such as antibiotics, antiproliferative agents or anti-inflammatory agents.
  • biocompatible polymer is, for example PLGA.
  • PLGA over a range of lactic acid:glycolic acid ratios, is resorbable by the body. Further, PLGA does not substantially irritate or inflame the adjacent tissue in a surgical site where it may be used.
  • the various components of the polymeric barrier compositions are dissolved or suspended in a suitable hydrophobic, volatile organic solvent, and this solution or suspension is applied to a casting surface, and the solvent evaporated, leaving behind the polymerized film.
  • a suitable solvent is one that is compatible with the polymers, elasticizing agents, medicaments, bone-growth enhancing agents and/or other medicaments included in the film.
  • Suitable solvents may include, for example, dichloromethane or acetone.
  • Methods for preparing the elasticizing agents such as amphipathic diblock copolymers are described ⁇ Letchford K et al, 2004. Synthesis and micellar characterization of short block length methoxy poly(ethylene glycol)-block- poly(caprolactone) diblock copolymers.
  • a hydrophilic polymer for example, MePEG
  • a hydrophobic polymer component for example epsilon- caprolactone.
  • the combined polymers were heated and mixed to produce a homogenous liquid.
  • Stannous octylate was added as a catalyst, and the polymerization reaction was allowed to proceed for at least 8 hours. The polymerization reaction was terminated by cooling to room temperature.
  • the casting surface may be a precast mould such as a 'negative' taken from a patient's jaw or teeth, or may be a precision-milled mould made from titanium or other suitable material.
  • a precast mould such as a 'negative' taken from a patient's jaw or teeth
  • flat films with little to no surface texture may be cast on TEFLONTM moulds.
  • films for example PLGA/MePEG films, may be cast to a fixed moulded shape other than a substantially flat surface.
  • a precast rigid form such as that taken from a mold of the patient's teeth and jaw before surgery may be used.
  • Such a mould may be made from a sculptable material, for example PROVILTM novo (Heraus), or other suitable casting polymer.
  • the cast of the patient's preoperative jaw may be used as a form, possibly with minor modifications as determined by the surgeon.
  • a PLGA film as described in an embodiment of this invention may be placed over the mold and moistened with water to set the three-dimensional shape. Once the film has gained a measure of rigidity, it may then be removed from the mould and placed over the exposed periodontal pocket, so that a small void is present under the film surface. This technique may thus provide a void for the bone to grow into without the need for placing infill material in the space.
  • Other methods and techniques for manipulating such polymeric barrier compositions known to a person of skill in the art may also be used.
  • Grooved surfaces for use in casting a grooved film may be prepared by micromachining a grooved surface of desired pitch, width and depth on a silicon wafer.
  • a textured surface for use in casting may be prepared by sand- blasting and acid-etching a titanium blank.
  • a film cast using this silicon wafer and titanium mould may have a grooved first side and a textured second side.
  • Groove width is for example, about 30 micrometers, with sides at an angle of, for example, about 125° and a pitch of, for example about 45 micrometers or about 175 micrometers.
  • a film may be cast to have a thickness from about 50 micrometers to about 200 micrometers inclusive.
  • the polymeric barrier compositions may include medicaments such as antibacterial medicaments or antibiotics in a therapeutically effective amount, for example tetracycline at about 5%.
  • the release profile of the antibiotic from the polymeric barrier composition for example a film, may be controlled by varying the amount of elasticizer; for example MePEG, in the film.
  • MePEG elasticizer
  • antibiotics examples include tetracyclines such as minocycline, doxycycline, oxytetracycline, demeclocycline, or methacycline which may be preferred for periodontal applications.
  • antibiotics such as penicillins, cephalosporins, aminoglycosides, erythromycins and related antibiotics, vancomycin, polypeptide antibiotics or sulfonamides. Dosage ranges and preferred applications are specific to the antibiotic selected, and examples of such may be found, for example, in the Merck Manual of Diagnosis and Therapy, 15 th edition (Merck).
  • the polymeric barrier composition may include medicaments such as antiproliferative medicaments.
  • An antiproliferative agent is an agent that exerts an inhibitory effect on cell proliferation.
  • the antiproliferative agent may have a cytostatic effect, where cell growth may be slowed or stopped, or a cytotoxic effect wherein cells are killed, by apoptosis or other biological mechanisms.
  • Antiproliferative drugs may include antimetabolites such as methotrexate; anticancer drugs such as estramustine, platinum containing compounds, or 5-fluorouracil; microtubule inhibitors such as paclitaxel, colchicine or vinca alkaloids including vincristine and vinblastine; topoisomerase inhibitors such as camptothecin, etoposide, doxorubicin, mitoxantrone; DNA intercalating agents such as anthracyclines; oxygen-radical producing agents such as napthoquinones; and antiangiogenic agents such as paclitaxel, thalidomide, VEGF related antibodies or statins; or derivatives of any of these
  • the antiproliferative agent may be applied to an outer surface boundary of the cast polymeric barrier composition, for example a film.
  • the antiproliferative medicament may be preferentially deposited as a border of about 1-2 mm width on the 'outer' side of the film (not facing the tooth), to inhibit epithelial cell and gingival fibroblast proliferation in a controlled manner.
  • this temporary inhibition of growth at the boundaries may prevent the invasion of the epithelial cells around the membrane and into the periodontal pocket.
  • This selective inhibition of cell growth may further give the osteoblasts more time to develop a bone or bone-like tissue barrier to epithelial cell infiltration around the film into the pocket.
  • This improvement may be achieved by dissolving or suspending the antiproliferative medicament in a small volume of suitable solvent and pipetting or painting a thin bead of the drug solution on boundary regions of the non-channeled or outer side of the membrane.
  • the solvent may further help to incorporate the antiproliferative medicament by partially dissolving the outer boundary region and allow medicament penetration into the matrix of the film.
  • anti-inflammatory agents may be incorporated into the polymeric barrier composition for release in a controlled manner over time. Inhibition of the inflammation that underlies periodontal disease and accompanies surgical repair of the damaged tissue and bone would be advantageous.
  • suitable medicaments may include those that inhibit leukocyte activation or migration into the area, inhibit the production of cytokines, chemokines or chemotactic mediators that exacerbate inflammation and osteoclast activity, or inhibit the production or action of metalloproteinases.
  • an amphipathic diblock copolymer for manufactured from methoxypolyethyleneglycol-block- polylactic acid was included with PLGA and a bone-growth enhancing agent.
  • GTR guided tissue regeneration
  • a resorbable barrier is one that includes material that is able to be dissolved and/or assimilated in the body.
  • the material may be digested or otherwise acted upon by enzymes or cells in the body of the host animal and be broken down into constitutive molecules, which are then metabolized or further processed for metabolism.
  • PLGA films are broken down to the constitutive lactic acid and glycolic acids.
  • the length of time that a barrier should remain at the surgical site may vary depending on the site, surgeon preference, rate of healing and other factors that may influence the surgical repair.
  • a barrier that is resorbed too quickly may permit ingrowth of unwanted cells, while a barrier that is resorbed too slowly may prevent healing of the site.
  • a surgeon may want to maintain a void or space around the wound site - this may be described as a wound space.
  • the presence of such a wound space may permit bone or bone-like tissue to grow into the space as the wound heals.
  • the barrier is too rigid, it may not be effectively shaped to the desired wound space and may permit the invasion of unwanted cells.
  • the barrier is too flexible, a wound space may not be maintained for sufficient time following surgery to permit bone or bone-like tissue to fill in. As osteoblasts proliferate and migrate up the inner surface channels of the grooved PLGA film, these cells may lay down calcified nodules and begin to form layers on the inner surface of the film.
  • These layers may form a stiffening structure so that as the film, for example a PLGA/MePEG film degrades, this layer of bone or bone-like tissue becomes structural, allowing growth of bone and/or bone-like tissue on the inner side (facing the tooth) into the wound space.
  • This new bone/bone-like tissue may serve as an additional barrier to unwanted cells such as epithelial cells and gingival fibroblasts migrating from the gingival flap side of the interface.
  • incorporation of a bone growth enhancing agent into the film provides controlled release of these agents at the surgical site, enabling a higher localized concentration than otherwise possible through systemic administration of these medicaments.
  • alendronate is released from the film in a controlled, time-dependent manner.
  • the polymeric barrier composition for example a PLGA/MePEG film
  • absorbs water and swell it increases in rigidity.
  • this swelling may further seal the outer boundary of the film, so that epithelial cells and gingival fibroblasts may be prevented from growing or migrating around the film and invading the wound space.
  • Swollen films maintain the feature of aligned osteoblastic cell growth along the residual channels on the films.
  • the resulting swelling may further promote the formation of the rough, swollen surface that encourages the attachment but discourages the migration of epithelial cells.
  • the degradation rate of the film is dependent on the ratio of lactic acid to glycolic acid in the copolymer, and on the molecular weight of the starting polymer. Degradation may further be affected by the concentration of the elasticizing agent, for example, MePEG, in the film.
  • the PLGA polymer may, for example, have a lactic acid:glycolic acid ratio from about 50:50 (w/w) to about 85:15 (w/w), inclusive. In alternate embodiments, the lactic acid:glycolic acid ratio may be, for example, about 55:45, or about 60;40, or about 65:35, or about 70:30, or about 75:25, or about 80:20 or about 85:15, inclusive, or any integer ratio in between. In an alternative embodiment, the lactic acid:glycolic acid may be as great as 95:5.
  • the concentration of elasticizing agent for example MePEG, may be about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%. In alternative embodiments, the elasticizer concentration may be from about 1% to about 40% inclusive, and any integer in between, inclusive.
  • polymeric barrier compositions provide, for example films, that have the feature of being flexible and elastic once cast, but become more rigid upon exposure to water.
  • the polymeric barrier compositions may include biocompatible polymers, elasticizing agents and bone-growth enhancing agents, and in select embodiments, medicaments such as antibiotics, anti-proliferative agents or anti ⁇ inflammatory agents.
  • biocompatible polymer is PLGA.
  • PLGA over a range of lactic acid:glycolic acid ratios, is resorbable by the body. Further, PLGA does not substantially irritate or inflame the adjacent tissue in a surgical site where it may be used.
  • Varying the elasticizing agent and/or the concentration of the elasticizing agent in the polymeric barrier composition provides for another method to alter the elasticity and rate of change in rigidity in the resulting film, offering an advantage to the surgeon.
  • Increasing the concentration of the elasticizing agent, for example MePEG in a film, for example a PLGA film increases the elasticity (as measured by Young's modulus) and decreases the glass transition temperature.
  • a therapeutically effective amount or concentration of elasticizing agent for a film for use in a particular surgical procedure may be dependent on both the specific needs of the surgical procedure and the preference of the surgeon.
  • Glass transition temperature is dependent on the concentration of the elasticizer, and may be calculated using, for example, the Fox equation. Other methods of determining a desired concentration will be known to those of skill in the art.
  • a film with a higher elasticizing agent concentration may be selected to provide a film that maintained elasticity for a longer period of time.
  • Other excipients, medicaments or materials known in the art may also be incorporated into the polymer barrier compositions to provide altered elastic properties. Properties of the excipient and/or elasticizing agent, such as molecular weight may enable further manipulation and control of the elasticity and handling of the film. For example, higher molecular weight MePEG or PEG may reduce the glass transition temperature of the polymeric barrier composition, resulting in reduced elasticity.
  • incorporation of bone-growth enhancing agents such as hydroxyapatite or calcium phosphate microparticles into the polymeric barrier composition provides enhanced structural rigidity of the resulting film, but the film does not become inflexible and brittle.
  • This was unexpected as a suspension of insoluble, inorganic material in a hydrophobic organic solvent/polymer mixture would have been expected to aggregate and not remain homogeneously distributed throughout the resulting film.
  • the microparticles remained homogenously dispersed throughout the film. More surprisingly, the presence of microparticles did not adversely affect channel formation when the films were cast on grooved templates.
  • the resulting films were flexible and had well formed channels with clear evidence of uniformly distributed microparticles along the channel sides without interference of channel structure. These films were found to have unusual properties in that instead of being purely elastic (i.e. returning to the original shape after stretching or manipulation), they could be shaped around forms and when the form was removed they retained much of the shape of the form without returning to the original flat film shape. This feature was unexpected and is advantageous in the application of such films in a clinical setting, as a surgeon may have more control over the shape and positioning of the film at a surgical site and may cast a film to a desired three-dimensional shape.
  • PLGA/MePEG films were produced ratios of 75% hydroxyapatite, 2.5% MePEG and 22.5% PLGA. It was found that these 75% hydroxyapatite films retained a flexible structure, although elasticity was reduced compared to films that did not include hydroxyapatite or other microparticulates. These films could be readily formed without breakage of the film structure. The films were still slightly elastic under mild stretching, and inclusion of 75% hydroxyapatite did not interfere with channel formation when casting. As observed with other PLGA/MePEG films, the hydroxyapatite-containing films became more rigid when water was introduced around the film. This characteristic of these hydroxyapatite-containing films enables the manufacture of grooved films with various levels of elasticity/rigidity.
  • hydroxyapatite or other bone-compatible material may promote the rapid formation of bone by the osteoblasts growing up the grooved channels. Not only might such cells adhere to such material, the material offers a readily available source of calcium for mineralization and bone formation.
  • the hydroxyapatite (or other microparticulate matter) may further offer scaffold type properties such that the periodontal space or void may remain empty or clot filled, without collapse of the film into the space.
  • Another advantage of the inclusion of insoluble microparticles is that they may form a physical barrier to epithelial cell ingrowth through a polymeric barrier composition film that may degrade prior to effective bone formation.
  • An additional embodiment may incorporate hydroxyapatite particles in combination with at least one bisphosphonate medicament (hydroxyapatite particles coated with the medicament, for example) in the polymer barrier compositions of this invention.
  • other materials may be included in the polymeric barrier compositions, for example PLGA/MePEG films, to control mechanical properties.
  • Inorganic salts for example, sodium chloride may be suspended in the films when casting.
  • Other examples of such materials may include calcium phosphates, calcium salts or materials compatible with bone formation, for example demineralized bone fragments, for example calcium triphosphate, or other materials with properties similar to hydroxyapatite.
  • these bone-enhancing or bone-compatible materials may also be incorporated on the surface of the films after casting. A surface coating of bioactive material may attract osteoblasts, and also supply the osteoblasts with an enhanced supply of calcium phosphate for localized bone deposition.
  • the bioactive material may be distributed on the surface and 'set in' by subsequent exposure to a compatible solvent, so that the surface is partially solubilized and the particles embedded in the film matrix on one side of the film only, providing an optimized surface for osteoblast adherence, growth and replication.
  • the bioactive material may be suspended in the PLGA/MePEG casting solution in a compatible solvent before casting, so that the bioactive material is uniformly incorporated throughout the film.
  • bioactive materials may include compounds such as talc, beryllium or silica; components of the extracellular matrix (such as fibronectin), polymers such as poly-lysine, tet-ammonium end terminated polymers, cationic polymers such as chitosan, inflammatory cytokines, chemotactic molecules, growth factors, fibrin/fibrinogen or other coagulation inducing molecules such as thrombin, inflammatory microcrystals such as sodium urate or calcium pyrophosphate, or silicates. Derivatives or analogues of these materials are also included in this definition.
  • a film may have a thickness from about 25 micrometers to about 250 micrometers.
  • a film may have a thickness from about 25 micrometers to about 75 micrometers, or from about 50 micrometers to about 100 micrometers, or from about 75 micrometers to about 125 micrometers, or from about 100 micrometers to about 150 micrometers, or from about 125 micrometers to about 175 micrometers, or from about 150 micrometers to about 200 micrometers, or from about 175 micrometers to about 225 micrometers, or from about 200 micrometers to about 250 micrometers, or from about 225 micrometers to about 275 micrometers.
  • a film may also be cast for example, with a different thickness around the edge from that of the rest of the film, for example a thinner edge extending from about 1 to about 5 millimeters in from the edge.
  • Smooth, rough or grooved surfaces with a variety of groove dimensions may be replicated on, for example, PLGA-MePEG films, using methods such as obtaining a negative impression of a desired surface texture, for example a sandblasted acid-etched surface, or a precision-milled grooved surface on a casting form, followed by film casting on the form.
  • a method of solvent casting for replicating the desired topography was successful in the embodiments presented herein, however other methods will be known to those skilled in the art.
  • the use of a channeled surface on the inside or 'tooth' side of, for example, a PLGA/MePEG film may facilitate the accelerated bone cell growth along the inside surface of the film, forming new bone or bone-like tissue.
  • the layers of new bone or bone-like on the inner surface of the film may have a stiffening effect, so that as the, for example, PLGA/MePEG film degrades, these new layers become structural, further facilitating bone or bone-like tissue growth on the inner side and into the wound space, and remain as a structural barrier to epithelial cell and gingival fibroblast growth found on the outer side of the film.
  • the polymeric barrier composition for example a film, integrates with the surrounding tissues and, upon water adsorption, swells and seals the contact area at the surgical site, providing a barrier to exclude bacteria, epithelial cells and gingival fibroblasts from the wound space.
  • the film upon water absorption and subsequent swelling, loses elasticity and may be of sufficient strength and rigidity to withstand soft tissue contraction at the surgical site and maintain the wound space volume for the bone-regenerating cells. Kits
  • kits are a set of reagents and instructions for using the set of reagents to perform a task or produce a product.
  • a kit for making a polymeric barrier film according to one embodiment of the invention may include predetermined or premeasured quantities of an lactic acid:glycolic acid polymer, elasticizing agent and bone growth enhancing agents, either dry or solubilized or suspended in a suitable solvent, and instructions for combining the set of reagents in an appropriate manner.
  • the instructions may further include instructions for casting a film and evaporating the solvent to produce a film.
  • the solvent may be supplied separately and the instructions may provide details as to the volume required to produce a film with particular concentrations of elasticizing agent and/or bone growth enhancing agent.
  • the kit may also include moulds or forms suitable for casting the film.
  • PoIy(D 1 L lactic acid) /MePEG amphipathic diblock copolymer was synthesized in the laboratory and were composed of MePEG copolymerized with polylactic acid, according to the methods of Letchford ⁇ Letchford K et al, 2004. Synthesis and micellar characterization of short block length methoxy poly(ethylene glycol)- block-poly(caprolactone) diblock copolymers. Colloids and Surface B: Biointerfaces 35:81-91)) using MePEG MW 2000 g/mol and weight percentages of D,L-lactic acid and MePEG of 40:60. Briefly, MePEG, was combined with polylactic acid and the combined polymers were heated and mixed to produce a homogenous liquid. Stannous octylate was added as a catalyst, and the polymerization reaction was allowed to proceed for at least 8 hours. The polymerization reaction was terminated by cooling to room temperature.
  • Polymer solutions for film casting were made by dissolving the appropriate amount of polymers (PLGA (85/15 or 50/50) and MePEG or amphipathic diblock copolymer) in dichloromethane. Alendronate, tetracycline or other medicaments may also be incorporated in the film casting solution. Solutions were allowed to stand with intermittent gentle agitation, usually about 1 hour.
  • Film thickness ranged from about 50 micrometers to about 200 micrometers. Replication of surface topographies on epoxy & PLGA
  • the cleaning procedure involved ultrasonication in a detergent (7X, ICN Biomedicals, Inc., Costa Mesa, CA), and then replicas were sputter coated (Randex 3140 Sputtering System, Palo Alto, CA) with 50nm of Ti on both sides.
  • Cell proliferation Cells were cultured and plated on the PLGA membranes as previously described and seeded at a concentration of 10,000 cells/mL for 1 , 3 and 5 days . All samples were then rinsed with 0.01 M PBS buffer and stained with propidium iodide. Cells were imaged with an epifluorescent microscope (Axioscop, Zeiss, Germany) equipped with a rhodamine filter and images were captured digitally with Northern Eclipse software (Empix). Twenty images were taken from two samples and the number of cells per unit area were counted manually. One-way ANOVA and Bonferoni post-hoc statistical test were used at each time point to find significant differences in cell number among different surfaces. The significance level was set at 0.05.
  • DSC Differential scanning calorimetry
  • the glass transition temperature (Tg) is a measure of the temperature below which molecules have low mobility.
  • a polymer is more rigid below its Tg, and can become more flexible above the Tg.
  • Theoretical Tg values for a polymer blend (such as MePEG in PLGA) may be calculated using the Fox equation:
  • Figure 2 illustrates the effect of increasing MePEG on the Tg value in the 50:50 PLGA copolymer
  • Figure 3 illustrates the effect of increasing MePEG concentration on the Tg value in the 85:15 PLGA copolymer.
  • the measured drop (open circle series) in Tg approximately matched the theoretical drop (closed circle series) as determined by the Fox equation for full miscibility.
  • Strain was determined as the change in film length: (extension)/original length (m).
  • Sample films (0.8 cm x 0.8 cm) formulated with 80% w/w PLGA (50/50) with 20% w/w MePEG were placed in 14 mL PBS in a culture tube and oscillated at 150 rpm in a 37°C incubator. The supernatant was replaced with fresh PBS at regular intervals and oscillation continued at 37°C to maintain sink conditions. At various timepoints the supernatant was completely removed and the film dried at 30°C under a stream of nitrogen gas. Once completely dry, the film was dissolved in 1 ml of chloroform and the amount of MePEG remaining in the film was quantified by gel permeation chromatography.
  • Quantitative gel permeation chromatography was performed on the film samples at ambient temperature using a Shimadzu LC-10 AD HPLC pump, a Shimadzu RID-6A refractive index detector coupled to a 50 Angstrom Plgel column (Hewlett Packard).
  • the mobile phase was chloroform with a flow rate of 1 ml/min.
  • the injection volume of the polymer sample was 50 uL at a polymer concentration of approximately 0.25% (w/v).
  • Components of the film samples were detected by refractive index detection and the peak areas were used to determine the amount of MePEG remaining in the films at each time point.
  • PLGA/MePeg films swell in PBS.
  • PLGA (85/15)/MePEG films (90% PLGA (85/15)/10% MePEG 350) with one grooved surface were cast on PROVILTM forms as described above, with 30 ⁇ m deep, 30 ⁇ m wide channels and a pitch of 45 ⁇ m on one side .
  • the mass and dimensions (thickness and area) were measured and recorded for each film sample.
  • the films were then placed in sterile PBS at 37 0 C, removed at various time points and swabbed dry with tissue (to remove surface water) and the mass and dimensions measured and recorded. The time dependent change in both mass and area are shown in Figures 6 and 7 respectively.
  • Drug release experiments were performed as follows: 10 mg film including PLGA (85/15) with MePEG at 0%, 10%, 20% or 30% (w/w). Film samples containing 5% (w/w) tetracycline were placed in 16 ml test tubes and 15 ml of 1OmM phosphate buffered saline (PBS) was pipetted on top. The tubes were capped and incubated at 37 0 C with end over end rotation at 8 rpm. At various timepoints, the entire volume of buffer was removed and the concentration of tetracycline present was analysed by UV/VIS absorbance spectroscopy..
  • PBS 1OmM phosphate buffered saline
  • Tetracycline was released into the buffer in a linear manner ( Figure 8).
  • the release profile of antibiotic from the film is advantageous for treatment of the periodontal pocket.
  • An initial burst of antibiotic release occurs over the first few days, followed by a sustained release over the life of the film.
  • This profile creates a high initial concentration of the antibiotic locally in the periodontal pocket to prevent the growth of residual and influxing bacteria at the most critical time - before the wound has sealed up. This is followed by the maintenance of lower concentrations, which may be sufficient to prevent growth of the smaller numbers of bacteria able to invade the area as time progresses.
  • Example 7 Stiffening and degradation of PLGA/MePEG films in rodent models.
  • Wistar rats weighing 400 - 500 g were purchased from the Animal Care Center of the University of British Columbia. All procedures involving animals were approved by the Animal Care Committee of the University of British Columbia.
  • the area was perfused with a small amount of sterile isotonic saline and the film sutured in place. At this point, the films retained their original elasticity/flexibility that facilitated placement on the artery.
  • the films were monitored for stiffness and rigidity for 10-15 minutes, and the wound subsequently closed.
  • Stiffer films had lost their elasticity to some degree at this point and were less deformable. 5 animals were sacrificed at 2 weeks post- implantation, 5 at 4 weeks post-implantation, and the remaining 5 sacrificed at 12 weeks post-implantation, and the residual films assessed for resorption, degradation, and general condition.
  • the films showed significant signs of stiffening after just 5 to 10 minutes of placement at the surgical site. As films stiffen, less deformation occurs when films are manipulated manually. Animals assessed at 2 weeks had significant whole film sections remaining in place, while animals treated for 4 weeks had some minor residual traces of PLGA films left at the surgical site but essentially the film was fully degraded at this time. Animals treated for 12 weeks were free of any sign of residual films. No toxicity or adverse effects were noted in the animals treated with these films.
  • PLGA films including elasticizing agents such as methoxypolyethylene glycol (MePEG), for example, demonstrate a shorter degradation profile, and greater elasticity than those of PLGA alone.
  • PLGA/MePEG films degrade over a 4 to 6 week period. When placed in rats, the PLGA/MePEG films were substantially resorbed within 4 weeks. This faster degradation profile offered by the inclusion and rapid dissolution of MePEG accelerates water-induced hydrolytic PLGA degradation by allowing extensive water penetration into the film in a homogenous manner. This homogeneity arises from the homogeneous dispersion of the MePEG elasticizing agent.
  • MePEG methoxypolyethylene glycol
  • Osteogenic cells from newborn rat calvaria were isolated as described ⁇ Bellows CG et al., 1986. Mineralized bone nodules formed in vitro from enzymatically released rat calvaria cell populations. Calcif. Tissue Int. 38:143-54; Hasegawa S et al., 1985. Mechanical stretching increases the number of cultured bone cells synthesizing DNA and alters their pattern of protein synthesis. Calcif Tissue lnt 37:4431-6). Briefly, osteoblast like cell populations were isolated, by timed enzymatic digestion, from the frontal, parietal and occipital bones of newborn (24- 36 h old) Sprague-Dawley rates.
  • Osteoblasts on the grooved surfaces migrated in the direction of the groove and were not noticeably affected by the pitch width. Osteoblasts appeared more elongated on the grooved surfaces with a narrow pitch (45 micrometers) in which more cells were found in the grooves compared to those cultured on the grooves with a wider pitch (175 micrometers), where more cells were found on the ridges. On both surfaces, osteoblasts were polarized with lamellipodia and ruffling at the leading edge of the cell. Osteoblast numbers increased over a 5 day growth period on both the tissue culture plastic as well as the PLGA film surfaces.
  • Epithelial cells were isolated from porcine periodontal ligament and cultured as described (Brunette, EM et al, 1976. Culture origin of epithelium-like and fibroblast-like cells from porcine periodontal ligament explants and cell suspensions. Arch Oral Biol 21:393-400). Briefly, cells were maintained in a-MEM (Stem Cell Technologies Inc.,) supplemented with 15% fetal bovine serum (Medicorp, Montreal, Canada), antibiotics (penicillin G— Sigma, St. Louis, USA), 100 mg/mL; gentamicin (Sigma), 50 mg/mL; amphotericin B (Fungizone — Gibco), 3 mg/mL) in a humidified atmosphere with 5% CO2 at 37 1C.
  • a-MEM Stem Cell Technologies Inc.,
  • Confluent layers trypsinised (0.25% Trypsin, 0.1 glucose, citrate-silane buffer, pH 7.8) and seeded on all surfaces at a concentration of 20,000 cells/ml for 24 h.
  • the cells were between passages 5 and 11 they were used for aligned growth experiments.
  • PLGA/MePEG films containing calcium pyrophosphate or hydroxyapatite microparticles PLGA/MePEG films containing calcium pyrophosphate or hydroxyapatite microparticles.
  • PLGA/MePEG films including 50% hydroxyapatite or calcium pyrophosphate microparticles (w/w) were produced as described above. After dissolution of PLGA and MePEG, 100 mg of either calcium pyrophosphate (monoclinic form) or 100mg of hydroxyapatite (30 urn diameter) were subsequently added to the solution with vortexing. The resulting film solution was applied to the forms as described. The final composition of the resulting films was 45% (w/w) PLGA (85/15), 5 % (w/w) MePEG and 50% (w/w) microparticles of either hydroxyapatite or calcium pyrophosphate.
  • the resulting films were flexible and had well formed channels with clear evidence of uniformly distributed microparticles along the channel sides without interference of channel structure. Additionally, these films demonstrated a 'memory' characteristic.
  • the films when cast around a PROVILTM form, retained the shape of the form when removed and did not return to the original flat dimension. The cast films were flexible but did not exhibit the same elasticity as PLGA/MePEG films lacking hydroxyapatite or calcium pyrophosphate microparticles.
  • PLGA/MePEG films with increased hydroxyapatite 22.5% w/w PLGA (85/15), 2.5% MePEG (mw 325), 75% hydroxyapatite) were produced as described above.
  • the resulting films also demonstrated a flexible structure (with more rigidity than the 50% hydroxyapatite film) and were mouldable (using precast forms) without breakage of the film structure. Moderate elasticity was retained with the shift in the hydroxyapatite/PLGA/MePEG ratio. Inclusion of increased hydroxyapatite microparticles did not interfere with groove formation, and the films also became increasingly rigid when exposed to an aqueous environment.
  • Drug-loaded films were synthesized and cast as above but incorporated 5% w/w of alendronate (a bis-phosphonate), premixed with dichloromethane, before adding the dichloromethane to dissolve the PLGA (85/15) and amphipathic diblock copolymer.
  • 10 mg film samples including 5% (w/w) alendronate were placed in 16 ml test tubes and 15 ml of 1OmM phosphate buffered saline (PBS, pH 7.4) was pipetted on top. The tubes were capped and incubated at 37 0 C with end over end rotation at 8 rpm.
  • the entire volume of buffer was removed and the concentration of alendronate present in the buffer was analysed by HPLC (C18: 1 ml/minute flow of 1 mM Na 2 EDTA;MeOH pH 6.5, fluorescamine derivitization and detection using fluorescence analysis).
  • Alendronate was released into the buffer in a linear manner ( Figure 9).
  • the addition of increasing amounts of amphipathic diblock copolymer in the PLGA film caused a concentration dependent increase in the release rate of the drug from the films.
  • Example 12 Growth of osteoblasts on alendronate containing PLGA/diblock films.
  • PLGA (85/15): 10% amphipathic diblock copolymer films containing 0.25% or 0.5% alendronate were synthesized and cast as described above. Osteoblast cells were cultured and seeded on the films as described above. Cells that adhered to the films were later imaged and counted with an epifluorescent microscope, following propidium iodide staining.
  • alendronate causes a temporary inhibition of osteoblast proliferation, but is not cytotoxic at these concentrations, as the cells recovered and demonstrated proliferation by 7 days. At lower concentrations the proliferation of osteoblasts was enhanced.
  • At least one bisphosphonate for example alendronate
  • the medicament may be incorporated and cast in the films.
  • Such bisphosphonate-enhanced films provide a controlled release of the medicament (Figure 9).
  • the localized release of alendronate from the film enhanced proliferation of osteoblasts.
  • Higher concentrations of alendronate appeared to initially suppress osteoblast proliferation, however proliferation was observed at later times ( Figure 10).

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Abstract

Composition comprenant un polymère d'acide lactique et d'acide glycolique, un agent d'élastification et un agent favorisant la croissance osseuse. La composition peut être utilisée pour la préparation d'un médicament pour le traitement d'une plaie chirurgicale.
PCT/CA2005/001631 2004-10-25 2005-10-24 Compositions barrieres polymeres pour plaies chirurgicales WO2006045183A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2295480A1 (fr) * 2009-09-10 2011-03-16 Occlugel Polymère implantable biorésorbable
US9034356B2 (en) 2006-01-19 2015-05-19 Warsaw Orthopedic, Inc. Porous osteoimplant

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01163135A (ja) * 1987-12-18 1989-06-27 Taki Chem Co Ltd 徐放性基剤の製造方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01163135A (ja) * 1987-12-18 1989-06-27 Taki Chem Co Ltd 徐放性基剤の製造方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JACKSON ET AL, INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 283, 2004, pages 97 - 109 *
MARRA ET AL, MATERIALS RESEARCH SOCIETY SYMPOSIUM-PROCEEDINGS, vol. 550, 1999, pages 155 - 160 *
MIKI ET AL, JOURNAL OF CRANIO-MAXILLOFACIAL SURGERY, vol. 28, 2000, pages 294 - 299 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9034356B2 (en) 2006-01-19 2015-05-19 Warsaw Orthopedic, Inc. Porous osteoimplant
EP2295480A1 (fr) * 2009-09-10 2011-03-16 Occlugel Polymère implantable biorésorbable
WO2011029867A1 (fr) * 2009-09-10 2011-03-17 Occlugel Polymère bio-résorbable implantable
US9320804B2 (en) 2009-09-10 2016-04-26 Occlugel Implantable bio-resorbable polymer

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