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WO2011122926A1 - Système d'administration de médicament dans un tissu osseux - Google Patents

Système d'administration de médicament dans un tissu osseux Download PDF

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Publication number
WO2011122926A1
WO2011122926A1 PCT/MY2010/000044 MY2010000044W WO2011122926A1 WO 2011122926 A1 WO2011122926 A1 WO 2011122926A1 MY 2010000044 W MY2010000044 W MY 2010000044W WO 2011122926 A1 WO2011122926 A1 WO 2011122926A1
Authority
WO
WIPO (PCT)
Prior art keywords
gentamycin
hydroxyapatite
biofilm
delivery system
drug delivery
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/MY2010/000044
Other languages
English (en)
Inventor
Fauziah Othman
Asmah Rahmat
Idris Besar
Rusnah Mustaffa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MALAYSIAN NUCLEAR AGENCY (NUKLEAR MALAYSIA)
Universiti Putra Malaysia (UPM)
Original Assignee
MALAYSIAN NUCLEAR AGENCY (NUKLEAR MALAYSIA)
Universiti Putra Malaysia (UPM)
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 MALAYSIAN NUCLEAR AGENCY (NUKLEAR MALAYSIA), Universiti Putra Malaysia (UPM) filed Critical MALAYSIAN NUCLEAR AGENCY (NUKLEAR MALAYSIA)
Priority to PCT/MY2010/000044 priority Critical patent/WO2011122926A1/fr
Publication of WO2011122926A1 publication Critical patent/WO2011122926A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates to a drug delivery system and more particularly the present invention relates to a drug delivery system in bone tissue. Most particularly the present invention relates to hydroxyapatite (HA) biomaterial coated with gentamycin contributing to the effort of reducing or eradicating biofilm formation of implants in bone tissue.
  • HA hydroxyapatite
  • a biofilm is a complex aggregation of microorganism marked by the excretion of a protective and adhesive matrix. Biofilms are also often characterized by surface attachment, structural heterogeneity, genetic diversity, complex community interactions and a extracellular matrix of polymeric substances.
  • biofilms Single-celled organisms generally exhibit two distinct modes of behavior: plank tonic (free floating) and attached state cells (closely packed and firmly attached).
  • biofilms can develop on the interiors of pipes, which can lead to clogging and corrosion. It has recently been shown that biofilm are present on the remove tissue of 80% of patients undergoing surgery for chronic sinusitis.
  • biofilms have been found to be involved in a wide variety of microbial infections in the body. Infectious processes in which biofilms have been implicated include: urinary tract infections, catheter infections, formation dental plaque and coating contact lenses, but also infections of permanent indwelling devices such as joint prostheses and heart valves.
  • biofilms are present on the removed tissue of 80% of patients undergoing surgery for chronic sinusitis.
  • the patients with the biofilms were shown to have been denuded of cilia and goblet cells, unlike the controls without biofilms who had normal cilia and goblet cell morphology.
  • Biofilms were also found on samples from two of 10 healthy controls mentioned.
  • the species of bacteria from interoperative cultures did not correspond to the bacteria species in the biofilm on the respective patient's tissue. In other words, the cultures were negative though the bacteria were present.
  • the new staining techniques are being developed to differentiate bacterial cells growing in living animals such as from tissues with allergy- inflammations.
  • the present invention relates to a drug delivery system in bone tissue for reducing or eradicating biofilm formation of implants in bone tissue.
  • the present invention includes a gentamycin-coated biomaterial that is used therein to reduce or eradicate the biofilm on the implant materials and wherein the gentamycin-coated biomaterial is a hydroxyapatite biomaterial coated with the gentamycin.
  • the biomaterial comprises of a single-phased hydroxyapatite scaffold with interconnected pore structure.
  • the hydroxyapatite is a synthetic, inorganic, biocompatible and osteoconductive material. Hydroxyapatite is used as bone graft substitutes in the field of dental surgery, orthorhinolaryngology and maxillofacial surgery. Hydroxyapatite could be combined with autogenous bone marrow aspirate of autogenous blood.
  • Figure 1 shows an image scanning electron micrograph of hydroxyapatite.
  • the size of the hydroxyapatite porosity is 70-80% total porosity and its pore size is between 100- 500 ⁇
  • Figure 2 shows an image scanning electron micrograph of hydoxyapatite coated with gentamycin solution.
  • the gentamycin solution has covered the microporous of the hydroxyapatite surface
  • Figure 3 shows an image scanning electron micrograph of osteoblast on hydroxyapatite
  • Figure 4 shows an image scanning electron micrograph of hydoxyapatite coated with O.lmg/ml gentamycin with osteoblast after 72 hours treatment. There is cell-to-cell attachment of the hydroxyapaptite-coated gentamycin on the osteoblast cell.
  • Figure 5 shows an image scanning electron micrograph of hydoxyapatite coated with lOmg/ml gentamycin with osteoblast after 72 hours treatment. There is less cell-to-cell attachment of the hydroxyapaptite-coated gentamycin on the osteoblast cell compare to O.lmg/ml gentamycin on osteoblast after 72 hours treatment.
  • Figure 6 shows a graph percentage of cell viability in osteoblast cells treated with HA coated with different titers of gentamycin.
  • Figure 7 shows an image scanning electron micrograph of catheter-associated biofilm after 10 days incubation with LB (Luria-Bertani) medium.
  • Figure 8 shows a graph of percentage viability of Staphylococcus aureus biofilm vs concentration of gentamycin in hydroxyapatite. From the graph, IC50 of gentamycin loaded hydroxyapatite on Staphylococcus aureus biofilm is 0.3mg/ml.
  • Biomaterials have been widely used for the tissue engineering of bone, teeth and liver and as medical devices such as urinary catheters and prosthetic heart valves.
  • a common complication with use of medicals implants is biofilm formation.
  • a biofilm is a complex aggregation of microorganisms marked by characterized by surface attachment, structural heterogeneity, genetic diversity, complex community interactions and an extracellular matrix of polymeric substances.
  • Biofilms have been found to be involved in a wide variety of microbial infections in the body. Infectious processes in which biofilms have been implicated include: urinary tract infections, catheter infections, formation of dental plaque and coating contact lenses. Due to the administration of antibiotics would increase drug penetration and also reduce the toxicity associated with systemic treatment with antibiotics, an in situ drug delivery system using biomaterial is proposed for the slow-release of antibiotics.
  • Gentamycin-coated biomaterial is expected to reduce or eradicate the biofilm on the implant materials.
  • the image of HA, gentamycin-coated HA, gentamycin-coated HA with osteoblast and also catheter-associated biofilm were examined under the scanning electron microscope (SEM).
  • SEM scanning electron microscope
  • the objectives of the present invention are to assess the antibacterial properties and host tissue response of Gentamycin-coated biomaterials and to bone tissues.
  • the drug efficacy in vivo in preventing biofilm formation is monitored and the innate adaptive host immune response towards Gentamycin-coated biomaterials has been studied.
  • this study contibutes to the new finding toward hydroxyapatite (HA) biomaterial coated with the gentamycin contributing to the effort of reducing or eradicating biofilm formation of implants in bone tissue.
  • This biomaterial comprises of a single-phased hydroxyapatite scaffold with interconnected pore structure almost similar to human cancellouse bone. It is synthetic, inorganic, biocompatible and osteoconductive. HA is available in blocks of standard sixe 0.5x0.5x1 cm; and in irregular shaped chips of 2-3mm. HA is intended to be used as bone graft substitutes in the field of dental surgery, orthorhinolaryngology and maxillofacial surgery. The device is designed as an osteoconductive space filer to be gently packed into bony voids or graps following tooth extraction or any surgical procedure.
  • the block is suitable for larger defects while the chips are to fill the remaining voids. It can be combined autogenous bone marrow aspirate of autogenous blood. It resorbs and will replace with bone during the healing process. HA is ideal for use in defects which require early cross-sectional strength due to it being osteoconductive and aid in the formation of mature bone across the defect and it is no side effect.
  • materials strategies to address bone defects include non-degradable bone cement, metals and ceramics. All of these options have their associated problems such as synthetic implants that may result in stress shielding in the surrounding bone. Therefore, the search for improved materials for repairing skeletal defects continues.
  • Tissue engineering approaches attempt to create tissue replacements by culturing cells onto synthetics three-dimensional polymer matrixes. Biomaterials have been widely used for tissue engineering of bone, teeth and liver.
  • Figure 6 shows the image of on hydroxyapatite coated with gentamycin for 24 hours by modified immersion technique.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Materials For Medical Uses (AREA)

Abstract

Selon la présente invention, le biomatériau d'hydroxyapatite (HA) a été examiné pour sa morphologie de surface. Il s'agit de copeaux de forme irrégulière de 2 à 3 mm. Toutefois, la taille des pores est comprise entre 150 et 350 μm, ce qui comprenait des micropores et des macropores, tandis que la porosité est comprise entre 65 et 70 %. Placé au contact de l'os viable, le nouvel os se forme sur et entre les pores de HA. Par conséquent, les micropores ont été recouverts lorsqu'ils ont été chargés en solution de gentamycine par les images de la HA chargée en gentamycine sous microscope électronique à balayage (SEM). La HA était biocompatible avec l'ostéoblaste par l'essai au moyen d'une analyse MTT. Il n'y avait aucun caractère significatif de la CI50 de la gentamycine lorsque le pourcentage de viabilité cellulaire était élevé. En ces termes, il n'y avait pas de caractère significatif de la CI50 de la gentamycine qui était de 0,3 mg/mL après traitement. Le pourcentage de viabilité du biofilm a chuté. Plus la concentration de la gentamycine ayant été chargée était élevée, plus le pourcentage de biofilm viable était faible. Ainsi, les résultats indiquaient que la HA chargée en gentamycine avait la capacité de réduire ou d'éradiquer la formation de biofilm qui s'est formé sur les dispositifs d'implant.
PCT/MY2010/000044 2010-03-31 2010-03-31 Système d'administration de médicament dans un tissu osseux Ceased WO2011122926A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/MY2010/000044 WO2011122926A1 (fr) 2010-03-31 2010-03-31 Système d'administration de médicament dans un tissu osseux

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/MY2010/000044 WO2011122926A1 (fr) 2010-03-31 2010-03-31 Système d'administration de médicament dans un tissu osseux

Publications (1)

Publication Number Publication Date
WO2011122926A1 true WO2011122926A1 (fr) 2011-10-06

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Family Applications (1)

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PCT/MY2010/000044 Ceased WO2011122926A1 (fr) 2010-03-31 2010-03-31 Système d'administration de médicament dans un tissu osseux

Country Status (1)

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WO (1) WO2011122926A1 (fr)

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ALT, V. ET AL.: "The effects of combined gentamicin- hydroxyapatite coating for cementless joint prostheses on the reduction of infection rates in a rabbit infection prophylaxis model", BIOMATERIALS, vol. 27, 2006, pages 4627 - 4634, XP025097500, DOI: doi:10.1016/j.biomaterials.2006.04.035 *
AU, L.F. ET AL.: "Cytotoxicity and scanning electron microscopy study of gentamycin-coated HA effect on biofilm", MED. J., vol. 63, no. A, July 2008 (2008-07-01), MALAYSIA, pages 16 - 17 *
LUCKE, M. ET AL.: "Gentamicin coating of metallic implants reduces implant-related osteomyelitis in rats", BONE, vol. 32, 2003, pages 521 - 531, XP002420394, DOI: doi:10.1016/S8756-3282(03)00050-4 *
STIGTER, M. ET AL.: "Incorporation of different antibiotics into carbonated hydroxyapatite coatings on titanium implants, release and antibiotic efficacy", JOURNAL OF CONTROLLED RELEASE, vol. 99, 2004, pages 127 - 137 *

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