WO2002074355A1 - Calcium phosphate materials containing active ingredients - Google Patents

Calcium phosphate materials containing active ingredients Download PDF

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Publication number
WO2002074355A1
WO2002074355A1 PCT/EP2002/002673 EP0202673W WO02074355A1 WO 2002074355 A1 WO2002074355 A1 WO 2002074355A1 EP 0202673 W EP0202673 W EP 0202673W WO 02074355 A1 WO02074355 A1 WO 02074355A1
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materials
particles
calcium phosphate
active ingredient
active ingredients
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PCT/EP2002/002673
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German (de)
French (fr)
Inventor
Peter Zeggel
Joachim Teller
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Dot Gmbh
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Priority to EP02729990A priority Critical patent/EP1370305A1/en
Publication of WO2002074355A1 publication Critical patent/WO2002074355A1/en

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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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/32—Phosphorus-containing materials, e.g. apatite
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • 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
    • 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
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/622—Microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/624—Nanocapsules
    • 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 invention relates to active ingredient-containing calcium phosphate materials and active ingredient-containing particles in the form of nano and microcapsules, where the materials can be present not only as dispersions, pastes, powders, granules or moldings but also as layers.
  • Calcium phosphate coating of bone implants represents an alternative solution to antibiotic prophylaxis carried out in vivo or, in the case of cemented bone implants, to antibiotic release from cement containing antibiotics.
  • this prophylaxis of an acute or creeping bacterial infection use is also possible in the case of an infection that has already occurred and the replacement of the prosthesis that has become necessary.
  • the release of antibiotics from the implant coating can allow a one-time change to a cement-free implant.
  • the use of antibiotic calcium phosphate layers is not only limited to bone prostheses but also refers to other metallic or ceramic implants. Appropriate coating of Schanz screws and Steinmann nails at the external fixator can delay or avoid locally inflammatory osteolysis.
  • the currently known active ingredient-containing calcium phosphate layers are based on different mixing strategies of the components calcium phosphate and biologically active substance.
  • EP 0806 212 AI claims a biomimetic coating in which the two components coprecipitate on an implant surface with a predetermined roughness from a surrounding, supersaturated solution.
  • the calcium phosphate layers with active substance doping that can thus be produced can only be used to a limited extent since they require special surface properties of the base material, do not have any chemical linkage of the active substance or its depots with the actual calcium phosphate structure, or are only designed for one active substance or one active substance group.
  • the currently known calcium phosphate materials with active substance inclusions which are designed as bone replacement materials, are also based on different mixing strategies of the respective components. According to Yamashita et al. (Intern. Orthopedics 22, 247 (1998)) and Shinto et al. (J. Bone Joint Surg. 74, 600 (1992)) antibiotics can be deposited in cylindrical cavities in hydroxyapatite ceramics. Other authors have also described binary and ternary mixtures of antibiotics with calcium phosphates: Thoma et al: Pharmazie 46, 266 (1991) ( ⁇ -tricalcium phosphate + gentamicin), Rogers-Foy et al .: J. Invest. Surg.
  • DE 100 06 992 AI which claims a coating process for implants and the implant itself, which is characterized in that so-called dispersion particles are embedded in defects in the calcium phosphate coating.
  • the dispersion particles consist of metal salts, plastic and / or ceramic material or of growth-promoting proteins.
  • the anchoring of the dispersion particles in the layer does not take place through targeted chemical interaction, but expressly as filling in of defects and thus as a structural element of the layer.
  • antibiotic or otherwise effective calcium phosphate materials with defined binding and release ratios on implant materials or . as a bone substitute as an alternative form of therapy there are numerous indications that antibiotic or otherwise effective calcium phosphate materials with defined binding and release ratios on implant materials or . as a bone substitute as an alternative form of therapy.
  • the present invention was therefore based on the object of making active substance-containing biomaterials accessible which are designed in such a way that they include any active substances and release them in a controlled manner.
  • the structuring of active substance-containing layers should be possible independently of the special surface properties of the base material.
  • the dosage form of the active ingredients should be designed in such a way that they can be fixed on implant surfaces, in bone substitute materials or in bone cements.
  • the calcium phosphate materials contain active substances in particles, the particles being fixed in the materials via ionic interactions. These particles are mainly nano and micro capsules or liposomes (vesicles). They are preferably located on the surface of implants, in bone substitute materials or in bone cements.
  • the active ingredients contained therein can belong to different groups of active ingredients and are released with a time delay. Examples of these are antibiotics, anti-inflammatory drugs, antihistamines, analgesics or cytostatics but also peptide structures such as oligopeptides, proteins and proteohormones or steroids.
  • the active substance-containing particles fixed in the calcium phosphate layer can have different structures (matrix or core-shell capsules), active substance loads, release kinetics or sizes. However, it has proven to be advantageous to anchor particles with diameters smaller than 1 micron in the calcium phosphate structure.
  • the calcium phosphate structures used can be a pure phase (e.g. hydroxylapatite) or different phases. It is also possible that calcium ions in these structures are partially caused by other cations, e.g. B. magnesium ions and phosphate units are replaced by other anions, for example Ca bonations.
  • the active substance-containing particles consist of materials which have anionic groups which are completely or partially neutralized by alkali and / or calcium ions. It is also possible to anchor the active substance-containing particles via cationic groups which are neutralized in whole or in part by phosphate ions.
  • phosphate or phosphonate groups have proven to be suitable as anionic groups.
  • Suitable materials for the particles containing the active substance are therefore phosphorylated polysaccharides and their derivatives, phosphorylated polyethers, polyesters and polyamides or vinyl polymers which contain phosphorylated or phosphonylated hydroxyalkyl or - aryl sequences or hydrocarbon radicals, or polymers of vinylphosphonic acid and its derivatives themselves.
  • the active ingredient-containing particles consist of a polymer which is wholly or partly formed from O-terminally phosphorylated poly (hydroxycarboxylic acids), preferably O-phosphoryl polylactide.
  • the active ingredient-containing calcium phosphate materials described above have a number of advantageous properties.
  • the active ingredient in question is not simply mixed with the calcium phosphate, but is in the form of particles (nano- or 'microencapsulations) which cause a delayed release of the active ingredient (controlled release) and are fixed in the calcium phosphate phase via ionic interactions.
  • nano- or 'microencapsulations By introducing the active ingredients in encapsulated form, there are no restrictions with regard to the biological, chemical and physical properties for the selected active ingredients.
  • the materials produced in this way can be sterilized by the usual methods.
  • Another advantage of using calcium phosphate materials as layers on implants is that no special surface properties (e.g. roughness) are required.
  • the adhesion of such calcium phosphate layers to metallic and ceramic base materials is not restricted by their content of active substances in particulate form.

Abstract

The invention relates to calcium phosphate materials containing active ingredients, said active materials being contained in the form of particles (nano- and microencapsulations) which are fixed by ionic interaction in the materials. Said materials are mainly used as layers in implants in human and veterinary medicine or in the form of dispersions, powders, granulates or moulded bodies as bone replacement materials. They enable controlled release of active ingredients from the implant surfaces whereon corresponding layers are placed or from bone replacement material. There is no limitation as to the active ingredients used and the requirements of the surface properties of the substrate material.

Description

IRKSTOFFHA TIGE CALCIUMPHOSPHAT-MATERIA IENIRCELECTIC CALCIUM PHOSPHATE MATERIA
Die Erfindung betrifft wirkstoffhaltige Calciumphosphat-Materialien sowie wirkstoffhaltige Partikel in Form von Nano- und Mikrokapseln, wobei die Materialien sowohl als Dispersionen, Pasten, Pulver, Granulate oder Formteile aber auch als Schichten vorliegen können.The invention relates to active ingredient-containing calcium phosphate materials and active ingredient-containing particles in the form of nano and microcapsules, where the materials can be present not only as dispersions, pastes, powders, granules or moldings but also as layers.
Für derartige Calciumphosphat-Schichten, die über antibiotische Eigenschaften verfügen gibt es bereits Anwendungen bzw. potentielle Anwendungsgebiete im human- und veterinärmedizinischen Bereich, insbesondere beim Einsatz von orthopädischen, traumatologischen und dentalen Implantaten. In diesem Sinne stellt die Antibiotikafreisetzung aus derFor calcium phosphate layers of this type which have antibiotic properties, there are already applications or potential fields of application in the human and veterinary field, in particular when using orthopedic, traumatological and dental implants. In this sense, antibiotic release from the
Calciumphosphatbeschichtung von Knochenimplantaten eine alternative Lösung zur in vivo durchgeführten Antibiotikaprophylaxe bzw. im Falle von zementierten Knochenimplantaten zum Antibiotikarelease aus antibiotikahaltigem Zement dar. Neben dieser Prophylaxe einer akuten oder schleichenden bakteriellen Infektion ist auch ein Einsatz bei bereits eingetretener Infektion und damit notwendig gewordenem Prothesenwechsel möglich. Hierbei kann die Freisetzung von Antibiotika aus der Implantatbeschichtung einen einzeitigen Wechsel auf ein zementfreies Implantat erlauben. Der Einsatz von antibiotischen Calciumphosphat-Schichten beschränkt sich nicht nur auf Knochenprothesen sondern bezieht sich auch auf andere metallische oder keramische Implantate. So kann eine entsprechende Beschichtung von Schanz-Schrauben und Steinmann-Nägeln beim Fixateur externe die lokal entzündlich bedingte Osteolyse verzögern oder vermeiden.Calcium phosphate coating of bone implants represents an alternative solution to antibiotic prophylaxis carried out in vivo or, in the case of cemented bone implants, to antibiotic release from cement containing antibiotics. In addition to this prophylaxis of an acute or creeping bacterial infection, use is also possible in the case of an infection that has already occurred and the replacement of the prosthesis that has become necessary. The release of antibiotics from the implant coating can allow a one-time change to a cement-free implant. The use of antibiotic calcium phosphate layers is not only limited to bone prostheses but also refers to other metallic or ceramic implants. Appropriate coating of Schanz screws and Steinmann nails at the external fixator can delay or avoid locally inflammatory osteolysis.
Die derzeit bekannten wirkstoffhaltigeii Calciumphosphat-Schichten basieren auf unterschiedlichen Mischungsstrategien der Komponenten Calciumphosphat und biologisch aktive Substanz.The currently known active ingredient-containing calcium phosphate layers are based on different mixing strategies of the components calcium phosphate and biologically active substance.
So wird in EP 0806 212 AI (1997) ein biomimetisches Coating beansprucht, bei dem die beiden Komponenten auf einer Implantatoberfläche mit vorgegebener Rauheit aus einer umgebenden, supergesättigten Lösung heraus copräzipitieren.For example, EP 0806 212 AI (1997) claims a biomimetic coating in which the two components coprecipitate on an implant surface with a predetermined roughness from a surrounding, supersaturated solution.
Radin et al. (Biomaterials 18, 777 (1997)) beschreiben eine Methode zum Einbringen des Antibiotikums Nancomycin in eine Calciumphosphat-Schicht durch Dip-coating und ( Fixierung des Wirkstoffes über Lipidstrukturen. Von David (Unfallchirurg. 97, 391 (1994)) ist eine ähnliche Methode bekannt geworden, bei der eine antibiotisch wirksame Beschichtung durch Eintauchen von Hydroxylapatit-beschichteten Implantaten in eine Silbersalzlösung erzeugt wird. Die biomimetische Copräzipitation von Calciumphosphat undRadin et al. (Biomaterials 18, 777 (1997)) describe a method for introducing the antibiotic nancomycin into a calcium phosphate layer by dip-coating and ( fixation of the active substance via lipid structures. Von David (Unfallchirurg. 97, 391 (1994)) is a similar method in which an antibiotic coating is produced by immersing hydroxylapatite-coated implants in a silver salt solution. The biomimetic coprecipitation of calcium phosphate and
BESTÄTIGUΝGSKOPIE Proteinen sowie deren Release wurde am Albuminmodell untersucht (Wen et al.: J. Biomed. Mater. Res. 46, 245 (1999)).BESTÄTIGUΝGSKOPIE Proteins and their release were investigated using the albumin model (Wen et al .: J. Biomed. Mater. Res. 46, 245 (1999)).
Die somit herstellbaren Calciumphosphat-Schichten mit Wirkstoffdotierung sind für sich nur eingeschränkt anwendbar, da sie spezielle Oberflächeneigenschaften des Grundmaterials erfordern, keine chemischen Nerknüpfung des Wirkstoffs oder dessen Depots mit der eigentlichen Calciumphosphat-Struktur aufweisen bzw. nur für einen Wirkstoff oder eine Wirkstoffgruppe konzipiert sind.The calcium phosphate layers with active substance doping that can thus be produced can only be used to a limited extent since they require special surface properties of the base material, do not have any chemical linkage of the active substance or its depots with the actual calcium phosphate structure, or are only designed for one active substance or one active substance group.
Die derzeit bekannten Calciumphosphat-Materialien mit Wirkstoffeinschlüssen, die als Knochenersatzwerkstoffe konzipiert sind, basieren ebenfalls auf unterschiedlichen Mischungsstrategien der jeweiligen Komponenten. Nach Yamashita et al. (Intern. Orthopaedics 22, 247 (1998)) und Shinto et al. (J. Bone Joint Surg. 74, 600 (1992)) können Antibiotika in zylindrischen Hohlräumen in Hydroxylapatit-Keramiken deponiert werden. Auch andere Autoren haben binäre und ternäre Mischungen aus Antibiotika mit Calciumphosphaten beschrieben: Thoma et al: Pharmazie 46, 266 (1991) (ß-Tricalcium- phosphat + Gentamicin), Rogers-Foy et al.: J. Invest. Surg. 12, 263 (1999) (Hydroxylapatit + Gentamicin), Martin et al.: Artif. Organs 22, 215 (1998) (Hydroxylapatit + Antibiotika + Kollagen). Von Itokazu et al. ist eine Methode bekannt geworden, nach der Hydroxylapatit- Blöcke mittels Zentrifugation mit Antibiotika angereichert werden (J. Med. Microbiol. 46, 779 (1997). All diesen Verfahren ist gemeinsam, dass reine Mischungen aus der jeweiligen Calciumphosphatphase und dem Antibiotikum erzeugt werden, ohne dass gezielte Wechselwirkungen zwischen diesen Komponenten bestehen.The currently known calcium phosphate materials with active substance inclusions, which are designed as bone replacement materials, are also based on different mixing strategies of the respective components. According to Yamashita et al. (Intern. Orthopedics 22, 247 (1998)) and Shinto et al. (J. Bone Joint Surg. 74, 600 (1992)) antibiotics can be deposited in cylindrical cavities in hydroxyapatite ceramics. Other authors have also described binary and ternary mixtures of antibiotics with calcium phosphates: Thoma et al: Pharmazie 46, 266 (1991) (β-tricalcium phosphate + gentamicin), Rogers-Foy et al .: J. Invest. Surg. 12, 263 (1999) (hydroxylapatite + gentamicin), Martin et al .: Artif. Organs 22, 215 (1998) (hydroxyapatite + antibiotics + collagen). By Itokazu et al. a method has become known, according to which hydroxylapatite blocks are enriched with antibiotics by centrifugation (J. Med. Microbiol. 46, 779 (1997). All these processes have in common that pure mixtures of the respective calcium phosphate phase and the antibiotic are produced, without specific interactions between these components.
Zu nennen ist auch noch die DE 100 06 992 AI, die ein Beschichtungsverfahren für Implantate sowie das Implantat selbst beansprucht, das dadurch gekennzeichnet ist, dass sogenannte Dispersionspartikel in Fehlstellen der Calciumsphosphat-Beschichtung eingelagert werden. Die Dispersionspartikel bestehen aus Metallsalzen, Kunststoff und/oder Keramikmaterial bzw. aus wachstumsfördernden Proteinen. Die Verankerung der Dispersionspartikel in der Schicht erfolgt nicht durch gezielte chemische Wechselwirkung, sondern ausdrücklich als Auffüllung von Fehlstellen und somit als Strukturelement der Schicht.Also to be mentioned is DE 100 06 992 AI, which claims a coating process for implants and the implant itself, which is characterized in that so-called dispersion particles are embedded in defects in the calcium phosphate coating. The dispersion particles consist of metal salts, plastic and / or ceramic material or of growth-promoting proteins. The anchoring of the dispersion particles in the layer does not take place through targeted chemical interaction, but expressly as filling in of defects and thus as a structural element of the layer.
Andererseits gibt es aus medizinischer Sicht zahlreiche Indikationen, die einen Einsatz von antibiotisch oder anderweitig wirksamen Calciumphosphat-Materialien mit definierten Bindungs- und Releaseverhältnissen auf Implantatmaterialien oder . als Knochenersatzwerkstoff als alternative Therapieform sinnvoll erscheinen lassen. Somit lag der vorliegenden Erfindung die Aufgabe zugrunde, wirkstoffhaltige Biomaterialien zugänglich zu machen, die so gestaltet sind, dass sie beliebige Wirkstoffe einschließen und kontrolliert freisetzen. Die Struktuiierung von wirkstoffhaltigen Schichten soll unabhängig von speziellen Oberflächeneigenschaften des Grundmaterials erfolgen können. Die Darreichungsform der Wirkstoffe soll dabei so gestaltet sein, dass ihre Fixierung auf Implantatoberflächen, in Knochenersatzwerkstoffen oder in Knochenzementen ermöglicht wird.On the other hand, from a medical point of view, there are numerous indications that antibiotic or otherwise effective calcium phosphate materials with defined binding and release ratios on implant materials or . as a bone substitute as an alternative form of therapy. The present invention was therefore based on the object of making active substance-containing biomaterials accessible which are designed in such a way that they include any active substances and release them in a controlled manner. The structuring of active substance-containing layers should be possible independently of the special surface properties of the base material. The dosage form of the active ingredients should be designed in such a way that they can be fixed on implant surfaces, in bone substitute materials or in bone cements.
Diese Aufgabe wird dadurch gelöst, dass die Calciumphosphat-Materialien Wirkstoffe in Partikeln enthalten, wobei die Partikel über ionische Wechselwirkungen in den Materialien fixiert sind. Bei diesen Partikeln handelt es sich hauptsächlich um Nano- und Mikrokapseln bzw. Liposomen (Vesikel). Sie befinden sich vorzugsweise auf der Oberfläche von Implantaten, in Knochenersatzwerkstoffen oder in Knochenzementen. Die darin enthaltenen Wirkstoffe können unterschiedlichen Wirkstoffgruppen angehören und werden zeitversetzt freigegeben. Beispiele dafür sind Antibiotika, Antiphlogistika, Antihistaminika, Analgetika oder Cytostatika aber auch Peptidstrukturen, wie Oligopeptide, Proteine und Proteohormone oder Steroide.This object is achieved in that the calcium phosphate materials contain active substances in particles, the particles being fixed in the materials via ionic interactions. These particles are mainly nano and micro capsules or liposomes (vesicles). They are preferably located on the surface of implants, in bone substitute materials or in bone cements. The active ingredients contained therein can belong to different groups of active ingredients and are released with a time delay. Examples of these are antibiotics, anti-inflammatory drugs, antihistamines, analgesics or cytostatics but also peptide structures such as oligopeptides, proteins and proteohormones or steroids.
Die in der Calciumphosphat-Schicht fixierten wirkstoffhaltigen Partikel können unterschiedliche Strukturen (Matrix- oder Core-Shell-Kapseln), Wirkstoffbeladungen, Freisetzungskinetiken oder Größen besitzen. Es hat sich aber als vorteilhaft erwiesen, vorzugsweise Partikel mit Durchmessern kleiner als 1 Mikrometer in der Calciumphosphat-Struktur zu verankern.The active substance-containing particles fixed in the calcium phosphate layer can have different structures (matrix or core-shell capsules), active substance loads, release kinetics or sizes. However, it has proven to be advantageous to anchor particles with diameters smaller than 1 micron in the calcium phosphate structure.
Bei den eingesetzten Calciumphosphat-Strulcturen kann es sich um eine reine Phase (z. B. Hydroxylapatit) oder um verschiedene Phasen handeln. Es ist weiterhin möglich, dass in diesen Strukturen Calciumionen partiell durch andere Kationen, z. B. Magnesiumionen und Phosphateinheiten durch andere Anionen, beispielsweise Ca bonationen, ersetzt sind. Um die Verankerung der Partikel mit der eigentlichen Calciumphosphat-Struktur zu gewährleisten, bestehen die wirkstoffhaltigen Partikel aus Materialien, die über anionische Gruppen verfügen, die ganz oder teilweise durch Alkali- und/oder Calciumionen neutralisiert sind. Es ist ebenso möglich, die Verankerung der wirkstoffhaltigen Partikel über daran befindliche kationische Gruppen, die ganz oder teilweise durch Phosphationen neutralisiert sind, zu bewirken.The calcium phosphate structures used can be a pure phase (e.g. hydroxylapatite) or different phases. It is also possible that calcium ions in these structures are partially caused by other cations, e.g. B. magnesium ions and phosphate units are replaced by other anions, for example Ca bonations. In order to ensure the anchoring of the particles with the actual calcium phosphate structure, the active substance-containing particles consist of materials which have anionic groups which are completely or partially neutralized by alkali and / or calcium ions. It is also possible to anchor the active substance-containing particles via cationic groups which are neutralized in whole or in part by phosphate ions.
Als anionische Gruppen haben sich besonders Phosphat- bzw. Phosphonatgruppen als geeignet erwiesen. Geeignete Materialien für die wirkstoffhaltigen Partikel sind daher phosphorylierte Poly- saccharide und deren Derivate, phosphorylierte Polyether, Polyester und Polyamide oder Vinylpolymere, die phosphorylierte bzw. phosphonylierte Hydroxyalkyl- bzw. — arylsequenzen oder Kohlenwasserstoffreste enthalten, bzw. Polymere aus Vinylphosphonsäure und deren Derivate selbst.In particular, phosphate or phosphonate groups have proven to be suitable as anionic groups. Suitable materials for the particles containing the active substance are therefore phosphorylated polysaccharides and their derivatives, phosphorylated polyethers, polyesters and polyamides or vinyl polymers which contain phosphorylated or phosphonylated hydroxyalkyl or - aryl sequences or hydrocarbon radicals, or polymers of vinylphosphonic acid and its derivatives themselves.
Da sich die Haupteinsatzgebiete der erfindungsgemäßen Materialien auf Implantatoberflächen, Knochenersatzwerkstoffe und Knochenzemente beziehen, ist es erforderlich, die Partikel möglichst biokompatibel und/oder biologisch abbaubar zu gestalten. Es hat sich deshalb als günstig erwiesen, dass die wirkstoffhaltigen Partikel aus einem Polymer bestehen, das gänzlich oder anteilig aus O-terminal phosphorylierten Poly(hydroxycarbonsäuren), vorzugsweise O-Phosphoryl-polylactid, gebildet wird.Since the main areas of application of the materials according to the invention relate to implant surfaces, bone substitute materials and bone cements, it is necessary to make the particles as biocompatible and / or biodegradable as possible. It has therefore proven to be advantageous for the active ingredient-containing particles to consist of a polymer which is wholly or partly formed from O-terminally phosphorylated poly (hydroxycarboxylic acids), preferably O-phosphoryl polylactide.
Die vorstehend beschriebenen wirkstoffhaltigen Calciumphosphat-Materialien besitzen eine Reihe von vorteilhaften Eigenschaften. So ist der betreffende Wirkstoff nicht schlechthin mit dem Calciumphosphat gemischt, sondern befindet sich in Form von Partikeln (Nano- oder ' Mikroverkapselungen), die eine zeitversetzte Wirkstoffabgabe (Controlled Release) bewirken und über ionische Wechselwirkungen in der Calciumphosphat-Phase fixiert sind. Durch das Einbringen der Wirkstoffe in verkapselter Form gibt es keine Einschränkungen bezüglich der biologischen, chemischen und physikalischen Eigenschaften für die gewählten Wirkstoffe. Die so hergestellten Materialien sind nach den üblichen Methoden sterilisierbar. - Ein weitere Vorteil beim Einsatz der Calciumphosphat-Materialien als Schichten auf Implantaten besteht darin, dass keine speziellen Oberflächeneigenschaften (z. B. Rauheit) erforderlich sind. Die Haftung solcher Calciumphosphat-Schichten auf metallischen und keramischen Basismaterialien wird durch ihren Gehalt an Wirkstoffen in partikulärer Form nicht eingeschränkt. The active ingredient-containing calcium phosphate materials described above have a number of advantageous properties. The active ingredient in question is not simply mixed with the calcium phosphate, but is in the form of particles (nano- or 'microencapsulations) which cause a delayed release of the active ingredient (controlled release) and are fixed in the calcium phosphate phase via ionic interactions. By introducing the active ingredients in encapsulated form, there are no restrictions with regard to the biological, chemical and physical properties for the selected active ingredients. The materials produced in this way can be sterilized by the usual methods. - Another advantage of using calcium phosphate materials as layers on implants is that no special surface properties (e.g. roughness) are required. The adhesion of such calcium phosphate layers to metallic and ceramic base materials is not restricted by their content of active substances in particulate form.

Claims

1. Wirkstoffhaltige Calciumphosphat-Materialien als Oberflächenschicht auf human- oder veterinärmedizinischen Implantaten oder als Knochenersatzmaterialien, gekennzeichnet dadurch, dass die Calciumphosphat-Materialien Wirkstoffe enthalten, die sich in Nano- oder Mikrokapseln oder Liposomen befinden, die über ionische Wechselwirkungen in den Materialien fixiert sind.1. Active ingredient-containing calcium phosphate materials as a surface layer on human or veterinary implants or as bone replacement materials, characterized in that the calcium phosphate materials contain active ingredients that are located in nano- or microcapsules or liposomes that are fixed in the materials via ionic interactions.
2. Wirkstoffhaltige Partikel zur Anwendung auf der Oberfläche von Implantaten, in Knochenersatzmaterialien oder in Knochenzementen, gekennzeichnet dadurch, dass es sich um Nano- bzw. Mikroverkapselungen oder Liposomen handelt.2. Active ingredient-containing particles for use on the surface of implants, in bone substitute materials or in bone cements, characterized in that they are nano- or microencapsules or liposomes.
3. Wirkstoffhaltige Calciumphospat-Materialien nach Anspruch 1, gekennzeichnet dadurch, dass die Materialien als Oberflächenschicht auf Implantaten im orthopädischen, trauma- tologischen oder dentalen Einsatzbereich Verwendung finden.3. Active ingredient-containing calcium phosphate materials according to claim 1, characterized in that the materials are used as a surface layer on implants in orthopedic, traumatological or dental applications.
4. Wirkstoffhaltige Calciumphosphat-Materialien nach Anspruch 1 und 3, gekennzeichnet dadurch, dass sie in Form von Dispersionen, Pasten, Pulvern, Granulaten, Formkörpern oder Schichten vorliegen.4. Active ingredient-containing calcium phosphate materials according to claim 1 and 3, characterized in that they are in the form of dispersions, pastes, powders, granules, moldings or layers.
5. Materialien und Partikel nach den Ansprüchen 1 bis 4, gekennzeichnet dadurch, dass die Partikel die darin enthaltenen Wirkstoffe zeitversetzt abgeben.5. Materials and particles according to claims 1 to 4, characterized in that the particles release the active substances contained therein with a time delay.
6. Materialien und Partikel nach den Ansprüchen 1 bis 5, gekennzeichnet dadurch, dass es sich bei den Wirkstoffen um Antibiotika oder Antiphlogistika handelt.6. Materials and particles according to claims 1 to 5, characterized in that the active ingredients are antibiotics or anti-inflammatory drugs.
7. Materialien und Partikel nach den Ansprüchen 1 bis 5, gekennzeichnet dadurch, dass es sich bei den Wirkstoffen um Oligpeptide, Proteine, Proteohormone oder andere Pep- tidstrukturen handelt.7. Materials and particles according to claims 1 to 5, characterized in that the active ingredients are oligpeptides, proteins, proteohormones or other peptide structures.
8. Materialien und Partikel nach den Ansprüchen 1 bis 7, gekennzeichnet dadurch, dass die Partikel unterschiedliche Struktur, Größe, Wirkstoff beladung oder Freisetzungskinetik aufweisen. 8. Materials and particles according to claims 1 to 7, characterized in that the particles have different structure, size, drug loading or release kinetics.
9. Materialien und Partikel nach den Ansprüchen 1 bis 8, gekennzeichnet dadurch, dass die Partikel vorzugsweise kleiner als 1 μm sind.9. Materials and particles according to claims 1 to 8, characterized in that the particles are preferably smaller than 1 micron.
10. Materialien nach Anspruch 1, gekennzeichnet dadurch, dass das Calciumphosphat aus einer oder verschiedenen Phasen besteht.10. Materials according to claim 1, characterized in that the calcium phosphate consists of one or different phases.
11. Materialien nach den Ansprüchen 1 bis 10, gekennzeichnet dadurch, dass im Calciumphosphat Calciumionen teilweise durch andere Kationen, beispielsweise Magnesiumionen, ersetzt werden.11. Materials according to claims 1 to 10, characterized in that in the calcium phosphate calcium ions are partially replaced by other cations, for example magnesium ions.
12. Materialien nach den Ansprüchen 1, 10 und 11, gekennzeichnet dadurch, dass Calciumphosphat Phosphateinheiten teilweise durch andere Anionen, beispielsweise Carbonat, ersetzt sind.12. Materials according to claims 1, 10 and 11, characterized in that calcium phosphate phosphate units are partially replaced by other anions, for example carbonate.
13. Materialien und Partikel nach den Ansprüchen 1 bis 12, gekennzeichnet dadurch, dass die wirkstoffhaltigen Partikel aus biologisch abbaubaren Stoffen bestehen.13. Materials and particles according to claims 1 to 12, characterized in that the active ingredient-containing particles consist of biodegradable substances.
14. Materialien und Partikel nach den Ansprüchen 1 bis 13, gekennzeichnet dadurch, dass die wirkstoffhaltigen Partikel aus Stoffen bestehen, die über anionische Gruppen verfügen, die ganz oder teilweise durch Alkali- und/oder Calciumionen neutralisiert sind oder über kationische Gruppen verfügen, die ganz oder teilweise durch Phosphationen neutralisiert sind.14. Materials and particles according to claims 1 to 13, characterized in that the active substance-containing particles consist of substances which have anionic groups which are completely or partially neutralized by alkali and / or calcium ions or have cationic groups which are entirely or are partially neutralized by phosphate ions.
15. Materialien und Partikel nach den Ansprüchen 1 bis 14, gekennzeichnet dadurch, dass die wirkstoffhaltigen Partikel aus Stoffen besteht, die über Phosphat- oder Phosphonatgrup- pen verfügen, die ganz oder teilweise durch Alkali- und/oder Calciumionen neutralisiert sind.15. Materials and particles according to claims 1 to 14, characterized in that the active ingredient-containing particles consist of substances which have phosphate or phosphonate groups which are completely or partially neutralized by alkali and / or calcium ions.
16. Materialien und Partikel nach den Ansprüchen 1 bis 15, gekennzeichnet dadurch, dass die wirkstoffhaltigen Partikel aus einem Polymer bestehen, dass O-terminal phosphoryliertes Polylactid enthält. 16. Materials and particles according to claims 1 to 15, characterized in that the active ingredient-containing particles consist of a polymer that contains O-terminally phosphorylated polylactide.
PCT/EP2002/002673 2001-03-15 2002-03-12 Calcium phosphate materials containing active ingredients WO2002074355A1 (en)

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