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WO1997038741A1 - Procede de fabrication d'un materiau biodegradable de substitution osseuse et d'implant et materiau ainsi obtenu - Google Patents

Procede de fabrication d'un materiau biodegradable de substitution osseuse et d'implant et materiau ainsi obtenu Download PDF

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Publication number
WO1997038741A1
WO1997038741A1 PCT/DE1997/000736 DE9700736W WO9738741A1 WO 1997038741 A1 WO1997038741 A1 WO 1997038741A1 DE 9700736 W DE9700736 W DE 9700736W WO 9738741 A1 WO9738741 A1 WO 9738741A1
Authority
WO
WIPO (PCT)
Prior art keywords
biodegradable
implant material
composite
inorganic
component
Prior art date
Application number
PCT/DE1997/000736
Other languages
German (de)
English (en)
Inventor
Dieter Reif
Barbara Leuner
Olaf GÜNTER
Original Assignee
Biovision Gmbh Entwicklung, Herstellung Und Vertrieb Von Biomaterialien In Ilmenau
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 Biovision Gmbh Entwicklung, Herstellung Und Vertrieb Von Biomaterialien In Ilmenau filed Critical Biovision Gmbh Entwicklung, Herstellung Und Vertrieb Von Biomaterialien In Ilmenau
Priority to AU26921/97A priority Critical patent/AU2692197A/en
Publication of WO1997038741A1 publication Critical patent/WO1997038741A1/fr

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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
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • A61L27/04—Metals or alloys
    • 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
    • C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones

Definitions

  • the invention relates to a method for producing a biodegradable bone replacement and implant material and a biodegradable bone replacement and implant material which can be used for the temporary filling of bone defects and as a starting material for the production of moldings for biodegradable implants
  • biodegradable and partially biodegradable composites are described in DE 41 20 325.
  • the materials have an open-pore structure and are characterized by proportions of calcium phosphate ceramic over 50% by mass.
  • the ceramic particles are coated with a maximum of 50% of their surface with a biopolymer to enable the bone to grow in well.
  • the biopolymer forms the cement substance for the calcium phosphate ceramic.
  • Various bone ceramics are preferred as inorganic composite components and as biopolymers, among others.
  • Polylactide and polyglycolide are proposed.
  • the composite components are heated by means of microwave radiation and sintered or, after softening, deformed by mechanical pressure.
  • the material consists of synthetic, biological compatible and biodegradable polymer with a modulus of elasticity similar to that of bone and an inorganic filler that is able to stimulate the absorption of the polymer in favor of new bone tissue.
  • the inorganic filler consists of calcium phosphate, especially TCP, and is contained in an amount of 0.5 to 30% by mass.
  • Tricalcium phosphate is preferably used as calcium phosphate, and polylactides and polyglycolides are proposed as polymers.
  • the composites are produced by mixing the shredded individual components and hot pressing.
  • EP 0 192 068 protects composites of 25 to 75% by mass of unsintered calcium phosphate ceramic, preferably hydroxylapatite, tricalcium phosphate, calcium pyrophosphate and 25 to 75% by mass biodegradable polymer.
  • the polymer components include Lactic and glycolic acid polyesters are used. Up to 30% by mass of water-soluble, pore-forming materials can be included as further additives.
  • the composite components are mixed and then polymerized.
  • Composites of biodegradable or non-biodegradable calcium phosphate ceramics preferably tricalcium phosphate or hydroxylapatite and polymers of lactic and glycolic acid are described in WO 90/01342.
  • the polymer component contains molecular weight-regulating coreactants in order to set molar masses in the range from 200 to 10,000 g / mol. This makes the composites kneadable to solid at body temperature.
  • the ceramic portion is in the range of 20 to 65% by mass as granules and / or powder.
  • the composites described in WO 88/06873 contain polyester of fumaric acid and a polyhydroxy alcohol as polymer components.
  • Calcium phosphate ceramics are suggested tricalcium phosphate or hydroxyapatite.
  • the composites contain other biodegradable calcium salts, such as calcium sulfate, calcium carbonate and calcium sulfate hemihydrate.
  • All of the composite materials described are intended for use in medical technology as implant and / or bone replacement materials or for anchoring orthopedic implants in the bone tissue.
  • Different processes are described for the production of the materials, all of which have in common that they do not subject the composite components to high thermal loads.
  • the spectrum of the calcium phosphate ceramics used is limited to the known calcium orthophosphates and hydroxyapatite.
  • the absorption rate of the inorganic constituents is thereby limited to a narrow range, or the inorganic component is not absorbed at all and remains as a foreign body in the organism.
  • methods of high shaping accuracy for the production of implants, such as injection molding are not provided for the materials described in the prior art, so that a deficit with regard to shape and dimensionally accurate composite implants must be deduced.
  • a general problem in the production of biodegradable composites using calcium orthophosphates and biomaterials derived therefrom is that they are subject to a more or less strong hydrolysis in the presence of water or moisture. As a result of this hydrolysis reaction, these biomaterials act like strong bases. This behavior limits their use as a composite component, especially when interacting with chemically sensitive biopolymers. In certain combinations, there may even be considerable chemical incompatibility of the composite constituents, which may result in the production and processing of the desired composite by thermal mixing and molding. make the rendering process impossible.
  • the object of the invention is to create a method and a material of the type mentioned at the outset in order to expand the field of composition for biodegradable bone substitute and implant materials and the possibilities for producing shaped bodies, and to improve the mechanical strengths of biodegradable bone substitute and implant materials .
  • the object is achieved with a method in which the basicity of the biodegradable inorganic constituent in at least one layer of its surface is adjusted to a pH value in the neutral range of 7 ⁇ 1, mixed intimately with the biodegradable organic constituent, and then is transferred into the composite.
  • Advantageous embodiments of this method are specified in subclaims 2 to 7.
  • the biodegradable bone substitute and implant material according to the invention consists of a composite based on a biodegradable organic polymer and a biodegradable inorganic component.
  • the biodegradable organic constituent is a representative of the in vivo degradable polymers, while the biodegradable inorganic constituent consists of particles of a slightly to sparingly soluble, synthetic, stoichiometric and / or non-stoichiometric composition, amorphous, amorphous crystalline and / or crystalline alkali Alkaline earth and / or alkaline earth salt mixture of one or more polybasic inorganic acids.
  • the particles of the salt mixture have at least one surface layer such a chemical composition that their freshly saturated aqueous solution has a pH in the range of 7 ⁇ 1.
  • the biodegradable organic polymer is preferably a polyester from the group of polyglycolides, polylactides or their copolymers.
  • the biodegradable organic polymer preferably consists of poly (L-lactide), poly (D-lactide), poly (D.L-lactide), poly (glycolide) or copolymers derived therefrom, the comonomer fraction being up to 50% by mass.
  • Comonomers in the form of copolymerizable cyclic esters include, in addition to the various lactide forms, glycolide, dioxanone, trimethyl lencarbonate or a lactone of ß-hydroxybutyric acid and / or ß-hydroxyvaleric acid in question.
  • the biodegradable organic polymer in the finished and sterilized composite molded body has at least a molecular weight of 100,000 g / mol.
  • a special form of the biodegradable organic polymer is designed as a polymer blend and represents a mixture of mechanically reinforcing, different high molecular weight polymers.
  • this functions as a matrix of the composite or cementes the particles of the biodegradable inorganic component.
  • the particles of the inorganic constituent are surrounded as completely as possible by the organic constituent and that a high interfacial strength is achieved.
  • the biodegradable inorganic component of the composite consists of particles of an alkali-alkaline-earth and / or alkaline-earth salt mixture of orthophosphoric acid, sulfuric acid, silica and / or carbonic acid.
  • Na 2 O and / or K 2 0 are preferably present as alkali oxides and CaO and / or MgO are preferably contained as alkaline earth oxides.
  • the particles of this salt mixture have a pH in the range of 7 ⁇ 1 in their freshly saturated aqueous solution. This value does not change by more than ⁇ 0.2 in a period of 30 minutes after the first measurement immediately after the saturated solution has been prepared.
  • the particles of the biodegradable inorganic component consist of an unsintered precipitate, a sintered and / or a melt product. Their size varies with the desired goal in
  • the biodegradable bone replacement and im- Plantate material contains the biodegradable organic component in an amount of 5 to 99 mass% and the biodegradable inorganic bed component in an amount of 1 to 95 mass%.
  • biodegradable inorganic composite component which produces a pH of around 7 when suspended in water leads to surprising results ⁇ as a much less degradation of the polymer component during thermal shaping than, for example when strongly alkaline alkaline earth metal and / or alkaline earth phosphates are added.
  • the known methods of acid-base reactions for salt formation are used to produce the biodegradable inorganic constituent.
  • the proportions of the components are calculated in such a way that, for example, when precipitating from aqueous solution or sintering suitable compounds or melting them, the salt mixture formed as a reaction product has a neutral character and the pH value of its freshly saturated aqueous solution corresponds to the criteria mentioned above .
  • the basicity of the biodegradable inorganic constituent is adjusted by composition of the determined amounts of Components of the salt mixture and their homogeneous mixing, sintering or fusion.
  • Biodegradable inorganic constituents according to the invention which are produced via high-temperature reactions, are generally referred to as ceramics, glasses or glass ceramics.
  • their manufacturing process which is based on solid-state diffusion or melting reactions, can also be viewed as an acid-base reaction or salt reaction.
  • the resulting reaction products are therefore classified as sparingly or sparingly soluble salts or salt mixtures, the chemical composition of which does not have to comply with the stoichiometric laws of defined chemical compounds.
  • Such materials include described in WO 91/07357.
  • the saiz mixture reacts
  • neutral and has a pH value in the range of the physiological value in its freshly saturated aqueous solution.
  • Salts or salt mixtures with such high pH values are unsuitable as a biodegradable inorganic component.
  • their use is possible in that the particles of the biodegradable inorganic component are subjected to at least superficial leaching or acid conversion before being combined with the biodegradable organic component.
  • the basic components of the material are neutralized and partially leached out.
  • the surface reaction layer also serves as a diffusion barrier and prevents further passage of the basic components from the particle core.
  • the thickness of the reaction layer is chosen at least so that the im The neutral pH of a freshly saturated aqueous solution does not change by more than ⁇ 0.2 within 30 minutes. This is generally sufficient to ensure processability with the polymer component.
  • Shaped bodies of the biodegradable bone substitute and implant material have an open-pore structure, depending on the manufacturing process, or are free of open and / or closed porosity.
  • the mixture of the composite components contains up to 60% pore-forming agents. This addition and the selected sintering conditions make it possible to set an open porosity in the range from 10 to 50%.
  • Shaped bodies, which are manufactured by the hot-pressing process or injection molding technology, on the other hand, are free of any kind of porosity, provided that one works with vacuum-dried starting materials.
  • Shaped bodies of the biodegradable bone substitute and implant material are produced after the dry mixing of the finely comminuted, vacuum-dried organic and inorganic composite components by one of the thermal processes sintering, hot pressing, extruding or injection molding.
  • the manufacturing process can also consist of combinations of these processes.
  • Favorable grain fractions of the composite components for the mixing process are ⁇ 500 ⁇ m, advantageously ⁇ 200 ⁇ m.
  • the biodegradable inorganic component predominates in the mixture of the composite components, the mixture is preferably produced from solutions and / or suspensions by evaporating the solvent and / or by precipitation of the dissolved components.
  • the polymer portion is dissolved in a suitable solvent, for example acetone or chloroform, the ceramic portion is homogeneously suspended and the polymer is precipitated by adding a suitable liquid, such as alcohol or water. During the precipitation the polymer encloses the suspended component and the composite components co-precipitate.
  • a suitable solvent for example acetone or chloroform
  • a suitable liquid such as alcohol or water
  • a complete coating of the entire ceramic grain by the polymer is obtained when the solvent is evaporated from a suspension of the biodegradable inorganic component in a solution of the biodegradable organic component.
  • this complete covering has advantages with regard to the interfacial strength between the biodegradable inorganic and organic constituents, and improves the mechanical properties of the composite. At the same time, it permits lower working temperatures during thermal shaping, which in turn reduces polymer degradation.
  • Such a polymer-encased biodegradable inorganic constituent can also be processed further by the process of dry mixing the composite components.
  • porous moldings of the biodegradable inorganic constituent according to the invention are obtained by soaking open-pored moldings of the biodegradable inorganic constituent with solutions of the biodegradable organic constituent and evaporating the solvent. This procedure leads to a high ceramic content Structural consolidation of the molded body of the biodegradable bone replacement and implant material.
  • the shaped bodies of the biodegradable bone substitute and implant material When using the biodegradable inorganic component in particle form, the shaped bodies of the biodegradable bone substitute and implant material obtain their final shape directly through the thermal shaping process, or their final shape is produced from a preform by thermal shaping. If the biodegradable inorganic constituent is used as an open-pore sintered shaped body, the pre- or final shape is predetermined by it. In all cases, the shaped body made from the biodegradable bone substitute and implant material according to the invention can still be machined in its geometric shape and the final dimensions by cutting shape change.
  • BaB1 is mixed intensively with a crushed and vacuum-dried poly (L-lactide-co-D, L-lactide) 70:30 in a particle size ⁇ 250 ⁇ m as a biodegradable organic component (boB).
  • the proportions of baB1 are 5, 10, 20 and 30% by mass.
  • the mixtures are injection molded into test specimens measuring 40 ⁇ 5 ⁇ 2 mm 3 and tested for their flexural strength.
  • the moldings are well shaped, of homogeneous structure, dense and free of porosity.
  • the bending strength values are summarized in the table below.
  • BaB1 as prepared in Example 1, is intimately mixed with a comminuted and vacuum-dried poly (D, L-lactide-co-glycolide) 85:15 as boB.
  • the particle size of the boB is ⁇ 500 ⁇ m.
  • the amount of baB1 is 20% by mass.
  • the dry mixture is extruded as a strand, chopped ⁇ 1 mm and pressed into cylinders and foils in heated molds.
  • the moldings have a homogeneous distribution of the components in the composite, are dense and non-porous.
  • Embodiment 3 Phase-pure sintered ⁇ -tri-calcium phosphate (TCP) is reacted with dilute orthophosphoric acid, which is adjusted to a pH of 2.0, in aqueous suspension for one hour.
  • the reaction product is washed, vacuum-dried and made available in a particle size ⁇ 100 ⁇ m as baB2 for further investigations.
  • a freshly saturated aqueous solution of baB2 has a pH of 7.4. This value practically does not change within an hour.
  • baB2 45% by mass of baB2 are intimately dry-mixed with 55% by mass vacuum-dried poly (D, L-lactide-co-glycolide) in a particle size of 250 to 500 ⁇ m as boB and cold-pressed into cylindrical compacts.
  • the compacts are sintered at 160 ° C for one hour.
  • the composite sintered bodies have an open porosity of 30%. Their compressive strength is 14 N / mm 2 .
  • Some of the composite sintered bodies are converted as preforms by hot pressing into dense, largely pore-free shaped bodies and another part is changed in their geometric shape by turning, drilling and milling.
  • Example 4 Example 4:
  • Example 3 50% by mass of a mixture as described in Example 3 are mixed homogeneously with 50% by mass of ammonium carbonate as pore-forming agent in a particle size of 250 to 500 ⁇ m without crushing the particles of the ammonium carbonate.
  • the mixture is cold pressed and the compact is sintered at 160 ° C for one hour.
  • the sintered body has an open porosity of 55% and can be machined very well.
  • pH pH of the freshly saturated aqueous solution at 37 ° C
  • pH 30 pH of the saturated aqueous solution after standing for 30 minutes at 37 ° C.
  • baB4 45% by mass baB4 are intimately mixed with 55% by mass poly (L-lactide-co-D, L-lactide) 70:30 as boB, formed into cylindrical pellets which are sintered at 150 ° C for 1.5 hours.
  • the cylindrical moldings have an open porosity of 40% and are very easy to machine. Their compressive strength is 12.6 N / mm 2 .
  • the composite sintered bodies, as produced according to Example 7, have an open porosity of 40%. Their compressive strength is significantly increased and is 18.0 N / mm 2 .
  • cylindrical composites are Sintered bodies with baB3 to baB5 compared with composite sintered bodies using the untreated glass ceramics GK3 to GK5 according to WO 91/07357.
  • the production of the composite sintered body corresponds to Examples 6 and 7. The results are summarized in the table.
  • Embodiment 10 A porous sintered molded body is produced from phase-pure ⁇ -TCP. This has an open porosity of 50%.
  • the sintered shaped body is treated with dilute orthophosphoric acid, adjusted to a pH of 2.0, treated for 1 hour, washed and vacuum-dried.
  • the sintered molding thus treated has a pH of 7.2 in its freshly saturated aqueous solution. This value does not change within an hour.
  • the sintered shaped body is available in this form as baB6 for composite formation.
  • the sintered shaped body baB6 is soaked with a solution of poly (L-lactide-co-D, L-lactide) 70:30 in chloroform, the solvent evaporates, the Soak repeatedly, the solvent evaporates again and then the body is vacuum dried.
  • the composite body has a compressive strength of 8.5 N / mm 2 compared to the untreated ceramic sintered molded body (5.5 N / mm 2 ). It absorbed 6.0% by mass of the boB.
  • baB6 60 mass% baB6 are homogeneously suspended in a solution of 40 mass% poly (D, L-lactide-co-glycolide) 50:50 as boB in acetone and kept in suspension. BaB6 and the boB are precipitated from this suspension together by injecting a water-alcohol mixture and vacuum-dried. The dry mixture is pressed into dense moldings in a heated mold. These are easy to machine.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Composite Materials (AREA)
  • Materials Engineering (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un procédé de fabrication d'un matériau biodégradable de substitution osseuse et d'implant, ainsi qu'un matériau à base d'un matériau composite formé d'un mélange de sels à pH neutre comprenant des sels alcalins-alcalino-terreux et/ou de sels alcalino-terreux d'un ou de plusieurs acides inorganiques polybasiques, tels que l'acide phosphorique, l'acide carbonique, l'acide silicique et l'acide sulfurique, en tant que constituants inorganiques biodégradables, et d'un représentant choisi dans le groupe des biopolymères dégradables in vivo, en tant que constituants organiques biodégradables. Les proportions, en quantités, des contituants du composite varient entre 5 et 99 % en masse pour le constituant organique biodégradable et entre 1 et 95 % en masse pour le constituant inorganique biodégradable. Des corps façonnés à partir dudit matériau biodégradable de substitution osseuse et d'implant sont fabriqués par moulage par injection, extrusion, frittage et pressage à chaud. Les formes géométriques et les dimensions de ces corps peuvent être modifiées par usinage par enlèvement de copeaux et par formage à chaud.
PCT/DE1997/000736 1996-04-12 1997-04-11 Procede de fabrication d'un materiau biodegradable de substitution osseuse et d'implant et materiau ainsi obtenu WO1997038741A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU26921/97A AU2692197A (en) 1996-04-12 1997-04-11 Process for producing a biodegradable bone replacement and implant material, as well as biodegradable bone replacement and implant material

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19614421.3 1996-04-12
DE19614421A DE19614421C2 (de) 1996-04-12 1996-04-12 Verfahren zur Herstellung eines biodegradierbaren Knochenersatz- und Implantatwerkstoffes und biodegradierbarer Knochenersatz- und Implantatwerkstoff

Publications (1)

Publication Number Publication Date
WO1997038741A1 true WO1997038741A1 (fr) 1997-10-23

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Country Link
AU (1) AU2692197A (fr)
DE (1) DE19614421C2 (fr)
WO (1) WO1997038741A1 (fr)

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US6998134B2 (en) 1998-09-11 2006-02-14 Gerhard Schmidmaier Biologically active implants
US9415009B2 (en) 2009-05-29 2016-08-16 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
US9463161B2 (en) 2009-05-29 2016-10-11 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and associated methods and systems
US11471468B2 (en) 2013-03-15 2022-10-18 Pearl Therapeutics, Inc. Methods and systems for conditioning of particulate crystalline materials

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US6811570B1 (en) 1997-10-21 2004-11-02 Augmentec Ag Implant made of a reabsorbable ceramic material
DE19805673C2 (de) * 1998-02-12 2002-09-26 Wolfgang Quante Verfahren und Kit zur Herstellung eines Knochenersatz- und Augmentationsmaterials
EP1357863B1 (fr) * 2001-01-02 2010-11-10 Advanced Ceramics Research, Inc. Compositions et procedes destines a des applications biomedicales
DE20205016U1 (de) * 2002-03-30 2003-08-14 Mathys Medizinaltechnik Ag, Bettlach Chirurgisches Implantat
DE10354758A1 (de) * 2003-11-21 2005-06-30 Schure, Frank, Dr. Chirurgisches Implantat
DE102004035182B4 (de) * 2004-07-14 2008-05-29 Innovent E.V. Technologieentwicklung Implantatmaterial, ein Verfahren zu seiner Herstellung und seine Verwendung
DE102005024296B4 (de) * 2005-05-19 2007-02-01 Bundesanstalt für Materialforschung und -Prüfung (BAM) Resorbierbarer, biokompatibler Formkörper und Verfahren zur Herstellung
DE102005029206A1 (de) 2005-06-22 2006-12-28 Heraeus Kulzer Gmbh Verformbares Implantatmaterial
DE102005039382B4 (de) * 2005-08-19 2008-03-13 Detzer, Fritz, Dr. med. dent. Hohlkörper aus biodegradierbarem Material, insbesondere zum Knochenaufbau im Kieferknochen eines Patienten und dessen Verwendung

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EP0050215A1 (fr) * 1980-10-20 1982-04-28 American Cyanamid Company Modification de l'acide polyglycolique pour obtenir des propriétés physiques "in vivo" variables
EP0144228A2 (fr) * 1983-12-01 1985-06-12 Ethicon, Inc. Appareil chirurgical résorbable, rempli de verre
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US6998134B2 (en) 1998-09-11 2006-02-14 Gerhard Schmidmaier Biologically active implants
US10646622B2 (en) 1998-09-11 2020-05-12 Gerhard Schmidmaier Biologically active implants
US9415009B2 (en) 2009-05-29 2016-08-16 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
US9463161B2 (en) 2009-05-29 2016-10-11 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and associated methods and systems
US10716753B2 (en) 2009-05-29 2020-07-21 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists or long-acting B2 adrenergic receptor agonists and associated methods and systems
US11471468B2 (en) 2013-03-15 2022-10-18 Pearl Therapeutics, Inc. Methods and systems for conditioning of particulate crystalline materials

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DE19614421A1 (de) 1997-10-16
AU2692197A (en) 1997-11-07

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