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WO2008099198A2 - Composés ostéogéniques - Google Patents

Composés ostéogéniques Download PDF

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Publication number
WO2008099198A2
WO2008099198A2 PCT/GB2008/000544 GB2008000544W WO2008099198A2 WO 2008099198 A2 WO2008099198 A2 WO 2008099198A2 GB 2008000544 W GB2008000544 W GB 2008000544W WO 2008099198 A2 WO2008099198 A2 WO 2008099198A2
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WO
WIPO (PCT)
Prior art keywords
poly
lactide
polymer
piperidone
osteogenic
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Ceased
Application number
PCT/GB2008/000544
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English (en)
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WO2008099198A3 (fr
Inventor
Bikramjit Chopra
Grahame Mckenzie
Bryn Hardwick
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Inion Ltd
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Inion Ltd
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Publication of WO2008099198A3 publication Critical patent/WO2008099198A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors

Definitions

  • the present invention relates to compounds having osteogenic properties, uses of said compounds, compositions comprising those compounds, methods of manufacturing compositions and methods useful in bone repair.
  • the traditional method for fixing broken bones includes repositioning the broken bone in the correct position and applying plaster of Paris or fibreglass to the outside of the limb concerned in order to form a 'cast' . Once the bone has set the cast may be removed.
  • More recently developed methods include the fitting of bone plates with screws and the like to keep the broken bone in position while healing occurs.
  • One such method is described in US 7,122,037.
  • Another method involves the positioning of a resorbable polymer composition around the broken bone which composition holds the bone in position while healing occurs and then slowly dissolves and is absorbed by the body of the patient as taught in US 6,607,548.
  • BMP bone morphogenic protein
  • US 6,926,903 teaches the use of resorbable polymer compositions comprising a compound which infers osteogenic properties to the composition.
  • This type of composition gives the advantage that whilst holding the broken bone in place for healing, the oestogenic compound may slowly release from the composition causing bone growth rate to increase at the site of the break.
  • Such compositions can result in significantly faster bone healing.
  • Plasticisers are used in resorbable polymer implants to make the implants flexible so they can be worked prior to curing.
  • NMP N-methyl-2-pyrrolidone
  • Some variability in the type of resorbable polymer is desired to allow practitioners to tailor the properties of implants to particular therapeutic needs .
  • the present invention relates to compounds, compositions and the use of these compounds and compositions for promoting bone regrowth and repair, to methods for manufacturing such compositions and to methods of treating patients with broken bones .
  • X is carbonyl, methylene or substituted methylene
  • R 1 is lower alkyl, lower alkoxy, alkaryl, alkyl carbonyl or alkoxy carbonyl;
  • R 2 and R 3 are independently hydrogen or lower alkyl; and wherein one of A and X is carbonyl; its pharmaceutically acceptable salts and prodrugs for use as a medicament.
  • Lower alkyl may be any branched or straight chain alkyl moiety having between 1 and 6 carbon atoms .
  • Preferred alkyl groups in compounds according to the invention are methyl, ethyl, propyl, isopropyl and secondary butyl.
  • Substituted methylene may be isoproylene or methylene substituted with one or two lower alkyl groups .
  • Preferably substituted methylene is isopropylene .
  • Lower alkoxy may be any lower alkyl moiety bound through an oxygen atom.
  • Preferred alkoxy groups are methoxy and ethoxy.
  • Alkaryl may be any lower alkyl group substituted with phenyl .
  • the preferred alkaryl group for the compounds of the invention is benzyl.
  • Alkylcarbonyl may be any lower alkyl group bound though a carbonyl group.
  • the preferred alkylcarbonyl is acetyl.
  • Alkoxycarbonyl may be any lower alkyl group bound though an oxygen atom and a carbonyl group. Preferred alkoxycarbonyl groups are methoxycarbonyl and tert-butoxycarbonyl.
  • A When X is carbonyl, A must be methylene so that the resultant compound is a 2-piperidone and when A is carbonyl, X must be methylene or substituted methylene so that the resultant compound is a 4-piperidine .
  • R 2 and R 3 are methyl
  • X is dimethylmethylene .
  • Preferred compounds according to the invention are selected from the group 1, 2, 2, 6, 6-pentamethyl-4 ⁇ piperidone, 1-acetyl- 4-piperidone, l-benzyl-2-piperidone, l-ethyl-4-piperidone, 1-methyl-2-piperidone, 1- (2-methylpropyl) -4-piperidone (N- secbutyl-4-piperidone ( , l- tert butoxycarbonyl-4-piperidone) (1- boc-4-piperidone) , 1-propyl-4-piperidone and l- ⁇ nethyl-4- piperidone .
  • salts and prodrugs may be of any type so long as when administered to a patient an appreciable portion of the free drug becomes available.
  • salts may be those of inorganic acids such as piperidonyl sulphates and chlorides .
  • the compounds are neither salts nor prodrugs .
  • the invention provides a resorbable polymer composition comprising a polymer matrix and an osteogenic compound having formula I, as described above, its pharmaceutically acceptable salts or prodrugs .
  • the polymer matrix may be selected from the group consisting of polyglycolide, polylactides, polycaprolactones , polytrimethylenecarbonates , polyhydroxybutyrates , polyhydroxyvalerates, polydioxanones , polyorthoesters, polycarbonates, polytyrosinecarbonates, polyorthocarbonates polyalkylene oxalates, polyalkylene succinates, poly (malic acid), poly(maleic anhydride), polypeptides, polydepsipeptides, polyvinylalcohol, polyesteramides, polyamides, polyanhydrides , polyurethanes, polyphosphazenes , polycyanoacrylates , polyfumarates, poly(amino acids), modified polysaccharides, modified proteins and their copolymers, terpolymers or combinations or mixtures or polymer blends thereof.
  • the polymer matrix is selected from the group consisting of polyglycolide, poly (L-lactide-co- glycolide) , poly (D, L-lactide-co-glycolide) , poly (L-lactide) , poly (D,L-lactide) , poly (L-lactide-co-D, L-lactide) , polycaprolactone, poly (L-lactide-co-caprolactone) , poly(D,L- lactide-co-caprolactone) polytrimethylenecarbonate, poly (L- lactide-co-trimethylenecarbonate) poly (D, L-lactide-co- trimethylenecarbonate) , polydioxanone and their copolymers, terpolymers or combinations or mixtures or polymer blends thereof .
  • the polymer matrix comprises Polylactide/Polyglycolide/Trimethylene carbonate copolymer (PLA/PGA/TMC) with a composition of 80/10/10, Poly D, L-lactide/Poly L-lactide/Trimethylene carbonate copolymer (PLDLA/PLA/TMC) with a composition of 55/40/5, or a matrix comprising 80 wt-% P(L/DL)LA (70/30) and 20 wt-% PLLA/TMC (70/30) .
  • PLA/PGA/TMC Polylactide/Polyglycolide/Trimethylene carbonate copolymer
  • PLA/PGA/TMC Poly D, L-lactide/Poly L-lactide/Trimethylene carbonate copolymer with a composition of 55/40/5
  • a matrix comprising 80 wt-% P(L/DL)LA (70/30) and 20 wt-% PLLA/TMC (70/30) .
  • the resorbable polymer composition may contain anywhere between the minimal amount of an osteogenic compound required for a pharmaceutical effect up to about 50% by weight of the composition.
  • the resorbable polymer composition is in the form of an implant.
  • the osteogenic compound makes up between 0.05 and 50% by weight of the composition. More preferably the osteogenic compound is present in an amount of between 0.1 and 10% by weight.
  • the osteogenic compound is spread throughout the resorbable polymer matrix evenly but in some embodiments the osteogenic compound may be positioned only in that portion of the device intended to lie against the bone. In other embodiments the osteogenic compound may have any distribution profile within the resorbable polymer composition.
  • the invention also provides the use of an osteogenic compound having formula I, as described above, its pharmaceutically acceptable salts or prodrugs, in the manufacture of a medicament for promoting osteogenisis, particularly for assisting in the healing of, or treating, a fractured bone.
  • the medicament may be in any form such as tablet, capsule, slow release composition, powder for inhalation, syrup and any other form known in the art .
  • the medicaments may be in the form of a mixture with any pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes a material which is not biologically or otherwise undesirable. Such a material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • the medicaments according to the invention may be manufactured using any methods known in the art.
  • the compositions may be dry milled and mixed prior to tableting and the composition may therefore necessarily contain other pharmaceutically expectable excipients such as a lubricant selected from the group consisting of calcium stearate, magnesium stearate, zinc stearate, stearic acid, talc and combinations thereof, a binding agent selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and a polyvinyl pyrrolidone (PVP) .
  • a lubricant selected from the group consisting of calcium stearate, magnesium stearate, zinc stearate, stearic acid, talc and combinations thereof
  • a binding agent selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and a polyvinyl pyr
  • Medicaments according to the invention may contain any pharmaceutically acceptable excipients such as binders, fillers, pigments, disintegrating agents, lubricants, wetting agents, buffers and other excipients conventionally used in the pharmaceutical and chemical fields.
  • excipients for use in the medicaments of the present invention are microcrystalline cellulose, lactose, starch, colloidal silica, talc, glycerol esters, sodium stearyl fumarate, and titanium dioxide.
  • compositions or medicaments of the invention may be administered with any inert diluent or with an edible carrier. They may be incorporated directly into food or beverages making up part of the patient's diet.
  • the compositions or medicaments of the invention may be formulated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspension syrups, wafers, and the like.
  • the tablets, troches, pills, capsules and the like may contain those excipients already mentioned and in some cases may also contain sweetening agents, such as sucrose, glucose, aspartame or saccharin, flavouring agents such as essential oils of mint, peppermint, spearmint or any other suitable flavouring.
  • sweetening agents such as sucrose, glucose, aspartame or saccharin
  • flavouring agents such as essential oils of mint, peppermint, spearmint or any other suitable flavouring.
  • the dosage unit may additionally contain a liquid carrier such as an oil or buffered aqueous solution.
  • Medicaments and compositions of the invention may also be formulated with phospholipids or fatty acids or other synthetic nanoparticles as carriers.
  • Medicaments and compositions of the invention may take the form of formulations for parenteral administration and may include sterile aqueous solutions or dispersions, and sterile powders for the preparation of sterile, injectable solutions or dispersions.
  • the solutions or dispersions may also contain buffers, diluents, and other suitable additives that may be designed to promote the cellular uptake of the active agents in the composition, for example, liposomes.
  • compositions for topical administration may be especially useful for localized treatment.
  • Formulations for topical treatment included ointments, sprays, gels, suspensions, lotions, creams, and the like.
  • Formulations for topical administration may include known carrier materials such as isopropanol, glycerol, paraffin, stearyl alcohol, polyethylene glycol, and the like.
  • the pharmaceutically acceptable carrier may also include a known chemical absorption promoter.
  • Absorption promoters include, for example, trichloroethanol, trifluoroethanol, and certain alcohols and mixtures thereof according to GB 1,001,949 to Meyer and GB 1,464,975 to AstraLakemedel) .
  • Medicaments and compositions of the invention suitable for rectal or vaginal administration may be presented as a suppository, which may include one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • the medicaments of the invention preferably comprise a resorbable polymer matrix, such as those exemplified herein.
  • the polymer matrix acts as a slow release composition in preferred embodiments, allowing the osteogenic compound to leach out of the resorbable composition over time and enhance bone repair.
  • the present invention provides a method for manufacturing an implant having osteogenic properties comprising the steps of; a) selecting polymer(s) or copolymer (s) ; b) adding an osteogenic compound, as discussed above, its pharmaceutically acceptable salts or prodrugs in an amount of between 0.05 and 50% by weight; c) processing the polymer (s) or copolymer (s) to form a polymer matrix; and d) forming the implant from said polymer matrix.
  • the present invention provides another method for manufacturing an implant having osteogenic properties comprising the steps of; a) selecting polymer(s) or copolymer (s) ; b) processing the polymer (s) or copolymer (s) to form a polymer matrix; c) forming the implant from said polymer matrix; and d) adding the implant to a solution of an osteogenic compound, as discussed above, its pharmaceutically acceptable salts or prodrugs so that an amount of between 0.05 and 50% by weight is adsorbed by the implant.
  • the step of processing the polymer (s) or copolymer (s) to form a polymer matrix may be carried out by any means known to one of skill in the art .
  • the processing step involves melt processing.
  • the method may involve incorporation of the osteogenic agent into the polymer both prior to blending and after the implant is made.
  • Preferred polymers or copolymers for use in the method of manufacture are those already discussed above and preferred osteogenic compounds are those previously discussed.
  • the implant forms include, but are not limited to, membranes, films, plates, mesh plates, screws, taps or other formed pieces .
  • the osteogenic compound may be a plasticiser for a particular polymer or copolymer blend.
  • the advantage of this aspect of the invention resides in the surprising finding that the compounds act both as osteogenic agents and as plasticizers .
  • osteogenic agents act in synergy with BMP and those other endogenous factors present that assist in bone repair, for example, BMP-2, BMP-4, BMP-7 and GDF-5.
  • Some aspects of the invention involve the inclusion of one or more of these endogenous factors within the formulation or polymer matrix so as to augment the naturally occurring factors which will be present at the site of a break.
  • the invention therefore also encompasses those formulations, uses and methods where an endogenous factor and the osteogenic agent are present and/or administered in synergistic amounts .
  • the osteogenic agent may be co-administered with one or more of recombinant human BMP-2, BMP-4, BMP- 7 and GDF-5.
  • Preferred osteogenic compounds of the invention are those that display a synergistic effect when co-administered with BMP-2.
  • the present invention provides a method of treating a person in need of bone repair comprising administering a compound according to the invention or a pharmaceutical composition according to the invention.
  • the method involves surgically implanting a resorbable polymer composition according to the invention.
  • Alkaline phosphatase is a commonly assessed biomarker associated with an osteogenic phenotype. Active osteoblasts robustly produce alkaline phosphatase, a chemical that has an essential role in making phosphate available for calcification of bone.
  • Osterix is a zinc finger-containing transcription factor that is essential for osteoblast differentiation and bone formation.
  • Example I Cell culture and induction of differentiation
  • the murine muscle myoblast cell line, C2C12 (Lot05/K/031) was obtained from European Collection of Cell Cultures (Salisbury, U.K.). The cells were maintained in DMEM containing foetal bovine serum (10%) , 1-glutamine (2mM) , penicillin G (lOO ⁇ g/mL) and streptomycin (100U/mL) , in a humidified atmosphere containing 5% CO 2 at 37 0 C.
  • C2C12 cells were seeded at a density of 0.5xl0 4 cells/mL into polystyrene 96 well plates (Appleton
  • C2C12 cells were seeded into 6 well plates at 30,000 cells/well in DMEM medium supplemented with foetal bovine serum (10%) , 1-glutamine (2OmM) , penicillin G (lOO ⁇ g/mL) and streptomycin (lOOU/mL) .
  • the following day the cells were treated with BMP-2 (lOOng/mL) and the osteogenic compound (5mM) and incubated for 48 hours in a humidified atmosphere containing 5% CO 2 at 37 0 C. Therafter, cells were harvested and total RNA isolated using the RNeasy mini-kit (Qiagen #74104) .
  • First-strand cDNA was synthesised from 500ng of RNA using random hexamers and Superscript II Reverse Transcriptase (Invitrogen #18064-022) .
  • Transcript expression of Osx was determined by real-time quantitative PCR (qPCR) analysis performed in a Chromo4 Real-Time PCR detector (BioRad Laboratories) using iQ SYBR Green Supermix (BioRad #170- 8882) and the primers to detect a 124bp sequence; Primers for Osterix qPCR; 5' GTCAAGAGTCTTAGCCAAACTC 3'; Fwd 5' AAATGATGTGAGGCCAGATGG 3' Rev. Osx expression was normalised against 18S ribosomal RNA expression.
  • qPCR real-time quantitative PCR
  • l-Methyl-2-piperidone (compound A) in the presence of BMP-2 (lOOng/mL) was shown to induce alkaline phosphatase in murine C2C12 cells, in a dose-related manner.
  • Maximum induction was observable at 5mM, and levels were almost back to those observable with BMP-2 (lOOng/mL) alone at by the time concentration of the active was down to lOO ⁇ M.
  • the level of alkaline phosphatase induction was more than three and a half time greater than BMP-2 (lOOng/mL) alone, with 1-Methyl-2-piperidone (5mM) .
  • NMP (5mM) in combination with BMP-2 (lOOng/mL) was used as a control, and produced the same three and a half fold increase in alkaline phosphatase levels compared to BMP-2 (lOOng.ml-1) alone.
  • 1- Methyl-2-piperidone (5mM, ImM and 500 ⁇ M) in combination with BMP-2 (lOOng/mL) induces the osteogenic phenotype marker, alkaline phosphatase in murine C2C12 cells. There appears to be activity right down to lOO ⁇ M although the results used in preparation of this application show a low significance at this concentration.
  • the level of alkaline phosphatase induction was just over 7% greater at lOO ⁇ M and just over 17% greater at l ⁇ M than BMP-2 (lOOng/mL) alone.
  • the level of alkaline phosphatase induction was just over 2.8 times greater at 5mM, 90% greater at ImM, just over 50% greater, and j ust over 15% greater at 100 ⁇ M, than BMP-2 ( lOOng/tnL) alone .
  • the level of alkaline phosphatase induction was just over 20% greater at 100 ⁇ M and just over 15% greater at l ⁇ M than BMP-2 (lOOng/mL) alone.
  • the level of alkaline phosphatase induction was just over 15% greater at 100 ⁇ M and more than 30% greater at l ⁇ M than BMP-2 (lOOng/mL) alone.
  • alkaline phosphatase induction was just over 15% greater at 100 ⁇ M and more than 30% greater at l ⁇ M than BMP-2 (lOOng/mL) alone.
  • the osteogenic compounds are added to the polymer matrix that has been already fashioned into the form of a medical implant.
  • Polymer compositions are prepared by dry-mixing commercially available granular-form base materials with commercially available copolymer additives.
  • the material composition was 80% w/w P(L/DL)LA (70/30) and 20% w/w PLLA/TMC (70/30).
  • the components are weighed according to a desired weight ratio into a container which is then rotated in a Turbula T2F shaker mixer for 30 minutes until a homogenous dry mixture is obtained.
  • the resulting mixture is then dried in vacuum at 60 0 C for 8 to 12 hours and subsequently melt-blended and injection-moulded into pieces of the desired shape.
  • the processes and tooling required to carry out injection moulding are well known to one skilled in the art of die making or plastics engineering.
  • the plates are usually sterilized by gamma irradiation with a nominal dose of 25 kGy. After sterilisation, the plates are submerged in the osteogenic compound for 30 seconds followed by resting at room temperature for half an hour.
  • the implant may also be fashioned into a barrier membrane for use in Guided Tissue Regeneration (GTR) to treat a periodontal defect.
  • GTR Guided Tissue Regeneration
  • the membrane comprises PLA/PGA-matrix; polymers.
  • the membrane is positioned in a slot of a package, such as a plastic blister.
  • the preparation of the membrane is conducted as one stage of surgical operation as follows :
  • an amount of an osteogenic compound or a solution thereof is poured into the membrane slot.
  • the membrane is fully immersed in the osteogenic compound or solution for an period of between 30 seconds and 3 minutes, preferably for 30 seconds .
  • the membrane is removed from the slot. 3.
  • the osteogenic compound is allowed to diffuse into the polymer matrix of the membrane for 15 to 20 minutes.
  • the membrane is ready for use as a barrier between the gingival soft tissue and the healing bone tissue and/or periodontal tissues in order to prevent the gingival soft tissue filling the defect side.
  • Implants of the invention can be used for example in guided bone regeneration applications, where the effect of an osteogenic compound loaded barrier membrane is required to avoid soft tissue ingrowth in the area where new bone formation is required, and to enhance bone regeneration.
  • osteogenic compounds of the invention When the osteogenic compounds of the invention are incorporated into compositions for use in securing broken bones, they result in a more rapid healing of bones.
  • the compounds act in a synergistic manner with BMP and other endogenous factors already present at the break site to enhance their effect on the healing process.
  • compositions may be applied as a solid 'cast' around the portion of bone to be repaired or may be applied between two or more fractured portions as a fluid, preferably viscous, so that the active compounds are present between the fractured pieces facilitating their reattachment to one another .
  • Compositions of the invention may be used for rebuilding bone, cosmetic surgery, trauma surgery, rebuilding fractures, and in the treatment of osteoporosis and osteosarcoma .
  • Patients may have any number of reactions and allergies to compounds used in prostheses and implanted devices which may only be discovered once the device is implanted.
  • the selection of osteogenic compounds which have an additional plasticising functionality allows for a lower number of compounds to be implanted in the body. This is advantageous as the lower number of different compounds implanted, the lower the chances are that a patient may have a complication due to the implant.

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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur certaines 2- et 4-pipéridones et sur leurs sels et promédicaments pharmaceutiquement acceptables ; sur des compositions les comprenant ; sur l'utilisation de ces composés et de ces compositions comme médicament et dans la fabrication de compositions pour favoriser la repousse et la réparation osseuses ; ainsi que sur des procédés de traitement d'os endommagés ou cassés.
PCT/GB2008/000544 2007-02-16 2008-02-15 Composés ostéogéniques Ceased WO2008099198A2 (fr)

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GB0703061A GB2446652A (en) 2007-02-16 2007-02-16 Osteogenic compounds
GB0703061.2 2007-02-16

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WO2008099198A2 true WO2008099198A2 (fr) 2008-08-21
WO2008099198A3 WO2008099198A3 (fr) 2009-01-15

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US7947649B2 (en) 2008-04-14 2011-05-24 Advanced Technologies And Regenerative Medicine, Llc Liquid buffered GDF-5 formulations
US7956028B2 (en) 2006-12-14 2011-06-07 Johnson & Johnson Regenerative Therapeutics, Llc Protein stabilization formulations
US7964561B2 (en) 2007-06-29 2011-06-21 Advanced Technologies And Regenerative Medicine, Llc Protein formulations for use at elevated temperatures
US8058237B2 (en) 2007-08-07 2011-11-15 Advanced Technologies & Regenerative Medicine, LLC Stable composition of GDF-5 and method of storage

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US7956028B2 (en) 2006-12-14 2011-06-07 Johnson & Johnson Regenerative Therapeutics, Llc Protein stabilization formulations
US8435943B2 (en) 2006-12-14 2013-05-07 Advanced Technogies And Regenerative Medicine, Llc Protein stabilization formulations
US8895506B2 (en) 2006-12-14 2014-11-25 DePuy Synthes Products, LLC Protein stabilization formulations
US7964561B2 (en) 2007-06-29 2011-06-21 Advanced Technologies And Regenerative Medicine, Llc Protein formulations for use at elevated temperatures
US8058237B2 (en) 2007-08-07 2011-11-15 Advanced Technologies & Regenerative Medicine, LLC Stable composition of GDF-5 and method of storage
US7947649B2 (en) 2008-04-14 2011-05-24 Advanced Technologies And Regenerative Medicine, Llc Liquid buffered GDF-5 formulations

Also Published As

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GB0703061D0 (en) 2007-03-28
GB2446652A (en) 2008-08-20
WO2008099198A3 (fr) 2009-01-15

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