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WO2009016333A1 - Composés ostéogéniques - Google Patents

Composés ostéogéniques Download PDF

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Publication number
WO2009016333A1
WO2009016333A1 PCT/GB2008/001923 GB2008001923W WO2009016333A1 WO 2009016333 A1 WO2009016333 A1 WO 2009016333A1 GB 2008001923 W GB2008001923 W GB 2008001923W WO 2009016333 A1 WO2009016333 A1 WO 2009016333A1
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Prior art keywords
poly
lactide
polymer
bmp
composition
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Ceased
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PCT/GB2008/001923
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English (en)
Inventor
Bikramjit Chopra
Grahame Mckenzie
Bryn Hardwick
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Inion Ltd
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Inion Ltd
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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
    • A61K31/5545—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having eight-membered rings not containing additional condensed or non-condensed nitrogen-containing 3-7 membered rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • 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
    • A61L31/14—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
    • 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
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • 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
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the 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 1 . 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.
  • 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 .
  • R is selected from H, methyl and acetyl; and X is methylene or ethylene; and its pharmaceutically acceptable salts and prodrugs for use as a medicament .
  • 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 sulphates and chlorides .
  • the compound is the compound according to formula I wherein X is methylene and R is hydrogen or methyl .
  • the compound is the compound according to formula I wherein X is ethylene and R is acetyl .
  • the invention provides a resorbable polymer composition
  • a resorbable polymer composition comprising a polymer matrix and a compound according to figure I
  • R is selected from H, methyl and acetyl; and X is methylene or ethylene; 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 the compound of formula I, its pharmaceutically acceptable salts or prodrugs, 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 compound of formula I, its pharmaceutically acceptable salts or prodrugs make up between 0.05 and 50% by weight of the composition. More preferably the compound of formula I, its pharmaceutically acceptable salts or prodrugs, is present in an amount of between 0.1 and 10% by weight .
  • the compound of formula I, its pharmaceutically acceptable salts or prodrugs are spread throughout the resorbable polymer matrix evenly but in some embodiments may be positioned only in that portion of the device intended to lie against the bone. In other embodiments the compound of formula I, its pharmaceutically acceptable salts or prodrugs, may have any distribution profile within the resorbable polymer composition.
  • R is selected from H, methyl and acetyl; and X is methylene or ethylene; its pharmaceutically acceptable salts or prodrugs, in the manufacture of a medicament for promoting osteogenesis, 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 compound of formula I, its pharmaceutically acceptable salts or prodrugs, 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 a compound according to figure I
  • R is selected from H, methyl and acetyl
  • X is methylene or ethylene; 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 a compound according to figure I
  • R is selected from H, methyl and acetyl; and X is methylene or ethylene; 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 a compound of formula I, its pharmaceutically acceptable salts or prodrugs , into the polymer both prior to blending and after the implant is made.
  • the implant forms include, but are not limited to, membranes, films, plates, mesh plates, screws, taps or other formed pieces .
  • the 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.
  • the present invention provides a method of treating a person in need of bone repair comprising administering a compound according to figure I
  • R is selected from H, methyl and acetyl; and X is methylene or ethylene; its pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition according to the invention.
  • the method involves surgically implanting a resorbable polymer composition according to the invention.
  • the medicament takes the form of a paste that may be applied between fractured portions of bone so as to provide a compound of formula I, its pharmaceutically acceptable salts or prodrugs, directly at the site of the break, thereby enhancing bone repair.
  • 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 (lOOU/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 Woods, Birmingham, U.K.) and maintained for 24 hours, after which they were treated with the three compounds of interest (detailed below) over a range of concentrations (5mM to lOO ⁇ M) in the presence of subthreshold concentration of BMP- 2 (lOOng/mL; obtained from Prof. Franz Weber, University of Zurich) ; appropriate vehicle controls were used.
  • the compounds tested were:
  • Compound 1 is n-methylcaprolactam
  • compound 2 is n- acetylcaprolactam
  • compound 3 is oenantholactam or 2- azacyclooctanone having CAS reference numbers 2556-73-2, 1888-91-1, and 673-66-5, respectively.
  • the compounds will be referred to by their compound numbers detailed above.
  • a combination of BMP-2 (lOOng/mL) with NMP (5mM) - a compound found to have osteogenic properties - was used as a standard reference. Cells were maintained in culture for 7 days prior to assessment of alkaline phosphatase activity. Results of the tests are shown below.
  • Compound 1 in the presence of BMP-2 was shown to induce alkaline phosphatase in murine C2C12 cells.
  • Compound 2 in the presence of BMP-2 (lOOng/mL) was shown to induce alkaline phosphatase in murine C2C12 cells. Induction was observable at 5mM and ImM and the levels of alkaline phosphatase induction were around 1.6 and 1.1 times greater than BMP-2 (lOOng/mL) alone, respectively.
  • 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 compound 1 (ImM) , compound 2 (5mM) or compound 3 (5mM) and incubated for 48 hours in a humidified atmosphere containing 5% CO 2 at 37°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 hexatners 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
  • Compound 1 (ImM) , compound 2 (5mM) and compound 3 (5mM) enhanced osterix gene expression in C2C12 cells by factors of around 266, 50 and 520, respectively, compared to BMP-2 (lOOng/mL) alone.
  • a compound according to formula 1 is 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 6O 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 a solution of either compound 1, compound 2 or compound 3 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 :
  • the compound is allowed to diffuse into the polymer matrix of the membrane for 15 to 20 minutes. 4.
  • 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.
  • compositions may be applied as a solid 'cast 1 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 .

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  • Materials For Medical Uses (AREA)

Abstract

Cette invention concerne une famille de lactames, des compositions comprenant cette famille de composés, l'utilisation de ces composés et compositions pour activer la recroissance et la réparation osseuses, et des méthodes de production desdites compositions sous la forme, par exemple, de matrices polymères résorbables contenant ces composés.
PCT/GB2008/001923 2007-07-30 2008-06-05 Composés ostéogéniques Ceased WO2009016333A1 (fr)

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GB0714791A GB2451451A (en) 2007-07-30 2007-07-30 Osteogenic compounds
GB0714791.1 2007-07-30

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WO2009016333A1 true WO2009016333A1 (fr) 2009-02-05

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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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EP1731178A2 (fr) * 2005-05-10 2006-12-13 University Of Zurich Composition polymère résorbable, implant et son procédé de préparation
WO2008132458A1 (fr) * 2007-04-30 2008-11-06 Inion Limited Compositions utiles dans la modulation de réponses immunitaires et le traitement ou la prévention de réponses inflammatoires et procédés apparentés

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WO2005014574A1 (fr) * 2003-07-25 2005-02-17 Novartis Ag Lactames substitues et utilisation de ceux-ci en tant qu'agents anti-cancereux
WO2006056695A1 (fr) * 2004-11-29 2006-06-01 Aventis Pharma S.A. Bengamides possedant un cycle caprolactame substitue, procede de preparation, compositions les contenant et utilisation
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WO2008132458A1 (fr) * 2007-04-30 2008-11-06 Inion Limited Compositions utiles dans la modulation de réponses immunitaires et le traitement ou la prévention de réponses inflammatoires et procédés apparentés

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KINDER F R ET AL: "SYNTHESIS AND ANTITUMOR ACTIVITY OF ESTER-MODIFIED ANALOGUES OF BENGAMIDE B", JOURNAL OF MEDICINAL CHEMISTRY, US AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 44, 1 January 2001 (2001-01-01), pages 3692 - 3699, XP002310388, ISSN: 0022-2623 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

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GB2451451A (en) 2009-02-04
GB0714791D0 (en) 2007-09-12

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