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WO2001060425A1 - Materiau biodegradable - Google Patents

Materiau biodegradable Download PDF

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Publication number
WO2001060425A1
WO2001060425A1 PCT/FI2001/000141 FI0100141W WO0160425A1 WO 2001060425 A1 WO2001060425 A1 WO 2001060425A1 FI 0100141 W FI0100141 W FI 0100141W WO 0160425 A1 WO0160425 A1 WO 0160425A1
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WO
WIPO (PCT)
Prior art keywords
fact
active agent
temperature
peptide
release
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PCT/FI2001/000141
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English (en)
Inventor
Jukka Veli SEPPÄLÄ
Teija Maria Karjalainen
Jaana Maria Rich
Harri Juhani Korhonen
Niina Kaarina Ahola
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Jvs-Polymers Oy
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Publication date
Application filed by Jvs-Polymers Oy filed Critical Jvs-Polymers Oy
Priority to AU2001237465A priority Critical patent/AU2001237465A1/en
Publication of WO2001060425A1 publication Critical patent/WO2001060425A1/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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than 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
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61L2300/604—Biodegradation

Definitions

  • Biomaterial is defined to be a synthetic structural material whose aim is to interact with the biological system, and to replace, to treat, promote healing and renewal of and to join tissue, organs or some function of the body.
  • Applications of these materials are reviewed in a publication edited by H ⁇ cker et al. ( Klee, D., Severich, B., Hocker, H., Macromol. Symp. 103 , January 1996, pp. 19 - 29).
  • fixation materials of different types for bone fracture treatment which can be used for manufacturing screws, nails or rods for the above mentioned application, just to mention an example.
  • These materials can be either non-biodegradable ones, e.g., metals or metal alloys, or polymeric materials degradable at a controlled rate in the body.
  • biodegradable materials are high molecular weight lactide homopolymers, and lactide copolymers with, for example, glycolide.
  • Useful parts or products are processed from these materials with processing methods for thermoplastics known in polymer technology, such as injection molding, hot pressing or extrusion.
  • Typical polymeric dental filling materials are chemically (for example, photochemically) curable plastics based on methyl methacrvlate, dimethyl acrylate and their derivatives.
  • Fixation bone cements for orthopedic hip prostheses are also based on monomer combinations methacrvlate type.
  • the curing is based on redox initiated free radical polymerization, and on thus accomplished by means of cross-linking and network formation.
  • the methacrvlate based implant materials are, however, neither biodegradable nor biocompatible to any particular extent, as Dr. Heikkila reports in his thesis (Heikkila, J., Bioactive glass as a bone substitute in experimental and clinical bone defects. Publications of University of Turku Series P. Vol. 240. 1996 ).
  • a bioactive implant material makes possible an active interaction between the tissue and the implant.
  • Heimke and Griss have characterized the concept of bioactivity and have been cited by Heikkila in his publication (Fig. 1 from Heikkila, J., Bioactive glass as a bone substitute in experimental and clinical bone defects, Publications of University of Turku Series P. Vol. 240, 1996. p. 18) .
  • a scheme to clarify the matter there is presented a non biocompatibie material, a bioinert but at the interphase biocompatibie material, and a bioactive material.
  • Bioactive materials have scarcely been reported in the literature. Especially in the case of bone cements bioactivity would be desirable and a significant benefit. Controlled biodegradation
  • implant materials Depending on the application and purpose of implant materials, they are expected to have either long lasting durability or controlled degradability in the body at a predetermined rate to harmless degradation products.
  • the wanted degradation rate is depending substantially on the renewal rate of the tissue. In the case of bone tissue, it may be case of several months, or even of a time span in the range of half an year to one year.
  • the mechanical properties required from implant materials are depending on the application. With bone implants usually a compression strength of at least 50 Mpa is necessary, as well as bending strength and tensile strength values which are at the level of those of bone.
  • Plasticizabilitv and hardening thereafter are either pieces of definite shape, i.e., processed before implanting to the final form using methods known in the plastics technology (as an example one can mention biodegradable bone nails based on polylactide, e.g., trade name Biofix), or bone cements based on methacrylate which typically have no biodergradability and lack bioactivity but as monomers, or as a blend of monomers, can be shaped in the target according to the needs, and can be hardened thereafter.
  • biodegradable bone nails based on polylactide e.g., trade name Biofix
  • bone cements based on methacrylate typically have no biodergradability and lack bioactivity but as monomers, or as a blend of monomers
  • plasticizable In surgery there would be plenty of applications for plasticizable, and afterwards to solid curable biodegradable polymeric materials. Then the idea is, that the material is plastic in connection to the surgical operation , and can be shaped according to the target's shapes or can be forced to penetrate even into small cavities, fractures and pores. Thereafter it again reversibly becomes solid, mechanically tough material which, however, has the property of controlled degradation. Thus plasticizable material can then be of the type of wax, plastic or rubber.
  • the implant material is placed to the target in connection to a clinical situation, e.g., in connecton to an operation. Then the applicability and the mouldability of the material has to be easy: it must be possible to, for example, inject it, or to place it with a special press. to the target, and its hardening has to have a certain induction period during which the material can be shaped. On the other hand, one has to take into account that the possible drug present and/or the contact with tissue do not allow use of methods where the temperature even for a short period exceeds the typical upper limit of 55 °C.
  • the publication WO 98/26814 brings a novel solution which significantly improves applicability of biodegradable implants, for example, in regenerating surgery and in long lasting drug therapy.
  • bioactive effective agents in the implant materials can be mentioned different kinds of drugs, hormones, tissue regeneration promoting components (such as hydroxy apatite in connection to bone tissue), and building substances of tissue, such as proteins.
  • the matrix material has to be such , that these components can easily be blended to form a j 'homogeneous blend.
  • There are unevitably limitations for the highest processing temperature due to the fact that many of the previously mentioned bioactive components do not resist elevated temperatures, but degrade, or their structure changes in a way, that the biological effects are reduced or lost.
  • the applications based on the controlled release of bioactive substances one has to know firstly the degradation and transition temperatures of these organic molecules.
  • a very special task is to produce a polymeric matrix enabeling controlled release for peptide active agents.
  • the denaturation temperatures of protein like peptide compounds consisting of amino acids is typically in the range of 50 - 60°C.
  • Theis means that the blending into the controlled release matrix or the production of the corresponding implant device, or processing or application of these has to take place at a temperature which is below the critical temperature.
  • the present invention enables the production of well functioning controlled release systems for peptide active agents.
  • Special requirements for the matrix in the controlled release applications are not only in the previously mentioned processing and applicability aspects of the implant, also the need to control the active agent release rate according to the need of the end use application and therapeutic need.
  • An important aspect affecting on the release rate and also a structural parameter for control of the same is the polarity of the polymer matrix.
  • the polarity, and thus the release rates of active agents can be regulated through the selection of so called initiator compound.
  • advantageous compounds are multifunctional alcohols, such as some glycols, glyuserol, pentaeritrythol or polyglycerol, just to mention a few, Also block copolymers of polyethylene oxide type can be used.
  • the implant material described in the publication WO 98/26814 is based on as such known structural units used in synthesis of polymeric biomaterials , and also on structural units derived from capronic acid.
  • Structural imits derived from lactic acid can be, in addition to lactic acid itself, L- , O-, and PL-lactide units.
  • Structural units derived from capronic acid can be, e.g.. ⁇ -caprolactone.
  • structural units can be organic carbonates, like trimethvlenecarbonate.
  • Lactones are cyclic esters based on hydroxyacids. Some of the most common lactones are L-lactide, PL-lactide, P-lactide and ⁇ -caprolactone. With these to the same group of cyclic monomers can also be included cyclic carbonates, like trimethylenecarbonate.
  • the polymerization of lactones and cyclic carbonates can be carried out, as is well known, through catalytic ring opening polymerization.
  • the catalyst used is typically some organometallic compound like tin(II)octoate (in other words stannous-2-ethylhexenoate), or trimethylaluminium.
  • the molecular weight control in this type of polymerization is based on the optimal selection of polymerization temperature and time, and it is possible also using so called initiator compounds, of which typical are multifunctional alcohols, e.g., glycerol. Puring the polymerization the polymer chains will start to grow from the -OH groups so that the molecular weight will be the lower the more initiator is present. By choosing the structure of the multifunctional alcohol the shape of the forming molecule can be affected. So, for example, glycerol forms a comb-like and pentaerythritol a star-shaped molecular structure, respectively.
  • the melting and plasticization temperature of the material must, of course, not to be too high in respect to the body temperature, taking into account the above described temperature resistance of tissue and of drug-like active agents.
  • melting or plasticizing the material according to the invention becomes a viscose mass or fluid which can be shaped, injected or otherwise used to fill hollows, fractures and cavities as well as to replace different kinds of tissue defects, as in bone grafting.
  • the temperature at which the material becomes plastic it has become possible to adjust the temperature at which the material becomes plastic to within the temperature range of 42 - 55 °C, or it can be adjusted to any temperature around this temperature range as well.
  • the melting temperature of the material can be checked by means of measurements of entalphy changes, using differential scanning calorimetry (DSC) as the method.
  • DSC differential scanning calorimetry
  • the control of the melting temperature of a polymeric material according to the invention is based on one hand on the specific monomer ratio selection in the starting materials, and, on the other hand, on the specific control of the molecular weight in the copolymerization. Both factors together namely affect the melting temperature of the copolymer, hence only certain combinations of them bring about the wished result.
  • Figure 1 is a graphical presentation the combinations of monomer compositions and average molecular weights for the L-lactide/caprolactone copolymers which produce a suitable melting temperature for implant use, indicated by points falling within the shaded area between curves in the . monomer molar ratio versus molecular weight coordination.
  • the implanted material is degradable in a controlled manner, or vice versa mechanically stable at least for a certain period of time.
  • the first stage in bidegradation of the materials according to the present invention is hydrolysis which splits polymer chains to shorter segments until the molecular size is at a level where the own enzymatic functions of the body can convert the degradation products to compounds which are natural in the body.
  • hydrophilic character of the polymer is an essential parameter affecting the degradation rate.
  • copolymers of the present invention it is possible to control hydrolytic degradation rate through control of monomer composition, and so also hydrophilic character, which according to what has been presented above directly affects the degradation rate of the material in the body.
  • Figure 2 indicates the dependence between the hydrolysis rate and monomer composition in the L-lactide / ⁇ -caprolactone copolymers prepared in the examples.
  • composition of the material comprises only or for the most part ⁇ -caprolactone, the rest being L-lactide, DL-lactide, P-lactide or trimethyl carbonate, the polymer is almost stable in the body, or degrades very slowly, typically during several years.
  • the monomer composition keeping this in mind, and through adjusting the molecular weight of the forming polymer by controlling the polymerization parameters, one can get benefit from the well-known biocompatibility and bioactivity of poly(hydroxy acid)s.
  • a waxy version of the copolymers according to the invention can be made to degrade even really fast, just by controlling both average molecular weight and monomer composition as described above. In that case the degradation rate in the body is typically from some days to some weeks.
  • a material according to the invention is in a molten state, i.e., while being at a temperature exceeding 37 °C, preferably at the temperature range of 42 - 55 °C, and most preferably at the temperature range of 43 - 48 °C, a plastic mass or a viscous fluid.
  • This makes it possible to shape the material by hand or by using specific tools to a desired shape to meet the needs of the target, or alternatively makes it possible that the material can. by different transportation methods, be used to fill different and variably shaped spaces, hollows, cavities and fractures numerously existing in surgery, dentistry and medicine.
  • advantegous in the method according to the WO 98/26814 is an unexpected observation that the plasticizable material according to the invention can above its melting temperature be in such a state that it can be applied to the target using a specific press.
  • Said press essentially consists of a heated cylinder , a die (which can be of different kinds according to the needs of the end uses), a piston , trigger , and a press mechanism .
  • the temperature of the cylinder can be regulated at a desired level by a thermostat so that the implantable material is either in a molten state or in a plasticized state inside the cylinder in front of the piston , and thus it can be transferred using the press device through the die to the target area. Because the temperature of the molten or plasticized polymeric material is higher than the body temperature but in any case such that there is no danger of tissue damage, the implant material can be transferred directly to the target area where it solidifies when cooling down.
  • Advantages of the method according to the invention are the simplicity for the user (, e.g., for the surgeon), hygienicity because the implant material is all the time in a closed chamber, and the point that there are no volatile components utilized in the method (an advantage in respect of industrial hygiene and working safety), and further that there is no heat generation in connection with the solidification (as usually is the case in the solidification of bone cements) and the risk of tissue damages can thus be avoided.
  • an additional benefit one can mention that by using differently shaped longer dies it becomes possible to inject the mass to narrow, deep and variously shaped channels to their very end or to their deepest points, to fractures, to cavities and the like as target areas.
  • Another preferred embodiment of the implantation method is the use of such a device which does not contain any specific piston, but the piston is replaced with a rod made up of polymeric material according to WO 98/26814 which penetrates through the unheated part of the cylinder to the heated part where it melts or plasticizes.
  • the feeding mechanism pushes the rod into the cylinder, and correspondingly the molten or plasticized polymeric material is extruded out through the die.
  • Still one advantageous method to implantate is the one where the temperature of the cylinder is raised above one hundred degrees centigrade and is held there for the time required for completing heat sterilization. In this case any separate sterilization is not needed, and the sterilized material remains in its closed space sterile and ready for use.
  • this form of implantation can be applied provided that there are no heat sensitive active agents, for example drugs, present as blend components. After the sterilization treatment the material is allowed to cool down to the temperature range of 37 - 55 °C so that it remains both sterile and in a molten or plasticized state for the implanting.
  • One specific way of implantation is the one where the polymer according to the invention is produced in a way that its melt viscosity is low enough to allow its injection to the target area with a suitable injection syringe.
  • the polymeric material when cooled down to its solid state at the body temperature is a waxy material.
  • the implant material according to WO 98/26814 can be applied in a way that the material forms a matrix in the controlled release of drugs, or it forms a matrix in blends containing bioactive inorganic materials where the bioactive component can be selected from the group including, for example, hydroxyapatite, a filler based on coral, bone allocrafts or its particles, titanium particles and carbon fibers, just to mention some.
  • the blend component can, of course, also be soluble to the polymeric matrix, as is the case in connection with the most drugs.
  • the solid components in the mixtures may be platelets or fibrous particles so that the composition is comparable to the polymer composites, and in which case the blend component essentially improves mechanical properties.
  • a special advantage is achieved in the aspect that the use of a biodegradable polymeric matrix yields adhesion between particles, plasticizability, ease of processing, and improved biocompatibility to this kind of materials containing solid particles.
  • the method according to the invention enables the controlled release and targeted location to the body, for example, in connection with an operation, or by injecting.
  • Both composite materials containing solid fillers and/or reinforcements and blends containing soluble components can be located according to the invention, for example, as is presented in WO 98/26814, easily and safely as a plastic mass or a viscous fluid directly to the end use tar 'sge"t.
  • the copolymers were prepared from ⁇ -caprolactone monomer ( ⁇ -CL), > 99% purity, Fluka Chemika , and O.L-lactide ( D,L-LA), Purac.
  • ⁇ -CL ⁇ -caprolactone monomer
  • D,L-LA O.L-lactide
  • Purac O.L-lactide
  • tin(II)octoate Stannous 2-ethylhexanoate; SnOct
  • 95 % purity Sigma.
  • the initiator was used glycerol, 99,5% purity, Fluka BioChemika, and polyglycerol, having in average 8 -OH groups ( Daicel PGL06).
  • D,L-lactide was purified with recrystallication from toluene ( b.p. 110 °C) using a mass ratio of 1 :2 toluene/lactide.
  • the lactide dissolved to a hot toluene was poured from round bottom flask to a decanter.
  • the lactide solubilized to the toluene was let to recrystallize overnight at 23 °C.
  • After filtration the crystallized lactide was dried under reduced pressure for 4 days at +40 °C and 4 mbar. The same stages were repeated once. In the polymerizations was thus used twice recrystallized D,L-lactide which was stored in an exsiccator in a refrigerator at +4 °C.
  • the used lactide has been placed into a vacuum chamber at +40 jC and 4 mbar.
  • the two-piece polymerization reactor (volume about 0,7 liter) was assembled, and the condition of the Teflon gasket belonging to the reactor was checked. The proper closure of the upper part and the lower part of the reactor was ensured by a iron wire closing device. The male parts of the glass joints belonging to the reactor were wiped slightly with a vacuum grease.
  • Poly-D.L-lactide and poly-epsilon-caprolactone polymerizations were carried out batchwise in an agitated reactor of volume 2.5 liters, equipped with two intermeshing agitators, which create especially good agitation into the reaction mixture in every point of the conical reaction chamber.
  • the oil thermostat used for the reactor heating was regulated to 140°C.
  • the oil temperature varies during a polymerization within 5°C above and below the set temperature.
  • Lactide was weighed first about 10 g into a small decanter (accuracy 0,0001 g). On the lactide the tin octoate and the glycerol was weighed using a Pasteur pipet. After this the decanter was poured into the reactor, and the rest of the lactide was weighed with another balance (accuracy 0,01 g) . ⁇ -Caprolactone was then either poured or pipeted on lactide.
  • the magnetic agitator has been added to the reactor before the reactor halves were closed.
  • the reactor was placed into a thermostat, and the agitation was adjusted to the speed of 250 1/min.
  • the reactor was flushed with Argon (AGA, grade S, 99,99%) for about 15 min.
  • Argon was fed to the reactor through a glycerol trap.
  • Finally the outside of the reactor was wrapped with a aluminum foil. When the forming copolymer started to become more viscous the agitation speed was adjusted again to the speed of 125 1/min.
  • the batch size was 500g D,L-lactide.
  • catalyst concentration was 0,02mol-% corresponding 0,295g in the reaction mixture, and the initiator content when glycerol was used 0,25%, and when polyglycerol was used 3,0mol- %. the amounts correspondingly in the reaction mixture 0,8 lg and 48.8g.
  • the batch size in the epsilon-caprolactone polymerization was lOOOg, the catalyst concentration 0.01mol-% corresponding 40,48g in the reaction mixture.
  • the monomers were weighted with an accuracy of 1 g, the catalyst and initiator with an accuracy of 0,001 g.
  • the reactor was flushed first with nitrogen ( Aga, grade 99,999%) for 5min and the reactor was closed. As the agitator speed 60 1/min was adjusted. The temperature of the reaction mixture was increased from room temperature ( 25°C) to the level of 140°C in 0,5h . whereafter the agitation was continued at this temperature for 3,5h.
  • Table 1 summarizes the copolymerizations and their results using ⁇ -caprolactone and D.L- lactide ( ⁇ -CL/D,L-LA), homopolymerisations of epsilon-caprolactone and the analysis results of the products.
  • the temperature was 140 °C and the polymerization time was 24 h (except in Example nr. 3 where it was 29 h).
  • the temperature reached was 140°C and the total polymerization time was 4h.
  • the temperature was 160°C and polymerization time 4h.
  • Molecular weights determined by gel permeation chromatography are presented in Table 1 in terms of number average molecular weight Mn, weight average molecular weight Mw, and the polydispersity PP calculated as the ratio of the previous ones Mw/Mn.
  • Table 1 there are also presented the transition temperatures of the polymerization products, i.e. melting temperature Tm and glass transition temperature Tg, determined using differential scanning calorimetry (PSC).
  • the GPC-samples for molecular weight measurements were prepared by dissolution of 15 mg of sample into 10 ml of chloroform. As columns were used columns of Polymer Laboratories Ltd with pore diameters of 100 - 10 000 A. The used detector was RI-, i.e.. refractive index detector, manufactured by Waters, and a 55 min run time with a flow rate of 1 ml/min were used. To determine the molecular weights of the samples were used polystyrene (PS) standards manufactured by Polymer Laboratories, and the calibration curve based on the same. Because there is no experimental Mark-Houwink constants a and K available, the molecular weights in the Table 1 are not absolute molecular weights for the samples but relative values in comparison with PS standards.
  • PS polystyrene
  • the used protein was albumin (BSA, molecular weight around 67 000 g/mol. Fluka) enrich from the serum of cows .
  • lysozyme molecular weight 14 600 g/mol. Fluka
  • ibuprofein molecular weight 206.28 g/mol
  • the polymer used in the release experiments was poiyD,L-lactide initiated with polyglycerol (PDLA-PGLE), the poly-D,L-lactide initiated by glycerol (PDLLA-G) and poly-epsilon-caprolactone and poly(epsilon-caprolactone-D,L-lactide) copolymer in which the monomer fed ratio was epsilon-CL D,L-LA 95/5 both initiated by using glycerol.
  • Polymers and proteins and caprolactone/lactide-copolymer and ibuprofein were homogeniously mixed in a DSM-midiextruder. The mixing time was 3min, and screw speed 50 1/min.
  • the polymer was fed to the extruder as a premixed solid with a powdery active agent.
  • the rectangular test specimens were cut from bars, having measures of 4,0 * 1.6 * 80mm, and which were injection molded by using DSM-mini injection molding device. The bars were cut into 4,0 mm pieces in legth.
  • the cylindrical test specimen were prepared by drawing the extrudate out of the DSM- midiextruder die. through an ice bath, so that the polymer was immediately solidified.
  • the cooled polymer rope with a diameter of 1.4mm was cut into peaces of 5mm.
  • the preparation of film form specimen was done with a table press Fontijne TP 400 by using a 0.25mm sheet mold and force of 150kN.
  • the cycle was as follows: preheating without compression 5min, compression with a force of 150 kN 5 min, cooling with a water cooled coled surface by using 150 kN force for 5min.
  • Thus prepared sheets were cut to square specimen of 20mm or 5mm in their edges.
  • the specimen were stored in refrigerator.
  • Film samples were prepared as described by using glycerol initiated poiy-D,L- lactide and epsilon-CL/D.L-LA 95/5 copolymer and both of the proteins . and epsiion- CL/DX-LA 95/5 copolymer and ibuprofein. The last was processed also into rectangular and cylindrical bars. The processing temperatures were adjusted for both of the mixtures based on GPC- and DSC-analysis, above the glass transition and melting temperatures.
  • the specimen based on polyglycerol initiated PDLLA were prepared by cutting from the midiexruder extrudate.
  • the specimen were prepared in a way that they weighted as much as the film form specimen.
  • the protein release experiments were carried out at 37°C in a thermostated shaker water bati .
  • the specimen which were 5 in parallel, were weighted into 50ml Erlenmeyer flasks.
  • 30ml of buffer solution was added, and they were sealed with caps.
  • each flask was removed from the bath, shaken thoroughly and 10ml of the solution was removed. The removed amount was replaced with an equal amount of clean buffer solution, and the flask was returned into the bath.
  • the removed solution was analysed by using Unica Helios Beta UV/VIS spectrometer , and the release curves were drawn based on the mean values of the parallel samples.
  • Figures 4 and 5 present the cumulative release rates for proteins BSA and lysozyme from all the matrix specimen materials. By comaring the figures , that the release rate of BSA from all the three polymers is the fastest. During a time period of one month (i.e. 30d) the cumulative release fraction of BSA from the glycerol initiated PDLLA is 42% and of lysozyme around 25%. From the polyglyserol initiated PDLLA releases BSA with the proportion of around 35% and lysozyme 15%.
  • the dissolution experiments of ibuprofein were carried out at a temperature of 37 C in a shaking air bath.
  • the specimen which were three parallel for each of the experimental point, were weighted into test tubes.
  • Into the tubes was added 5-10 ml buffer solution depending on the specimen type, and they were sealed with caps.
  • the test tubes were placed into the air bath, and measurements were carried out during the week daily by removing the tubes out of the bath, shaking them and the test specimen were removed. From the hydrolysis medium the released ibuprofein was analyzed by using Unicam Helios Beta UV/VIS spectrometer, and the release curves were drawn as mean values based on the parallel samples results.
  • Figure 6 presents the cumulative release rate of ibuprofein for different specimen calculated on surface area.
  • the release rate from films is the fastest, since the ibuprofein is released already during 24 hours.
  • the release rate calculated for surface area is the fastest from the rectangular bars, and the release from them continued at least for a week. From cylindrical samples all the ibuprofein was released in about four days time. The results indicate, that the release rate of the active agent can be controlled through the selection of the shape of the implanted specimen.
  • the release rate is for the BSA the greatest 0,06 mg/mm2*d and the smallest 0,0000014 mg/mm2*d.
  • the release rate of lysozyme during a week is between 0,00000055 - 0,06mg/mm2*d.
  • the release rate of ibuprofein during a month is in the range of 0,1 - 23 mg/mm2*d .
  • the results indicate, that the the release rate of a protein type blended active agent out from a polymeric matrix material according to the invention, van be controlled through the selection of the initiator component selection in the polymer production.
  • the control of the active agent release rate can be based on the matrix polymer properties as well as on the specimen shape, and it can be varied in very large range.
  • the release total time can on the other hand be varied from a couple of hours to several months, even up to several years time spans.
  • the figures 4 and 5 present cases , in which about half ( figure 4) or about one third ( figure 5) of certain protein type active agent releases in about a month.
  • Figure 6 presents a case in which the small molecular active agent release rate is adjusted to occure in a weeks time after the implantation.
  • the controlled release of heat sensitive active agents like peptides without the reduction of their therapeutic effectiveness is based in our invention on the fact that these agents are blended into the polymeric matrix material at a temperature which is above the melting temperature of the polymer melting temperature but at the same time below the decomposition or denaturation temperature of the active agent.
  • the active agents can be in the mixture completely dissolved, or they can be dispersed and partially solubilized into the matrix polymer.
  • the release itself occurs by diffusion mechanism, and it is of primary importance for the therapeutic methods , that the release rate is even at the desired level or that it is changing in a desired way with time, so that the release profile is desired.
  • Another possibility is to control the active agent release from the polymeric matrix by adjusting the shape of the implantable specimen, due to the fact that the releasing surface area and the area/volume-ratio of the specimen are essentially important for the diffusional behavior.
  • the material according to the invention can be processed with known processing methods be processed into bars, discs, cylindrical specimen, fibers , fabrics, tubes, spheres, microspheres and particles, just to mention some.

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  • Health & Medical Sciences (AREA)
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  • Vascular Medicine (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
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  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
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Abstract

La présente invention concerne essentiellement des matériaux synthétiques hydroxyacides, biocompatibles, et peut être même dégradables à une vitesse régulée. Ces matériaux sont des polymères ou des copolymères de dérivés d'hydroxyacides organiques, tels que les lactides et les lactones. A une température de fusion comprise entre 0 et 100 C (régulée pour atteindre plus préférablement entre 2 et 20 C au-dessus de la température du corps), ces matériaux sont à l'état fondu, sous forme de masses plastiques ou de liquides visqueux, et par conséquents ceux-ci sont moulables avec les mains, et peuvent être injectés ou traités avec un dispositif de moulage de masses visqueuses. Par ailleurs, à température normale du corps, ces matériaux sont semblables à du plastique solide, de la cire ou du caoutchouc, à partir desquels on peut obtenir des agents actifs à une vitesse régulée, particulièrement dans le cas de médicaments sensibles à la chaleur ou de libération contrôlée d'autres agents actifs efficaces, de sorte que ces matériaux agissent comme une matrice par rapport aux implants ou aux dispositifs implantés dans le corps, dans le cadre de traitements thérapeutiques.
PCT/FI2001/000141 2000-02-15 2001-02-14 Materiau biodegradable WO2001060425A1 (fr)

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AU2001237465A AU2001237465A1 (en) 2000-02-15 2001-02-14 Biodegradable material

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FI20000317 2000-02-15
FI20000317A FI20000317A (fi) 2000-02-15 2000-02-15 Biologisesti hajoava materiaali

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072663A1 (fr) * 2001-03-12 2002-09-19 Chemical & Medical Research Co., Ltd. Procede de preparation de polyester biodegradable et polyester biodegradable ainsi obtenu

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0747072A2 (fr) * 1995-06-07 1996-12-11 United States Surgical Corporation Matériau biodégradable moulable
US5733950A (en) * 1988-10-03 1998-03-31 Atrix Laboratories, Incorporated Biodegradable in-situ forming implants and methods of producing the same
WO1998026814A1 (fr) * 1996-12-17 1998-06-25 Jvs-Polymers Oy Materiau plastifiable pour implant

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5733950A (en) * 1988-10-03 1998-03-31 Atrix Laboratories, Incorporated Biodegradable in-situ forming implants and methods of producing the same
EP0747072A2 (fr) * 1995-06-07 1996-12-11 United States Surgical Corporation Matériau biodégradable moulable
WO1998026814A1 (fr) * 1996-12-17 1998-06-25 Jvs-Polymers Oy Materiau plastifiable pour implant

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072663A1 (fr) * 2001-03-12 2002-09-19 Chemical & Medical Research Co., Ltd. Procede de preparation de polyester biodegradable et polyester biodegradable ainsi obtenu
US7138179B2 (en) 2001-03-12 2006-11-21 Chemical & Medical Research Co., Ltd. Method for preparing biodegradable polyester and itself prepared thereby

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FI20000317A0 (fi) 2000-02-15
AU2001237465A1 (en) 2001-08-27

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