WO1993001841A1 - Ameliorations de billes acryliques renfermant des antibiotiques - Google Patents

Ameliorations de billes acryliques renfermant des antibiotiques Download PDF

Info

Publication number
WO1993001841A1
WO1993001841A1 PCT/EP1992/001619 EP9201619W WO9301841A1 WO 1993001841 A1 WO1993001841 A1 WO 1993001841A1 EP 9201619 W EP9201619 W EP 9201619W WO 9301841 A1 WO9301841 A1 WO 9301841A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibiotic
polymerisation
bone
synthetic resin
therapeutic agent
Prior art date
Application number
PCT/EP1992/001619
Other languages
English (en)
Inventor
Brian R. D. P. Bradnock
Hamish Turner Law
Original Assignee
Bradnock Brian R D P
Hamish Turner Law
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 Bradnock Brian R D P, Hamish Turner Law filed Critical Bradnock Brian R D P
Publication of WO1993001841A1 publication Critical patent/WO1993001841A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J2237/00—Discharge tubes exposing object to beam, e.g. for analysis treatment, etching, imaging
    • H01J2237/30—Electron or ion beam tubes for processing objects
    • H01J2237/317—Processing objects on a microscale
    • H01J2237/31701—Ion implantation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to orthopaedics and to improvements in the design of polymethyl methacrylate (PMMA) beads containing admixed antibiotic or other therapeutic agents.
  • PMMA polymethyl methacrylate
  • Antibiotic-containing PMMA beads are intended for implantation within the body at the time of operation during orthopaedic surgical procedures in order to provide prophylactic post-operative antibiotic cover, or may be used in the treatment of deep infections involving bone.
  • Deep infection following bone or joint surgery is a known complication of such procedures with an incidence of about 1.5 percent.
  • joint replacement surgery it is the cause of a small but significant proportion of failures, usually requiring the removal of the prosthetic components to allow effective treatment of the infected bone.
  • osteomyelitis may be caused by staphyloccocal infection, perhaps by haematogenous spead from some superficial infected site or following trauma, by salmonella, tuberculosis or other organisms. These are serious conditions requiring careful management.
  • Antibiotics administered systemically are not very effective in the treatment because of the relatively sparse blood perfusion in bone and, consequently, the low concentration of antibiotic obtained at the site of the infection.
  • the bone cement is an acrylic resin (polymethyl methacrylate, abbreviated PMMA) which is usually supplied for use in the operating theatre in a two component form, a powder, consisting of small granules of partially polymerised methacrylate, and a liquid, consisting mainly of monomeric methyl methacrylate but containing also a catalyst and other agents which serve to promote a further polymerisation reaction during "curing".
  • PMMA polymethyl methacrylate
  • the powder and liquid are mixed together in theatre immediately before the cement is required for use.
  • the mixture assumes the consistency of a thick "dough" one or two minutes after mixing and is applied to the bone and/or prosthetic components in this condition. Within ten minutes or so the mixture has set into a hard, solid mass effectively anchoring the prosthetic component to the bone.
  • Antibiotics in the form of dry powders, can be added to the bone cement at the time of mixing and become dispersed and embedded in the cured PMMA mass.
  • the cement is slightly porous and permeable to water and water-soluble molecules so that the antibiotic slowly diffuses out from the solid cement and into the surrounding tissues, thus maintaining high bactericidal concentrations at and near the operation site.
  • Some of the commercially-produced formulations of bone cement contain inorganic materials to render the cement more opaque to x-rays and thus to help visualise the shape and extent of the cement mantle on post-operative x-ray examination.
  • Bariu m sulphate or zirconium dioxide are two compounds which are commonly used. It has been shown that the presence of these inorganic additives greatly increases the diffusion coefficient of water soluble molecules in the cement. Almost all antibiotic therapy with PMMA-dispensed agents is based on the use of radio-opaque bone cement formulations, since the rate of drug delivery from PMMA with no inorganic additive is usually too low.
  • antibiotic-containing PMMA beads have become commercially available, usually in the form of "chains" threaded on a flexible stainless steel wire. These ' are used in the treatment of bone infections and can be packed into the space resulting from surgical removal of infected or damaged bone or within the medullary cavity of long bones. These chained beads may be removed after the infection has been brought under control thus minimising needless and undesirable exposure to continuing dosage of antibiotic which carries the risk of the development of antibiotic-resistant organisms.
  • the PMMA is used solely as a vehicle for the antibiotic and, since it is not required to provide a strong means of attachment for a prosthetic component, its mechanical properties are not important. High concentrations of antibiotic (which impair the mechanical properties of the cured cement) may therefore be used.
  • Antibiotic -containing beads are most usually pre-manufactured and delivered to the theatre in sterile packs ready for use.
  • the polymerisation reaction is exothermic, thus the temperature of the cement rises during the curing process.
  • the maximum temperature attained will depend on the thickness of the cement mantle, the proximity of metallic prosthetic components and so on.
  • the temperature at the centre of a ball of cement several centimetres in diameter will reach approximately 120 degrees Centigrade during the curing process and sections only two millimetres thick will exceed 80 degrees Centigrade.
  • Many of the antibiotics which are suitable for use prophylactically or therapeuticaliy in the control of deep infections involving bone are unstable at these temperatures and are therefore rendered ineffective during the cement polymerisation reaction.
  • the purpose of the present invention is to provide a method of manufacturing antibiotic-containing PMMA beads which avoids exposure o: the antibiotic to damaging temperatures.
  • Bumps or other raised areas may be formed on one cr other of the metal sheets to control the separation between them during the rolling process. These operations must be completed before the polymerisation reaction has progressed more than a few percent but this does not present a difficulty.
  • the rolled-down sandwich is then set aside to allow the cement to cure. Because of the thin section of cement, in contact on each side with the metal plates, the temperature rise during polymerisation is limited by the conduction of heat away from the polymer into the metal. In this way the maximum temperature which is attained may be limited to less than 10 Centigrade degrees above the ambient temperature. If a particularly heat-sensitive antibiotic is being used lower maximum temperatures may be obtained by providing means of cooling the plates, by working in a cooler environment or by using precooled materials, plates and rollers.
  • the cement When curing is complete the cement is broken out from the containing plates and is then broken up by passing it through serrated rollers so as to produce granules. These are subsequently graded in size by means of sieves.
  • the granule size has a considerable effect on the rate at which the antibiotic will be released, by diffusion, from the completed bead and in consequence the maximum size and the spectrum of sizes which are used in the later stages requires to be carefully controlled.
  • the maximum dimensions of the granules will most often be in the range 0.5 to 1 .7 millimetres, although the invention is not restricted to this range of sizes.
  • the bead further small quantities of the monomeric methyl methacrylate and catalyst are added to the granular mix and the bead formed by moulding or other appropriate process.
  • a hole for the wire on which the beads will be strung is formed at this stage.
  • the diameter of the completed beads will be, typically, between 10 and 20 millimetres.
  • the granules are compacted and will become firmly bonded to each other at their points of contact as a result of further polymerisation which takes place at these points. Though this reaction is again exothermic and some temperature rise will take place the quantity of reacting material is small, dependent mainly on the amount of liquid monomer which is added, and the maximum temperature attained is therefore acceptable.
  • the resulting bead has an open, porous structure with intergranuiar voids which are large compared to those found in conventionally prepared, cured PMMA.
  • the mechanical strength is thus relatively low but this is of no consequence since the material is not required to be load-bearing.
  • the porosity will considerably increase the rate of diffusion of the water soluble antibiotic molecules from the bead and into the surrounding tissues after implantation, which is advantageous.
  • the diffusion rate can be adjusted to suit the pharmacological requirements by variation of the granule size (and size distribution) and. of course, by selection of the original antibiotic content.
  • PMMA beads of the form described above may be used with advantage to provide long duration, continuing delivery of therapeutic agents other than antibiotics.
  • anti-tuberculous drugs and compounds used in chemotherapy for tumour may be incorporated. Many such agents are heat sensitive and thus unsuitable for incorporation into PMMA beads of "solid" design.

Abstract

Les implantations de petites billes de méthacrylate de polyméthyle renfermant des antibiotiques, comme ciment de prothèse osseuse, ont été utilisées pour assurer la couverture prophylactique à l'issue d'interventions chirurgicales orthopédiques ou de traitements d'infections osseuses. Le choix de l'antibiotique est restreint par la température de la réaction de polymérisation exothermique, altérant de nombreux agents antibiotiques qui seraient autrement très utiles. En réalisant la polymérisation en deux étapes et en prévoyant des moyens de refroidissement au cours de la première, la température maximale à laquelle l'agent thérapeutique est exposé se trouve considérablement abaissée, ce qui permet d'éviter ainsi son altération par la chaleur. Des considérations similaries s'appliquent également lorsque, par exemple, on met en ÷uvre des substances pharmaceutiques anti-tuberculeuses et des agents chimiothérapeutiques pour le traitement des tumeurs osseuses, substances qui pour la plupart sont sensibles à la chaleur. Elles peuvent être incorporées dans les billes de méthacrylate de polyméthyle ainsi modifiées.
PCT/EP1992/001619 1991-07-23 1992-07-16 Ameliorations de billes acryliques renfermant des antibiotiques WO1993001841A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919115901A GB9115901D0 (en) 1991-07-23 1991-07-23 Improvements in antibiotic-containing acrylic beads
GB9115901.2 1991-07-23

Publications (1)

Publication Number Publication Date
WO1993001841A1 true WO1993001841A1 (fr) 1993-02-04

Family

ID=10698837

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/001619 WO1993001841A1 (fr) 1991-07-23 1992-07-16 Ameliorations de billes acryliques renfermant des antibiotiques

Country Status (2)

Country Link
GB (1) GB9115901D0 (fr)
WO (1) WO1993001841A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002009783A1 (fr) * 2000-08-01 2002-02-07 Coripharm Medizinprodukte Gmbh & Co. Kg Systeme modulaire d'implant contenant des agents actifs et son procede de fabrication
US8921365B2 (en) 2007-07-23 2014-12-30 Biomet Deutschland Gmbh Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition
US9155671B2 (en) 2012-10-16 2015-10-13 Surmodics, Inc. Wound packing device and methods
US10029031B2 (en) * 2015-10-28 2018-07-24 Warsaw Orthopedic, Inc. Bone void filler having sustained therapeutic agent release
US10201457B2 (en) 2014-08-01 2019-02-12 Surmodics, Inc. Wound packing device with nanotextured surface

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0111759A2 (fr) * 1982-12-11 1984-06-27 Beiersdorf Aktiengesellschaft Matériau chirurgical
US4554686A (en) * 1984-02-29 1985-11-26 Technical Research Associates, Inc. Polymethylmethacrylate bone cements and methods for preparing such bone cements
WO1986002370A1 (fr) * 1984-10-16 1986-04-24 Ferring Laboratories, Inc. Ciment osseux polymerisant a froid
DE3738422A1 (de) * 1987-11-12 1989-05-24 Beiersdorf Ag Chirurgisches material
GB2219303A (en) * 1988-06-01 1989-12-06 Tecres Spa Two phase acrylic cement mixture, particularly suitable for orthopaedics
EP0361408A2 (fr) * 1988-09-26 1990-04-04 Wolff & Kaaber A/S Ciment osseux
FR2638972A1 (fr) * 1988-11-14 1990-05-18 Osteal Medical Laboratoires Ciment pour la fixation de protheses osseuses

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0111759A2 (fr) * 1982-12-11 1984-06-27 Beiersdorf Aktiengesellschaft Matériau chirurgical
US4554686A (en) * 1984-02-29 1985-11-26 Technical Research Associates, Inc. Polymethylmethacrylate bone cements and methods for preparing such bone cements
WO1986002370A1 (fr) * 1984-10-16 1986-04-24 Ferring Laboratories, Inc. Ciment osseux polymerisant a froid
DE3738422A1 (de) * 1987-11-12 1989-05-24 Beiersdorf Ag Chirurgisches material
GB2219303A (en) * 1988-06-01 1989-12-06 Tecres Spa Two phase acrylic cement mixture, particularly suitable for orthopaedics
EP0361408A2 (fr) * 1988-09-26 1990-04-04 Wolff & Kaaber A/S Ciment osseux
FR2638972A1 (fr) * 1988-11-14 1990-05-18 Osteal Medical Laboratoires Ciment pour la fixation de protheses osseuses

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH vol. 20, 1986, pages 839 - 852 G.M. BRAUER ET AL. 'DPENDENCE OF CURING TIME, PEAK TEMPERATURE, AND MECHANICAL PROPERTIES ON THE COMPOSITION OF BONE CEMENT' *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002009783A1 (fr) * 2000-08-01 2002-02-07 Coripharm Medizinprodukte Gmbh & Co. Kg Systeme modulaire d'implant contenant des agents actifs et son procede de fabrication
US8003121B1 (en) 2000-08-01 2011-08-23 Aap Biomaterials Gmbh & Co. Kg Modular implant system containing active substances and method for the production thereof
US8921365B2 (en) 2007-07-23 2014-12-30 Biomet Deutschland Gmbh Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition
US9968710B2 (en) 2007-07-23 2018-05-15 Biomet Deutschland Gmbh Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition
US9155671B2 (en) 2012-10-16 2015-10-13 Surmodics, Inc. Wound packing device and methods
US10080688B2 (en) 2012-10-16 2018-09-25 Surmodics, Inc. Wound packing device and method
US10201457B2 (en) 2014-08-01 2019-02-12 Surmodics, Inc. Wound packing device with nanotextured surface
US10029031B2 (en) * 2015-10-28 2018-07-24 Warsaw Orthopedic, Inc. Bone void filler having sustained therapeutic agent release

Also Published As

Publication number Publication date
GB9115901D0 (en) 1991-09-04

Similar Documents

Publication Publication Date Title
US7138442B2 (en) Reduced exothermic bone replacement cement
AU701508B2 (en) Controlled dissolution pellet containing calcium sulfate
JP2700881B2 (ja) 医薬デポ剤
AU736940B2 (en) Hydrogel composites and superporous hydrogel composites having fast swelling, high mechanical strength, and superabsorbent properties
US3882858A (en) Surgical synthetic-resin material and method of treating osteomyelitis
US3507952A (en) Sustained release bolus for animal husbandry
US5266248A (en) Method of producing hydroxylapatite base porous beads filler for an organism
JP2003533468A (ja) タンパク質マトリクス物質、製造並びにその製造及び使用
IE37160B1 (en) Preparations containing silicone rubber
JPS61243015A (ja) 細胞増殖抑止剤を含有するデポ医薬
WO1996011715A1 (fr) Composition de reparation des tissus durs et son unite de distribution
GB2091554A (en) Rod-like Moulded Drug
Otsuka et al. Antibiotic delivery system using bioactive bone cement consisting of Bis-GMA/TEGDMA resin and bioactive glass ceramics
JP2004236729A (ja) 骨セメント組成物
WO1993001841A1 (fr) Ameliorations de billes acryliques renfermant des antibiotiques
JPS626522B2 (fr)
JPH04164456A (ja) 水酸化アパタイト多孔質生体充填剤並びにその製造方法
JPH02255139A (ja) 成形手術用デバイス
US4652443A (en) Slow-release composite and process for producing the same
CN108159021B (zh) 一种载有促进骨形成蛋白及消除关节炎症状药物的双层复合缓释微球及其制备方法
JPH0244050A (ja) 水硬性ペレット
EP0339035A1 (fr) Enveloppes contenant de l'hydrogel.
JPH0734817B2 (ja) 医科用および歯科用硬化性材料および多孔性材料
Ladola Superporous hydrogel (SPH): A novel and advanced technique of oral controlled release drug delivery system
Otsuka et al. A Novel Skeletal Drug Delivery System Using Self-Setting Bioactive Glass Bone Cement IV: Cephalexin Release From Cement Containing Polymer-Coated Bulk Powder

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE

122 Ep: pct application non-entry in european phase