EP4337273A1 - Osteoconductive implant material with bmp-2 delivery - Google Patents

Osteoconductive implant material with bmp-2 delivery

Info

Publication number
EP4337273A1
EP4337273A1 EP22723746.8A EP22723746A EP4337273A1 EP 4337273 A1 EP4337273 A1 EP 4337273A1 EP 22723746 A EP22723746 A EP 22723746A EP 4337273 A1 EP4337273 A1 EP 4337273A1
Authority
EP
European Patent Office
Prior art keywords
pellets
encapsulating
calcium phosphate
bmp
pellet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22723746.8A
Other languages
German (de)
French (fr)
Inventor
Helen Cox
Shakesheff Kevin
Matthews CHARLES
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Locate Bio Ltd
Original Assignee
Locate Bio Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Locate Bio Ltd filed Critical Locate Bio Ltd
Publication of EP4337273A1 publication Critical patent/EP4337273A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • 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
    • A61L27/56—Porous materials, e.g. foams or sponges
    • 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
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/622—Microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
    • 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
    • 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
    • A61L2430/38—Materials or treatment for tissue regeneration for reconstruction of the spine, vertebrae or intervertebral discs

Definitions

  • the invention relates to osteoconductive implant material formed from polymer pellets, and to the use of such material in bone repair.
  • Bone healing is a physiological process in which the body facilitates the repair of the bone after an external injury, infection, surgical intervention or a disease.
  • the physiological healing process can require very long periods and, in many cases, it cannot re-establish the original bone properties.
  • therapies that accelerate and improve bone healing are of vital importance.
  • these therapies present osteoconductive, osteoinductive, and osteogenic approaches.
  • a variety of substitutes like gold, stainless steel, titanium, natural/synthetic polymers and ceramics have been tried.
  • the main concerns with the use of these materials for bone reconstruction were their poor ability to vascularise, integrate, and undergo remodelling.
  • tissue engineering techniques biologically enhanced allografts, cell-based therapies, and gene-based therapies
  • Tissue engineering has been defined as the application of scientific principles to the design, construction, modification, and growth of living tissue using biomaterials, cells, and factors alone and in combination. It involves the use of osteoconductive biomaterial scaffolds, with osteogenic cell 2 populations and osteoinductive bioactive factors. All these approaches have the potential to significantly increase our ability to treat diseases for which no effective treatment currently exists.
  • Osteoconductive implants can provide an appropriate mechanical environment, architecture and surface chemistry for angiogenesis and tissue formation.
  • the localisation of regenerative agents, such as growth factors, can also be achieved using osteoconductive implants.
  • the use of implants as drug or cell delivery systems has great potential but is also very challenging due to the need to tailor the porosity, strength and degradation kinetics of the implant to the tissue type whilst achieving the appropriate kinetics of release of agents, such as proteins that act as growth factors or cells.
  • osteoconductive implants are typically either a pre-formed water- insoluble matrix, with large interconnected pores or they are a hydrogel.
  • Such materials are implanted into a patient for augmented in vivo tissue repair and/or regeneration.
  • the pre-formed water-insoluble matrices must be shaped to fill a cavity within the body, requiring knowledge of the cavity dimensions and limiting the shape of cavity that can be filled.
  • a number of hydrogel materials have been designed that can be delivered directly into the body through a syringe. The gel forms within the body following a trigger signal, for example a temperature change or UV light exposure.
  • a trigger signal for example a temperature change or UV light exposure.
  • Such systems have the advantage that they can fill cavities of any shape without prior knowledge of the cavity dimensions.
  • such hydrogels lack large interconnected porous networks and, hence, release of an agent from the gel is limited by poor diffusion properties.
  • Resorbable putty or resorbable pastes are promising approaches. This area has been widely researched both academically and industrially, with several products such as C-Graft PuttyTM, Grafton® already having been commercialised.
  • the major obstacles in the success of such approaches are the successful delivery and retention of materials to the required site of action, as well as their malleability before the surgery.
  • Other important obstacles include the ability to deliver additional bioactive therapeutics, to have tailored resorption rates, and to form structures with high level porosity and macropores. 3
  • W02008093094 and W02004084968 (both of which are incorporated herein by reference) describe compositions and methods for forming tissue scaffolds from polymer pellets, such as PLGA and PLGA/PEG polymer blends.
  • Such scaffolds have been developed to be capable of moulding or injection prior to setting in situ at the site of tissue repair.
  • a porous structure is achieved by leaving gaps between the pellets and optionally further providing porous polymer pellets.
  • Lumbar cages are interbody fusion devices intended for use as an aid in spinal fixation, for example for a spinal fusion of a patient with degenerative disc disease. These implants are typically designed for bone in-growth and biological fixation and are used with bone graft substitute material to grow new bone for fixation.
  • the ideal bone graft substitute material needs to be sufficiently malleable for the surgeon to insert into the lumbar cage, not too loose such that material is shed, and also osteoconductive, with the ability to support cell ingrowth and provide controlled release of BMP-2. Such material properties can be challenging to provide.
  • An aim of the present invention is to provide improved compositions, methods and processes for forming osteoconductive implant material for use in tissue repair, for example, which may be used in a lumbar cage.
  • an osteoconductive implant material composition comprising:
  • BMP-2 encapsulating pellets comprising or consisting of:
  • the osteoconductive implant material composition is capable of being formed into a malleable putty when it is mixed with or includes the aqueous carrier, for example that can be manipulated into a lumbar cage for implant, and without shedding.
  • the material provides a beneficial BMP-2 controlled release for enhanced conductivity, whilst remaining porous for cell ingrowth.
  • the osteoconductive implant material is also biocompatible and biodegradable for implantation and degradation in vivo.
  • the calcium phosphate may be osteoconductive.
  • the calcium phosphate comprises or consists of b-tricalcium phosphate (b-TCP).
  • the calcium phosphate such as b-TCP
  • the calcium phosphate, such as b-TCP may be provided in the calcium phosphate-encapsulating pellet (pellet (A)) in an amount of between about 40% and about 60% w/w.
  • the calcium phosphate, such as b-TCP may be provided in the calcium phosphate- encapsulating pellet (pellet (A)) in an amount of between about 40% and about 55% w/w.
  • the calcium phosphate such as b-TCP
  • the calcium phosphate-encapsulating pellet (pellet (A)) may be provided in the amount of between about 45% and about 55% w/w.
  • the calcium phosphate, such as b-TCP may be provided in the calcium phosphate-encapsulating pellet (pellet (A)) in the amount of between about 40% and about 50% w/w.
  • the calcium phosphate, such as b-TCP may be provided in the calcium phosphate-encapsulating pellet (pellet (A)) in the amount of about 50% w/w.
  • the amount of encapsulated calcium phosphate, such as b-TCP is optimised for its therapeutic effect, in particular a level sufficient enough for enhancing osteoconductivity, but is also provided at a level that is capable of being appropriately encapsulated in a hot melt extrusion process to form the pellet.
  • the calcium phosphate such as b-TCP
  • the calcium phosphate, such as b-TCP is provided in a particulate form of less than 10 pm in size.
  • the calcium phosphate, such as b-TCP is provided in a particulate form of between about 1 pm and about 4 pm in size.
  • the calcium phosphate, such as b-TCP is provided in a particulate form of about 2 pm in size. It is understood that the reference to the particle size is an average size of the largest diameter in a population of the particles.
  • the size of the encapsulated calcium phosphate, such as b-TCP is optimised to be sufficiently avoid or reduce inadvertent release from the material and causing an immune reaction in vivo, and to also allow for extrusion.
  • calcium phosphate pellets are provided as component A (i.e. calcium phosphate not encapsulated by polymer).
  • Such calcium phosphate comprising pellets may comprise or consist of b-TCP.
  • the calcium phosphate pellets, such as b- TCP pellets may be between about 0.5mm and about 2.5mm in size.
  • the calcium phosphate pellets, such as b-TCP pellets are between about lmm and about 2mm in size.
  • the size may refer to the largest diameter of the pellet and is understood to be the average size in a population of pellets.
  • “Calcium phosphate pellets” may otherwise be termed “calcium phosphate granules” herein.
  • the size of the calcium phosphate pellets is optimised to be sufficiently large enough to provide macroporosity in the material but sufficiently small for malleability and to form an acceptable putty when mixed with the other components.
  • the calcium phosphate pellets such as b-TCP pellets, may have macroporosity (having pores of >100pm in size) and/or microporosity (having pores of ⁇ 10 pm in size).
  • the calcium phosphate pellets, such as b-TCP pellets may have interconnected porosity (for example, capable of wicking fluid therethrough).
  • the BMP-2 may comprise recombinant BMP-2 (rBMP-2).
  • the BMP-2 may comprise human BMP-2 (hBMP-2).
  • the BMP-2 comprises or consists of recombinant human BMP-2 (rhBMP-2).
  • the BMP-2 is provided in the BMP-2 encapsulating pellet (pellet B) in an amount of between about 0.01% and about 1% w/w. In another embodiment, the BMP-2 is provided in the BMP-2 encapsulating pellet (pellet B) in the amount of between about 0.01% and about 0.5% w/w. In another embodiment, the BMP-2 is provided in the BMP-2 encapsulating pellet (pellet B) in the amount of between about 0.1% and about 0.5% w/w. The BMP-2 may be provided in the BMP-2 encapsulating pellet (pellet B) in the amount of 0.19% w/w. In a preferred embodiment, the BMP-2 may be provided in the BMP-2 encapsulating pellet (pellet B) in the amount of about 0.2% w/w.
  • the BMP-2 encapsulating pellet (pellet B) may comprise or consist of between about 5% and about 15% poloxamer 407. In another embodiment, the BMP-2 encapsulating pellet (pellet B) may comprise or consist of between about 8% and about 12% poloxamer 407. In a preferred embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of about 10% poloxamer 407.
  • the poloxamer 407 is provided in powder form, for example prior to any addition of an aqueous carrier.
  • the poloxamer 407 may be micronized powder.
  • the poloxamer is less than 105pm in size. At least 85% of the poloxamer 407 particles may be less than 60pm in size, preferably less than 53pm in size.
  • the poloxamer 407 may be encapsulated in the BMP-2 encapsulating pellets (pellet
  • the poloxamer 407 aids the controlled release of the BMP-2 from the pellet and does not significantly reduce the pH, in contrast to some plasticiser additives such as PEG400.
  • the level of poloxamer is optimised to a sufficient amount to increase release rate of the BMP-2, but not in an amount sufficient to interfere with 7 the hot melt extrusion process.
  • poloxamer 407 can be classed as a plasticiser in the art, it has been demonstrated to not reduce the Tg of the polymer, such as PLGA.
  • the polymer of the BMP-2 encapsulating pellet comprises or consists of PLGA poly(lactide-co-glycolide).
  • the PLGA of the BMP-2 encapsulating pellet (pellet B) may comprise or consist of PLGA 45:50 - 55:45.
  • the PLGA is PLGA 50:50.
  • the PLGA of the BMP-2 encapsulating pellet may be acid terminated PLGA, such as PLGA 50:50A.
  • the PLGA of the BMP-2 encapsulating pellet may be P DI XGA.
  • the PLGA may be only comprise the L-form of lactic acid.
  • the L:G (lactide to glycolide ) ratio is advantageously optimised for providing an appropriate BMP-2 release profile.
  • the BMP-2 encapsulating pellet (pellet B) may comprise or consist of between 60% and about 90% (w/w) of PLGA, such as PLGA 50:50. In another embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of between 70% and about 80% (w/w), such as PLGA50:50. The BMP-2 encapsulating pellet (pellet B) may comprise or consist of between 75% and about 76% (w/w), such as PLGA50:50. In a preferred embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of about 75.5% (w/w), such as PLGA50:50.
  • the amount of PLGA polymer is optimised for an ability to be processed by hot melt extrusion, for example in the presence of other components, such as cyclodextrin.
  • the PLGA of the BMP-2 encapsulating pellet (pellet B) may have a molecular weight of between about 40kDa and about 80 kDa MWt. In another embodiment, the PLGA of 8 the BMP-2 encapsulating pellet (pellet B) may have a molecular weight of between about 60kDa and about 70 KDa MWt.
  • the molecular weight of the PLGA is optimised such that it degrades at a desired rate for providing a desired BMP-2 release profile.
  • the polymer of the calcium phosphate-encapsulating pellet (pellet A) comprises or consists of PLGA poly(lactide-co-glycolide).
  • the PLGA may comprise or consist of PLGA 75:25 to PLGA 95:5 (75-95:5-25).
  • the polymer of the calcium phosphate-encapsulating pellet (pellet A) may comprise or consist of a PLGA 75:25 to PLGA 95:5.
  • the polymer of the calcium phosphate- encapsulating pellet (pellet A) may comprise or consist of a PLGA 93-97:7-3.
  • the polymer of the calcium phosphate-encapsulating pellet (pellet A) comprises or consists of PLGA 95:5.
  • the polymer of the calcium phosphate-encapsulating pellet (pellet A) may comprise or consist of ester terminated PLGA, such as PLGA 95: 5 A.
  • the PLGA of the calcium phosphate-encapsulating pellet may be P DL LGA.
  • the PLGA may be only comprise the L-form of lactic acid.
  • the L:G (lactide to glycolide ) ratio is advantageously optimised to prevent too rapid degradation, which can cause biocompatibility issues due to the acidity of the degradation products.
  • the calcium phosphate-encapsulating pellet (pellet A) may comprise or consist of between about 40% and about 60% (w/w) PLGA, such as PLGA 95:5. In another embodiment, the calcium phosphate-encapsulating pellet (pellet A) comprises or consists of between about 45% and about 55% (w/w) PLGA, such as PLGA 95:5. The calcium phosphate-encapsulating pellet (pellet A) may comprise or consist of between about 49% and about 51% (w/w) PLGA, such as PLGA 95:5. In a preferred embodiment, the calcium phosphate-encapsulating pellet (pellet A) comprises or consists of about 50% (w/w) PLGA, such as PLGA 95:5. 9
  • the amount of PLGA 95:5 polymer is optimised for a sufficient level of degradation and replacement by bone and the ability to be processed by hot melt extrusion.
  • the PLGA of the calcium phosphate-encapsulating pellet (pellet A) may have a molecular weight of between about 50kDa and about 90 kDa MWt.
  • the molecule weight of the PLGA is optimised such that it degrades at a desired rate in vivo.
  • the polymer of the BMP-2 encapsulating pellet comprises or consists of P DI XGA 50:50 and the polymer of the calcium phosphate- encapsulating pellet (pellet A) comprises or consist of P DI XGA 95 :5.
  • the BMP-2 encapsulating pellet (pellet B) comprises or consists of about 75.5% (w/w) PLGA, such as PLGA 50:50
  • the calcium phosphate-encapsulating pellet (pellet A) comprises or consist of about 50% (w/w) PLGA, such as PLGA 95:5.
  • the viscosity modifier is the viscosity modifier
  • the BMP-2 encapsulating pellet (pellet B) may comprise between about 5% and about 15% w/w of the viscosity modifier.
  • the viscosity modifier may comprise or consist of poloxamer 407. Therefore, in one embodiment, the BMP-2 encapsulating pellet (pellet B) may comprise between about 5% and about 15% w/w poloxamer 407. In another embodiment, the BMP-2 encapsulating pellet (pellet B) comprises between about 8% and about 12% w/w viscosity modifier, such as poloxamer 407. In a preferred embodiment, the BMP-2 encapsulating pellet (pellet B) comprises about 10% w/w of the viscosity modifier, such as poloxamer 407.
  • the viscosity modifier is provided for and optimised for increasing the BMP-2 release rate, whilst also not significantly interfering with the hot melt extrusion process.
  • the BMP-2 encapsulating pellet may not comprise a plasticiser.
  • the poloxamer 407 is not, and does not act as, a plasticiser (e.g. the poloxamer 407 does not and is not intended to significantly reduce the glass transition temperature (Tg) of the pellet).
  • the poloxamer 407 is provided in powder form, for example prior to any addition of an aqueous carrier.
  • the poloxamer 407 may be micronized powder.
  • the poloxamer is less than 105pm in size. At least 85% of the poloxamer 407 particles may be less than 60pm in size, preferably less than 53pm in size.
  • the BMP-2 encapsulating pellet (pellet B) may comprise or consist of between about 10% and about 30% w/w 2-hydroxypropyl- -cyclodextrin. In one embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of between about 10% and about 20% w/w 2-hydroxypropyl- -cyclodextrin. In another embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of between about 12% and about 15% w/w 2-hydroxypropyl- -cyclodextrin. In a preferred embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of between about 14%, more preferably 14.3% w/w 2-hydroxypropyl- -cyclodextrin.
  • the 2-hydroxypropyl- -cyclodextrin is for protection of the BMP-2 during a hot melt extrusion process, and it can be optimised for sufficient protection of the BMP-2 and to not significantly interfere with the hot met extrusion process.
  • the 2-hydroxypropyl- -cyclodextrin may advantageously aid the release of BMP-2, because of its high solubility, opening up pores and allowing water ingress.
  • the BMP-2 encapsulating pellet (pellet B) and/or the calcium phosphate-encapsulating pellet (pellet A) is shaped as a hollow pellet, such as with an open hollow extending through the pellet, in accordance with those described in International Patent Application Publication No. W02018150166A1 (which is 11 incorporated herein by reference).
  • the BMP-2 encapsulating pellet (pellet B) and/or the calcium phosphate-encapsulating pellet (pellet A) may be shaped as a hollow cylindrical pellet.
  • the hollow pellets may comprise an open hollow.
  • the hollow pellets may have a tubular structure, with the hollow extending therethrough.
  • the hollow tube may be open at one end or more preferably at both ends of the pellet structure.
  • the hollow pellets may be substantially O-shaped in cross section.
  • the invention also envisages a hollow in the form of a channel running through a pellet structure, whereby the channel may be open substantially along its length, i.e.
  • the hollow pellets may comprise a C-shaped or U-shaped cross-section such that the hollow channel is open substantially along its length.
  • the hollow pellets are tubular in structure and open at both ends.
  • the hollow pellets may comprise substantially parallel walls (for example in the sense that opposite walls of a tube are generally parallel to each other).
  • the hollow pellets may not be spherical.
  • the hollow pellets may not comprise or consist of hollow microspheres (e.g. substantially spherical particles with a substantially hollow core).
  • the hollow pellets may be tubular. In one embodiment, the hollow pellets are tubular with a substantially circular cross-section. Alternatively, the hollow pellets may be any suitably shaped cross-section, such as circular, triangular, square, semi-circular, pentagonal, hexagonal, heptagonal, octagonal, or the like. In one embodiment wherein the hollow pellets are tubular, the outer surface of the hollow pellets may be substantially circular in cross-section and the inner surface of the hollow pellets may be substantially circular in cross-section. In another embodiment, the cross-sectional shape of the outer surface may be different to the cross-sectional shape of the inner surface. For example, the outer surface may be circular in cross-section, and the inner surface may be square in cross-section, or vice versa. In an example where the hollow pellets are formed by extrusion, the cross-sectional shape of the inner and outer surfaces of the tube-like structure may be determined by the shape of the extrusion die. 12
  • the hollow pellets may have a length that is equal to or greater than their diameter. In one embodiment, the length is greater than the diameter.
  • the hollow pellets may have an aspect ratio of at least 0.5: 1, 1: 1, 1: 1.5, 1:2 or 1:3 length to diameter.
  • the hollow pellets may have an aspect ratio of no more than 1:5, 1:4, 1:3 or 1:2 length to diameter.
  • the hollow pellets may have an aspect ratio of between about 0.5: 1 and about 1:5 length to diameter.
  • the hollow pellets may have an aspect ratio of between about 1: 1 and about 1:5 length to diameter.
  • the hollow pellets may have an aspect ratio of between about 0.5: 1 and about 1:5 length to diameter.
  • the hollow pellets may have an aspect ratio of between about 0.5: 1 and about 1:5 length to diameter.
  • the length of the hollow pellets may be uniform in the composition of hollow polymer pellets or a population of hollow polymer pellets in a composition may be irregular in length relative to each other.
  • the hollow pellets may have a size in their longest dimension of between about 300 pm and about 1300 pm. In another embodiment, the hollow pellets may have a size in their longest dimension of between about 300 pm and about 1000 pm. In another embodiment, the hollow pellets may have a size in their longest dimension of between about 300 pm and about 900 pm. The hollow pellets may have a size in their longest dimension of between about 600 pm and about 1300 pm.
  • the external diameter of the hollow pellets may be between about 300 pm and about 900 pm. In another embodiment, the external diameter of the hollow pellets (i.e. the distance between opposing outer surfaces (e.g. external/outer diameter of a tube) may be between about 600 pm and about 900 pm. In another embodiment, the external diameter of the hollow pellets (i.e. the distance between opposing outer surfaces (e.g. external/outer diameter of a tube) may be between about 300 pm and about 700 pm.
  • the thickness of the walls of the hollow pellets may be between about 100 and 200pm. In a preferred embodiment, the thickness of the walls of the hollow pellets may be between about 120 pm and 170pm.
  • the internal diameter of the hollow polymer pellets may be between about 100 and about 300 pm. In another embodiment, the internal diameter of the hollow 13 polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 10 and about 300 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 20 and about 300 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 10 and about 200 pm.
  • the internal diameter of the hollow polymer pellets may be between about 20 and about 200 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 10 and about 100 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 20 and about 100 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 20 and about 50 pm.
  • the internal diameter of the hollow polymer pellets may be about 200 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 20 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 40 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 50 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g.).
  • the internal diameter of a tube may be at least about 800 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 100 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 150 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 200 pm. Such 14 hollow/lumen sizes allow for advantageous cell infiltration into the hollow polymer pellets.
  • the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 400pm, but will pass through a sieve or filter with a pore size of about 500pm.
  • the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 400pm, but will pass through a sieve or filter with a pore size of about 600pm.
  • the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 400pm, but will pass through a sieve or filter with a pore size of about 800pm.
  • the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 300pm, but will pass through a sieve or filter with a pore size of about 500pm.
  • the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 300pm, but will pass through a sieve or filter with a pore size of about 600pm.
  • the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 300pm, but will pass through a sieve or filter with a pore size of about 800pm.
  • the hollow (or otherwise “lumen”) of the hollow polymer pellets may be at least 10% of the volume of the hollow polymer pellets. In another embodiment, the hollow of the hollow polymer pellets may be at least 20% of the volume of the hollow polymer pellets. In another embodiment, the hollow of the hollow polymer pellets may be at least 30% of the volume of the hollow polymer pellets. In another embodiment, the hollow of the hollow polymer pellets may be at least 40% of the volume of the hollow polymer pellets. In another embodiment, the hollow of the hollow polymer pellets may be at least 50% of the volume of the hollow polymer pellets. Such hollow/lumen volumes allow for advantageous cell infiltration into the hollow polymer pellets.
  • the hollow polymer pellets may be solid (with the exception of the hollow itself), that is the material of the hollow polymer pellet may be solid without a porous structure.
  • the hollow polymer pellets may be comprised of porous material, such that the walls of the hollow polymer pellet structure are porous.
  • the BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length.
  • the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm.
  • the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm.
  • the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm
  • the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm.
  • the BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length, and the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm.
  • the BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length, and the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm.
  • the BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length, and the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm, and the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm.
  • the BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length; and the thickness of the walls of the hollow pellets (pellet A and pellet B) may be between about 120 pm and 170pm.
  • the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm.
  • the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm.
  • the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm, and the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm; and the thickness of the walls of the hollow pellets (pellet A and pellet B) may be between about 120 pm and 170pm.
  • the BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length; the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm; and the thickness of the walls of the hollow pellets (pellet A and pellet B) may be between about 120 pm and 170pm.
  • the BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length; the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm; and the thickness of the walls of the hollow pellets (pellet A and pellet B) may be between about 120 pm and 170pm.
  • the BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length, and the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm, and the thickness of the walls may be between about 120 pm and 170pm; and the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm, and the thickness of the walls o may be between about 120 pm and 170pm.
  • the size, length, diameter, volume or thickness of the hollow polymer pellets, or features thereof may refer to the average size of a population of hollow polymer pellets. In one embodiment, the size, length, diameter, volume or thickness of the hollow polymer pellets, or features thereof, may refer to the largest size, length, 17 diameter, volume or thickness of the hollow polymer pellet.
  • the size of the hollow polymer pellets may be advantageously chosen by the skilled person for the intended application or type of osteoconductive implant material required. For example, the use of larger sized hollow polymer pellets may be for increased porosity, where the gaps between the hollow polymer pellets may be larger relative to the use of smaller hollow polymer pellets.
  • Such size control can provide control over the agent release rate, whereby a faster release rate may be provided by the choice of larger hollow polymer pellets. For example when extruding the hollow polymer pellet material, the draw-off rate can be changed pull the hollow polymer pellets into thinner diameters. Additionally, morphology can be influenced by a change in temperature and thus cooling time.
  • the morphology and dimensions of the pellets A and/or B are optimised, such that they are large enough to allow for sufficient porosity of the resulting material and small enough to produce a good putty for handling and avoiding shedding of the pellets from the material.
  • the aqueous carrier is aqueous carrier
  • the aqueous carrier may be isotonic, for example relative to body fluid.
  • the aqueous carrier comprises or consist of saline.
  • the aqueous carrier comprises or consists of physiological saline.
  • the saline may comprise or consist of about 0.9% w/v NaCl.
  • the aqueous carrier may be sterile/sterilised.
  • the aqueous carrier does not comprise a plasticiser.
  • the osteoconductive implant material composition may be a composition for producing an osteoconductive scaffold. 18
  • composition components (A), (B), (C) and optionally (D) may be mixed together into a single composition.
  • the composition further comprises (D) an aqueous carrier.
  • the composition may be in the form of a putty.
  • the BMP-2 encapsulating pellets (B) may be provided in an amount of between about 10% and about 45% w/w of the composition (in the absence of the aqueous carrier (D). In another embodiment, the BMP-2 encapsulating pellets (B) may be provided in an amount of between about 10% and about 30% w/w of the composition (in the absence of the aqueous carrier (D). In one embodiment, the BMP-2 encapsulating pellets (B) are provided in an amount of between about 20% and about 30% w/w of the composition (in the absence of the aqueous carrier (D).
  • the BMP-2 encapsulating pellets (B) are provided in an amount of about 20% w/w of the composition (in the absence of the aqueous carrier (D).
  • the BMP- 2 encapsulating pellets (B) may be provided in an amount of about 23% w/w of the composition (in the absence of the aqueous carrier (D).
  • the proportion of BMP-2 encapsulating pellets (B) is optimised for sufficient dosing and release profile of BMP-2 relative to the acid degradation of the PLGA.
  • the calcium-phosphate-encapsulating pellets (A) may be provided in an amount of between about 10% and about 52% w/w of the composition (in the absence of the aqueous carrier (D). In another embodiment, the calcium -phosphate-encapsulating pellets (A) may be provided in an amount of between about 25% and about 50% w/w of the composition (in the absence of the aqueous carrier (D). In another embodiment, the calcium -phosphate-encapsulating pellets (A) are provided in an amount of between about 35% and about 45% w/w of the composition (in the absence of the aqueous carrier (D). In a preferred embodiment, the calcium -phosphate-encapsulating pellets (A) are provided in an amount of about 40% w/w of the composition (in the absence of the aqueous carrier (D).
  • the calcium-phosphate pellets (A) may be provided in an amount of between about 25% and about 50% w/w of the composition (in the absence of the aqueous carrier 19
  • the calcium -phosphate pellets (A) are provided in an amount of between about 30% and about 40% w/w of the composition (in the absence of the aqueous carrier (D). In a preferred embodiment, the calcium -phosphate pellets (A) are provided in an amount of about 35% w/w of the composition (in the absence of the aqueous carrier (D)
  • the relative proportion of calcium phosphate pellets or calcium phosphate-encapsulating pellets (A) is optimised to provide a putty with sufficient handling characteristics.
  • component (A) a mixture of calcium phosphate pellets and calcium phosphate- encapsulating pellets are provided as component (A).
  • the viscosity modifier (C) is provided in an amount of about 40% w/w of the composition (in the absence of the aqueous carrier (D).
  • the viscosity modifier (C) may be provided in an amount of about 42% w/w of the composition (in the absence of the aqueous carrier
  • the viscosity modifier (C) may be provided in an amount of about 40.5% w/w of the composition (in the absence of the aqueous carrier (D).
  • the relative proportion of viscosity modifier is optimised to gel at room temperature (e.g. about 24°C) to form a putty, but also at a level to be soluble.
  • the composition is suitable for forming an osteoconductive implant material in a subject when mixed with the aqueous carrier (D).
  • composition may form a putty when mixed with the aqueous carrier (D). 20
  • the aqueous carrier e.g. physiological saline (component D) may be provided at a ratio of between 0.3 and about 0.8 parts to 1 part powder mixture (v/w) of the calcium phosphate pellets and/or calcium phosphate-encapsulating pellets (A), the BMP-2 encapsulating pellets (B) and the viscosity modifier (C).
  • the aqueous carrier e.g. physiological saline
  • component D may be provided at a ratio of between 0.3 and about 0.8 parts to 1 part powder mixture (v/w) of the calcium phosphate pellets and/or calcium phosphate-encapsulating pellets (A), the BMP-2 encapsulating pellets (B) and the viscosity modifier (C).
  • the aqueous carrier e.g.
  • physiological saline (component D) may be provided at a ratio of between 0.5 and 0.6 parts to 1 part powder mixture (v/w) of the calcium phosphate pellets and/or calcium phosphate-encapsulating pellets (A), the BMP-2 encapsulating pellets (B) and the viscosity modifier (C).
  • the aqueous carrier e.g. physiological saline
  • component D may be provided at a ratio of 0.6 parts to 1 part powder mixture (v/w) of the calcium phosphate pellets and/or calcium phosphate- encapsulating pellets (A), the BMP-2 encapsulating pellets (B) and the viscosity modifier (C).
  • the aqueous carrier e.g. physiological saline
  • component D may be provided at a ratio of 0.4 parts to 1 part powder mixture (v/w) of the calcium phosphate pellets and/or calcium phosphate-encapsulating pellets (A), the BMP-2 encapsulating pellets (B) and the viscosity modifier (C).
  • the relative proportion of the aqueous carrier to the dry powder components is optimised to fully wet the composition and form a putty, but to avoid too low viscosity and poor handling characteristics.
  • composition may be sterile/sterilised.
  • composition may or may not set into a solid non-malleable scaffold.
  • the composition may be filled within a cage, such as an anterior lumbar cage.
  • the anterior lumbar cage may comprise an El Capitan Anterior Lumbar Interbody Fusion (ALIF) System, or a Transforaminal Lumbar Interbody Fusion (TLIF) system.
  • the composition may be used for any bone fusion procedure, e.g. Anterior cervical discectomy and fusion (ACDF), Transforaminal Lumbar Interbody Fusion (TLIF), extreme lateral interbody fusion (XLIF), Anterior Lumbar Interbody Fusion (ALIF), Oblique Lateral Interbody Fusion (OLIF), Posterior Lumbar Fusion (PLF), Occipitocervical Fusion (OCF), or posterior cervical fusion.
  • ADF Anterior cervical discectomy and fusion
  • TLIF Transforaminal Lumbar Interbody Fusion
  • XLIF extreme lateral interbody fusion
  • ALIF Anterior Lumbar Interbody Fusion
  • OLIF Oblique Lateral Interbody Fusion
  • PEF Occipitocervical Fusion
  • the composition comprises or consists of: 21
  • BMP-2 encapsulating pellets comprising or consisting of:
  • composition comprises or consists of:
  • BMP-2 encapsulating pellets comprising or consisting of:
  • composition comprises or consists of:
  • -PLGA 50:50 poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), -2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
  • (C) a viscosity modifier comprising 40% w/w poloxamer 407 (powder); and optionally
  • composition comprises or consists of:
  • -PLGA 50:50 poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), -2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
  • (C) a viscosity modifier comprising 42% w/w poloxamer 407 (powder); and optionally
  • composition comprises or consists of:
  • -PLGA 50:50 poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), -2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
  • a method of spinal fixation of a patient comprising the steps of filling a lumbar cage with the osteoconductive implant material according to the invention herein and implanting the lumbar cage into the patient.
  • the lumbar cage may be implanted between two adjacent vertebrae of the patient.
  • the method or use in treatment may comprise an Anterior Lumbar Interbody (ALIF) fusion procedure.
  • the method or use in treatment may comprise any spinal fusion procedure, such as Anterior cervical discectomy and fusion (ACDF), Transforaminal Lumbar Interbody Fusion (TLIF), extreme lateral interbody fusion (XLIF), Anterior Lumbar Interbody Fusion (ALIF), Oblique Lateral Interbody Fusion (OLIF), Posterior Lumbar Fusion (PLF), Occipitocervical Fusion (OCF), or posterior cervical fusion.
  • the method or use may be in spinal fusion procedures in adult patients with degenerative disc disease (DDD) at one level from L4-S1.
  • DDD degenerative disc disease
  • the osteoconductive implant material according to the invention herein for use in bone repair or in an Anterior Lumbar Interbody (ALIF) fusion procedure.
  • ALIF Anterior Lumbar Interbody
  • the osteoconductive implant material of the invention may be used for fixing a screw or rod into bone, or fixing a plate onto bone. According to another aspect of the present invention, there is provided the osteoconductive implant material according to the invention herein for use in bone grafting.
  • the use in bone grafting or repair may be to augment the grafting of natural bone from the subject or from a donor.
  • the bone grafting may be to fill a void in a subject’s bone, such as a damaged bone, with the material of the invention.
  • the invention may be used in any bone grafting fusion procedure.
  • the osteoconductive implant material according to the invention herein for use in spinal fusion such as Transforaminal Lumbar Interbody Fusion (TLIF).
  • TLIF Transforaminal Lumbar Interbody Fusion
  • the osteoconductive implant material according to the invention herein for use as a bone void filler, such as in an Anterior Lumbar Interbody (ALIF) fusion procedure.
  • ALIF Anterior Lumbar Interbody
  • the invention may be used in the treatment of idiopathic scoliosis, neuromuscular scoliosis, degenerative disc disease, spondylosis, spondylolisthesis, or any other condition that may be treated by bone repair, bone grafting, or bone replacement.
  • the 2-hydroxypropyl- -cyclodextrin may be co-encapsulated with the BMP-2 in the polymer.
  • kits for forming an osteoconductive implant material comprising:
  • BMP-2 encapsulating pellets comprising or consisting of:
  • the components (A), (B) and (C) may be retained in separate packets, such as sachets. Two, or all of, components (A), (B) and (C) may be retained in the same packets, such as sachets.
  • the aqueous carrier (D) may be kept separate, for example in a sachet or bottle, until it is used to mix with the components.
  • the kit may comprise an oxygen scavenger and/or desiccant.
  • the skilled person will be familiar with suitable oxygen scavengers sufficient to maintain substantially oxygen free environment.
  • the oxygen scavenger may at least absorb more than 20 ml oxygen within 7 days under 25 ⁇ 2°C.
  • the oxygen scavenger may at least absorb more than 40 ml oxygen within 7 days under 25 ⁇ 2°C.
  • Example oxygen scavengers may comprise one or more, or all of, silicide, carbon hydride compound, resin powder, activated carbon, silica gel, and inorganic additives.
  • the skilled person will be familiar with suitable desicants sufficient to maintain low moisture content.
  • Desiccant material may comprise a molecular sieve.
  • the kit may comprise or consist of:
  • -40-60% w/w PLGA having an L:G ratio of 75-95:5-25, and -40-60% w/w calcium phosphate, wherein the calcium phosphate is encapsulated within the PLGA;
  • BMP-2 encapsulating pellets comprising or consisting of:
  • the kit may comprise or consist of:
  • -PLGA 50:50 poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), -2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
  • (C) a viscosity modifier comprising 40% w/w poloxamer 407 (powder); and optionally
  • the kit may comprise or consist of:
  • -PLGA 50:50 poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), -2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
  • (C) a viscosity modifier comprising 42% w/w poloxamer 407 (powder); and optionally
  • an osteoconductive implant material comprising the mixture of (A) calcium phosphate pellets or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
  • BMP-2 encapsulating pellets comprising or consisting of:
  • Components (A), (B) and (C) may be provided as a dry mix prior to mixing with (D) the aqueous carrier.
  • Components (A), (B) and (C) may be sterilised prior to mixing with (D) the aqueous carrier. The mixture may be manipulated into a putty consistency.
  • an osteoconductive implant material in accordance with the invention herein, the method comprising the provision of and mixing of components (A), (B) and (C), and optionally (D).
  • Components (A), (B) and (C) may be sterilized prior to mixing with (D) the aqueous carrier.
  • Sterilization may be by irradiation.
  • sterilisation is carried out by irradiation of a sealed packaging comprising one or more, or all components (A), (B), (C) and (D).
  • the sealed packaging is gas-impermeable.
  • the sealed packaging preferably comprising an oxygen scavenger and/or desiccant.
  • the oxygen scavenger and/or desiccant may be provided in one or more gas-permeable packaging, such as a porous polyethylene, which may be sealed together with one or more, or all components (A), (B), (C) and (D) within the gas-impermeable packaging.
  • at least the BMP-2 encapsulating pellets are protected from oxygen and/or free radicals during irradiation by such packaging.
  • the sealed packaging may be sealed in a low- or zero-oxygen environment, such as in a nitrogen environment.
  • the sealed packaging may not comprise oxygen.
  • the sealed 28 packaging may comprise nitrogen gas (instead of air).
  • the sealed packaging may be sealed by vacuum packing, for example, drawn to about 2mbar of pressure.
  • the sealed packaging comprises an oxygen scavenger and/or a desiccant.
  • the BMP-2 encapsulating pellets (B) may be formed by hot melt extrusion (HME).
  • the BMP-2 encapsulating pellets (B) are formed by combining -60-90% w/w PLGA having an L:G ratio of 45-55:55-45,
  • the hot melt extrusion process for the b BMP-2 encapsulating pellets may have a feed rate of 1-4%.
  • the feed rate for the BMP-2 encapsulating pellets may be about 2%.
  • the feed rate for the BMP-2 encapsulating pellets is about 2.2%.
  • the hot melt extrusion and pelletisation parameters such as the feed rate, screw speed and pelletiser settings may be adjusted for providing the required pellet consistency and size in accordance with the invention herein.
  • the hot melt extrusion process for the BMP-2 encapsulating pellets may have a screw speed of 10-30 rpm. In a preferred embodiment, the screw speed for the BMP-2 encapsulating pellets is about 20 rpm.
  • the hot melt extrusion process for the BMP-2 encapsulating pellets may have a feed rate of 1-4% and a screw speed of 10-30 rpm.
  • the feed rate for the BMP-2 encapsulating pellets may be about 2% and the screw speed may be 10-30 rpm, or more preferably about 20 rpm. In a preferred embodiment, the feed rate is about 2.2% and the screw speed is about 20 rpm.
  • the hot melt extrusion process for the BMP-2 encapsulating pellets may comprise the use of a pelletiser with the settings of 1-6 m/min and 0.1-2 mm, more preferably 3 m/min and 0.6 mm. 29
  • the hot melt extrusion process for the BMP-2 encapsulating pellets may have a feed rate of 1-4% and a screw speed of 10-30 rpm with pelletiser settings of 1-6 m/min and 0.1-2 mm, more preferably 3 m/min and 0.6 mm.
  • the feed rate for the BMP-2 encapsulating pellets may be about 2% and the screw speed may be 10-30 rpm, or more preferably about 20 rpm, with pelletiser settings of 1-6 m/min and 0.1-2 mm, more preferably 3 m/min and 0.6 mm.
  • the feed rate for the BMP-2 encapsulating pellets is about 1.8% and the screw speed is about 20 rpm, and with pelletiser settings of 1-6 m/min and 0.1-2 mm, more preferably 3 m/min and 0.6 mm.
  • the hot-melt extrusion process for the BMP-2 encapsulating pellets may comprise heating and extruding the composition through the temperatures steps of about 50- 90°C, 70-110°C, 70-110°C, 70-110°C (each temperature representing a different step/section of extruder as the material passes through) optionally with a total time of 10 minutes or less.
  • the hot-melt extrusion process may comprise heating and extruding the composition through the temperatures steps of about 60°C, 80°C, 80°C, 80°C (each temperature representing a different step/section of extruder as the material passes through) optionally with a total time of 10 minutes or less.
  • the hot-melt extrusion process may not exceed 110°C and/or may not exceed 10 minutes.
  • the hot-melt extrusion process advantageously provides conditions where extrusion of the material is possible at a sufficient temperature, whilst avoiding significant heat damage to the BMP-2.
  • the calcium phosphate-encapsulating pellets (A) may be formed by hot melt extrusion (HME).
  • HME hot melt extrusion
  • the calcium phosphate-encapsulating pellets (A) may be formed by combining 40-60% w/w PLGA having an L:G ratio of 75-95:5-25, and 40- 60% w/w calcium phosphate to form a mixture and extruding the mixture in a hot melt extrusion process.
  • the hot melt extrusion process for the calcium phosphate-encapsulating pellets may have a feed rate of 1-3%.
  • the feed rate may be about 2%.
  • the feed rate for the calcium phosphate-encapsulating pellets is about 1.8%.
  • the hot melt extrusion process for the calcium phosphate-encapsulating pellets may have a screw speed of 10-20 rpm. In a preferred embodiment, the screw speed for the b-TCP encapsulating pellets is about 15 rpm.
  • the hot melt extrusion process for the calcium phosphate-encapsulating pellets may have a feed rate of 1-3% and a screw speed of 10-20 rpm.
  • the feed rate for the calcium phosphate-encapsulating pellets may be about 2% and the screw speed may be 10-20 rpm, or more preferably about 15 rpm. In a preferred embodiment, the feed rate is about 1.8% and the screw speed is about 15 rpm.
  • the hot melt extrusion process for the calcium phosphate-encapsulating pellets may comprise the use of a pelletiser with the settings of 0.5-5 m/min and 0.2-2 mm, more preferably 1.4 m/min and 1.3 mm.
  • the hot melt extrusion process for the calcium phosphate-encapsulating pellets may have a feed rate of 1-3% and a screw speed of 10-20 rpm with pelletiser settings of 0.5-5 m/min and 0.2-2 mm, more preferably 1.4 m/min and 1.3 mm.
  • the feed rate for the calcium phosphate-encapsulating pellets may be about 2% and the screw speed may be 10-20 rpm, or more preferably about 15 rpm, with pelletiser settings of 0.5-5 m/min and 0.2-2 mm, more preferably 1.4 m/min and 1.3 mm.
  • the feed rate for the calcium phosphate-encapsulating pellets is about 1.8% and the screw speed is about 15 rpm, and with pelletiser settings of 0.5-5 m/min and 0.2-2 mm, more preferably 1.4 m/min and 1.3 mm.
  • the hot melt extrusion process for the calcium phosphate-encapsulating pellets may comprise heating and extruding the composition through the temperatures steps of about 70-100°C, 100-150°C, 100-150°C, 100-150°C (each temperature representing a different step/section of the extruder as the material passes through).
  • the hot melt extrusion process for the calcium phosphate-encapsulating pellets may comprise heating and extruding the composition through the temperatures steps of about 80°C, 120°C, 120°C, 120°C (each temperature representing a different step/section of the extruder as the material passes through).
  • the extrusion process advantageously provides temperatures sufficient to extrude polymer material containing calcium phosphate, such as b-TCP, but not such that the polymer material is damaged.
  • the method may further comprise the insertion of the osteoconductive implant material into a lumbar cage.
  • the osteoconductive implant material of the invention such as the putty
  • autologous bone fragment may be mixed with the osteoconductive implant material of the invention and placed outside the lumbar cage.
  • the osteoconductive implant material of the invention may further comprise autologous bone fragments from a subject to be treated.
  • “Autologous bone” is considered to be donor bone taken from a patient/subject to be treated and re-implanted back into another site of the same patient/subject.
  • Poloxamer 407 is a hydrophilic non-ionic surfactant of the more general class of copolymers known as poloxamers. Poloxamer 407 is a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by a-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzymatic conversion. Typical cyclodextrins are constituted by 6-8 glucopyranoside units. These subunits are linked by 1,4 glycosidic bonds. The cyclodextrins have toroidal shapes, with the larger and the smaller openings of the toroid exposing to the solvent secondary and primary hydroxyl groups respectively b (beta)-cyclodextrin has 7 glucose subunits.
  • BMP-2 bone morphogenetic protein 2
  • BMP-2 bone morphogenetic protein 2
  • a “putty” is understood to be a solid material with high plasticity, similar in texture to clay or dough. Putty is a malleable solid material, for example malleable by hand. The putty may be manipulated into a shape, which is retained.
  • room temperature is intended to refer to a temperature of from about 15°C to about 25°C, such as from about 20°C to about 25°C.
  • encapsulated is intended to refer to one substance (such as BMP-2 or calcium phosphate) being substantially mixed within and throughout the material of another substance, such as the polymer described herein.
  • the encapsulation may be by extrusion, preferably hot-melt extrusion. Encapsulation does not describe substances/agents that have been surface loaded into the other substance, such as a polymer. The loading of an agent/substance into and through the pores of a porous substance such as a polymer is also not considered to be encapsulation within that substance. In particular, an encapsulated substance will form part of the same material with the encapsulating substance.
  • Figure 2. Pictorial summary of the preparation of LDGraft at the point of use for spinal fusion.
  • Figure 3. Morphology of b-TCP structural pellets manufactured by hot melt extrusion having [A] 50% w/w b-TCP content and [B] 60% w/w content.
  • FIG. 4 [A] Morphology of hollow pellets in close association with each other. [B] Demonstration of interconnected porosity caused by pellet lumen. Note - there is no poloxamer 407 present for this demonstration.
  • FIG. 8 BMP-2 structural pellets manufactured by HME containing [A] 100 mM cyclodextrin HPB and [B] 50 mM cyclodextrin as an excipient to protect the BMP-2 structure.
  • FIG. 1 Activity of BMP-2 measured by ALP expression in C2C12 cells.
  • [A] is data achieved from active BMP-2 released by the feedstock
  • [B] is data achieved from active BMP-2 released from the BMP-2 scaffold pellets.
  • Figure 10 Sub-optimal pellets caused by incorrect manufacturing parameters.
  • TCP based material [C] Split pellets comprising of PLGA5050 based material.
  • FIG. 13 Overview of packaging for LDGraft.
  • FIG. 14 Three packaging configurations to protect the BMP-2 protein during processing by X-ray to terminally sterilise.
  • 20200202YF is the BMP- 2 protein as supplied.
  • LOCBAT0115 is the BMP-2 extracted from a batch after hot melt extrusion. As is: This BMP-2 sample underwent the sterilisation process without protectants.
  • LCl-3 are the lead configurations for packaging.
  • Figure 3 shows the morphology of b-TCP structural pellets manufactured by hot melt extrusion having [A] 50% w/w b-TCP content and [B] 60% w/w content.
  • the higher b-TCP content has caused the pellets to crumble during the pelletisation process resulting in small shards of material as well as roughly cut pellets which are not satisfactory for the final product as porosity would be reduced as small pieces would block open pores.
  • the pellets manufactured with 50% w/w b-TCP [Fig. 3A] do not crumble and have a lumen to maximise porosity.
  • Figure 4 further demonstrates the porosity of the material when the pellets are closely associated with each other as within the LDGraft putty.
  • the LDGraft will be packed into an interbody spinal fusion cage and the poloxamer 407 will leach away from the site, the remaining pellets will provide good porosity and have a structure which is similar to that shown in Fig. 4A.
  • the material readily wicks fluid through the interconnected open pores [Fig. 4B] pH drop caused by PLGA degradation (PLGA 5050 vs PLGA 955)
  • pre-formed scaffolds were prepared by allowing the closely associated pellets manufactured from PLGA50:50 based materials and PLGA95:5 based materials sinter at a temperature slightly higher than their glass transition temperature.
  • aqueous carrier l%w/v F127. 0.5%w/v in 0.9%w/v saline
  • the paste was injected into individual pre-drilled open cell SawboneTM defects measuring 6 mm in diameter and 10 mm in depth. All the materials were allowed to sinter overnight (50 °C- check) in a humid environment.
  • the Sawbone samples having filled defects were transferred to 20 ml of sterile phosphate buffered saline (PBS) and the pH value was measured. On a weekly basis, the pH was re-measured and the PBS replaced with fresh.
  • PBS sterile phosphate buffered saline
  • Figure 6 shows two rheology plots [A] is the phase shift angle against temperature and [B] the loss modulus against temperature.
  • the test was an oscillatory test having 0.1% strain and a speed of 1 Hz.
  • the temperature ramp was set at 10 to 80 °C with an interval of 30 seconds.
  • Tg glass transition temperature
  • PEG400 has a major effect in the reduction of Tg.
  • Tg is indicated a number of ways, the peak loss modulus gives a single value whereas the peak phase shift angle tends to overestimate and therefore the onset of phase shift to peak is quoted in table 8 below.
  • the Tg stated on the certificate of analysis for the PLGA5050 is 48 oC which gives confidence in the data achieved.
  • Table 8 Measurement of glass transition temperature by loss modulus and phase shift angle.
  • Cyclodextrin concentration required for HME process and BMP-2 protection Active BMP-2 is a protein which is sensitive to heat, moisture and oxygen radicals and therefore it must be afforded as much protection as possible in the formulation, the manufacturing process and the packaging.
  • Figure 7 show the impact of cyclodextrin at different concentrations within the formulation on the structure of the BMP-2 molecule where the material was subjected lyophilisation (part of the 42 manufacturing process prior to hot melt extrusion) and heat (during hot melt extrusion).
  • the BMP-2 was solubilised in 1% v/v acetic acid ⁇ hydroxypropyl beta cyclodextrin between 0 and 100 mM.
  • Figure 7 shows although 1 mM cyclodextrin HPB offers some protection for the BMP- 2 molecule, maximum protection (as shown by an absence of a band at approximately 35 kDa) is achieved at 50 mM and maintained at 100 mM.
  • BMP-2 can be detected by ELISA methods, this does not determine whether the molecule remains active and therefore a study was performed to determine activity through alkaline phosphatase expression in C2C12 cells.
  • lyophilised feedstock for HME was retained and this was tested for BMP- 2 release alongside the manufactured BMP-2 scaffold pellets.
  • a 100 mg sample of feedstock or pellets was placed into a transwell which was suspended within a culture well containing C2C12 cells. At regular intervals, the transwell containing the test samples was transferred to fresh C2C12 cells. An ALP assay was then performed on the cells to determine activity.
  • the data in Figure 9 has been normalised to the ALP activity of a standard amount of BMP-2 (0.2 pg/ml) the activity of which was determined at each time point.
  • the activity of the BMP-2 within the feedstock dropped off after 11 days whereas activity of BMP-2 release from the PLGA material could be detected for up to 74 days in culture. This indicates the role that encapsulation of the BMP-2 into the PLGA has in 43 prolonging the release and activity over entrapment of the BMP-2 within the feedstock.
  • Hot melt extrusion is a continuous process and parameters/settings were altered ‘in process’ to achieve optimum pellet shape and size.
  • Figure 11 shows the optimal pellet morphology for b-TCP scaffold pellet and BMP-2 scaffold pellet morphology.
  • Figure 12 gives an overview of the manufacturing processes for LDGraft pellets and Figure 13 shows an overview of the packaging process.
  • oxygen scavengers and desiccant into the packaging has been shown to further protect the material during the sterilisation process which is performed using X-ray.
  • BMP-2 protein needs to be protected throughout the manufacturing process including terminal sterilisation.
  • cyclodextrin provides protection especially during the manufacturing process, but it has been found that packaging configurations 45 incorporating desiccants and oxygen scavengers are also advantageous against the effects of irradiation required for terminal sterilisation.
  • LC1 The LDGraft material is packaged in a porous polyethylene (HPDE) pouch (Tyvek® pouch) with two oxygen scavenger pouches, one either side of the Tyvek pouch. A desiccant pouch is included and all four components are further packaged in a laminated foil pouch under nitrogen.
  • HPDE porous polyethylene
  • LC2 This has the same packaging configuration as LC1 but, the LDGraft and oxygen scavengers are re-packaged without the desiccant into a fresh foil pouch under nitrogen just prior to sterilisation by X-ray.
  • LC:3 This configuration has the same four components but, the desiccant is separated away from the LDGraft material. Again, it is packaged into a foil pouch under nitrogen.
  • Oxygen scavenger used was PharmaKeep KD-20TM (Mitsubishi Gas Chemical Company Inc.), comprising silicide, carbon hydride compound, resin powder, activated carbon, silica gel, and inorganic additives. Each one packet absorbs oxygen more than 20 ml within 7 days under 25 ⁇ 2°C.
  • FIG. 16 This Figure shows the results for non-reducing SDS-PAGE for the following samples:
  • LOCBAT0115 is the BMP-2 extracted from a batch after hot melt extrusion (i.e the cyclodextrin is providing the protection from the heat of the HME process).
  • the present invention may be used for treatment in any of the following diseases/conditions, procedures or forms provided in the following table.

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Abstract

The invention relates to an osteoconductive implant material composition comprising or consisting of: (A) calcium phosphate pellets and/or calcium phosphate-encapsulating pellets, wherein the calcium hosphate-encapsulating pellets comprise or consist of: 40-60% w/w PLGA having an L:G ratio of 75-95:5-25, and 40-60% w/w calcium phosphate, wherein the calcium phosphate is encapsulated within the PLGA; (B) BMP-2 encapsulating pellets comprising or consisting of: 60-90% w/w PLGA having an L:G ratio of 45-55:55-45, 10-30% w/w 2-hydroxypropyl-β-cyclodextrin, 5-15% w/w poloxamer 407, and BMP-2, wherein the BMP-2 is encapsulated within the PLGA; and (C) a viscosity modifier optionally comprising or consisting of poloxamer 407; and optionally (D) an aqueous carrier. The invention further relates to associated methods, treatment, and kits.

Description

1
Osteoconductive Implant Material with BMP-2 Delivery
The invention relates to osteoconductive implant material formed from polymer pellets, and to the use of such material in bone repair.
Background
Within the field of regenerative medicine there are many opportunities for new clinical procedures that stimulate and support tissue repair. Examples of clinical opportunities include regeneration of cardiac muscle after an infarction, induction of bone growth in spinal fusion, healing of diabetic foot ulcers and limitation or, perhaps, reversal of damage due to stroke. Examples of tissues where treatment could facilitate healing are brain tissue, liver tissue and pancreatic tissue, amongst others.
One area where tissue healing is important is bone healing, for example for people with bone disorders. Bone healing is a physiological process in which the body facilitates the repair of the bone after an external injury, infection, surgical intervention or a disease. The physiological healing process can require very long periods and, in many cases, it cannot re-establish the original bone properties. For this reason, therapies that accelerate and improve bone healing are of vital importance. Usually, these therapies present osteoconductive, osteoinductive, and osteogenic approaches. In the majority of osteoconductive approaches, a variety of substitutes like gold, stainless steel, titanium, natural/synthetic polymers and ceramics have been tried. The main concerns with the use of these materials for bone reconstruction were their poor ability to vascularise, integrate, and undergo remodelling. This may result in structural failure of the implant under load or pathological changes in the surrounding bone, as seen in stress shielding. The other issues are inflammatory scarring, neoproliferative reaction in the adjacent tissues and infection. Because of their high osteoinductive potential and remodelling characteristics, bioactive substitutes have been used with promising results. This led to the evolution of tissue engineering techniques (biologically enhanced allografts, cell-based therapies, and gene-based therapies) to treat bone disorders. Tissue engineering has been defined as the application of scientific principles to the design, construction, modification, and growth of living tissue using biomaterials, cells, and factors alone and in combination. It involves the use of osteoconductive biomaterial scaffolds, with osteogenic cell 2 populations and osteoinductive bioactive factors. All these approaches have the potential to significantly increase our ability to treat diseases for which no effective treatment currently exists.
Osteoconductive implants can provide an appropriate mechanical environment, architecture and surface chemistry for angiogenesis and tissue formation. The localisation of regenerative agents, such as growth factors, can also be achieved using osteoconductive implants. The use of implants as drug or cell delivery systems has great potential but is also very challenging due to the need to tailor the porosity, strength and degradation kinetics of the implant to the tissue type whilst achieving the appropriate kinetics of release of agents, such as proteins that act as growth factors or cells.
In broad terms, osteoconductive implants are typically either a pre-formed water- insoluble matrix, with large interconnected pores or they are a hydrogel. Such materials are implanted into a patient for augmented in vivo tissue repair and/or regeneration. In terms of implantation, the pre-formed water-insoluble matrices must be shaped to fill a cavity within the body, requiring knowledge of the cavity dimensions and limiting the shape of cavity that can be filled. In contrast, a number of hydrogel materials have been designed that can be delivered directly into the body through a syringe. The gel forms within the body following a trigger signal, for example a temperature change or UV light exposure. Such systems have the advantage that they can fill cavities of any shape without prior knowledge of the cavity dimensions. However, such hydrogels lack large interconnected porous networks and, hence, release of an agent from the gel is limited by poor diffusion properties.
Resorbable putty or resorbable pastes are promising approaches. This area has been widely researched both academically and industrially, with several products such as C-Graft Putty™, Grafton® already having been commercialised. The major obstacles in the success of such approaches are the successful delivery and retention of materials to the required site of action, as well as their malleability before the surgery. Other important obstacles include the ability to deliver additional bioactive therapeutics, to have tailored resorption rates, and to form structures with high level porosity and macropores. 3
W02008093094 and W02004084968 (both of which are incorporated herein by reference) describe compositions and methods for forming tissue scaffolds from polymer pellets, such as PLGA and PLGA/PEG polymer blends. Such scaffolds have been developed to be capable of moulding or injection prior to setting in situ at the site of tissue repair. A porous structure is achieved by leaving gaps between the pellets and optionally further providing porous polymer pellets.
Lumbar cages are interbody fusion devices intended for use as an aid in spinal fixation, for example for a spinal fusion of a patient with degenerative disc disease. These implants are typically designed for bone in-growth and biological fixation and are used with bone graft substitute material to grow new bone for fixation. However, the ideal bone graft substitute material needs to be sufficiently malleable for the surgeon to insert into the lumbar cage, not too loose such that material is shed, and also osteoconductive, with the ability to support cell ingrowth and provide controlled release of BMP-2. Such material properties can be challenging to provide.
An aim of the present invention is to provide improved compositions, methods and processes for forming osteoconductive implant material for use in tissue repair, for example, which may be used in a lumbar cage.
SUMMARY OF INVENTION
According to a first aspect of the invention, there is provided an osteoconductive implant material composition comprising:
(A) calcium phosphate pellets or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
-polymer, and
- calcium phosphate, wherein the calcium phosphate is encapsulated within the polymer;
(B) BMP-2 encapsulating pellets comprising or consisting of:
-polymer,
-2-Hydroxypropyl- -cyclodextrin,
-poloxamer 407, and
-BMP-2, wherein the BMP-2 is encapsulated within the polymer; and
(C) a viscosity modifier comprising poloxamer 407; and optionally 4
(D) an aqueous carrier.
Advantageously, the osteoconductive implant material composition is capable of being formed into a malleable putty when it is mixed with or includes the aqueous carrier, for example that can be manipulated into a lumbar cage for implant, and without shedding. In addition the material provides a beneficial BMP-2 controlled release for enhanced conductivity, whilst remaining porous for cell ingrowth. The osteoconductive implant material is also biocompatible and biodegradable for implantation and degradation in vivo.
The calcium phosphate and calcium phosphate-encapsulating pellets
The calcium phosphate may be osteoconductive. In a preferred embodiment the calcium phosphate comprises or consists of b-tricalcium phosphate (b-TCP).
The calcium phosphate, such as b-TCP, may be encapsulated within the polymer by a hot melt extrusion process. In one embodiment, the calcium phosphate, such as b-TCP, may be provided in the calcium phosphate-encapsulating pellet (pellet (A)) in an amount of between about 40% and about 60% w/w. In another embodiment, the calcium phosphate, such as b-TCP, may be provided in the calcium phosphate- encapsulating pellet (pellet (A)) in an amount of between about 40% and about 55% w/w. Alternatively, the calcium phosphate, such as b-TCP, may be provided in the calcium phosphate-encapsulating pellet (pellet (A)) in the amount of between about 45% and about 55% w/w. Alternatively, the calcium phosphate, such as b-TCP, may be provided in the calcium phosphate-encapsulating pellet (pellet (A)) in the amount of between about 40% and about 50% w/w. In a preferred embodiment, the calcium phosphate, such as b-TCP, may be provided in the calcium phosphate-encapsulating pellet (pellet (A)) in the amount of about 50% w/w. Advantageously, the amount of encapsulated calcium phosphate, such as b-TCP, is optimised for its therapeutic effect, in particular a level sufficient enough for enhancing osteoconductivity, but is also provided at a level that is capable of being appropriately encapsulated in a hot melt extrusion process to form the pellet. 5
The calcium phosphate, such as b-TCP, may be provided in a particulate form of between about 0.5 pm and about 20 pm in size. In one embodiment, the calcium phosphate, such as b-TCP, is provided in a particulate form of less than 10 pm in size. In another embodiment, the calcium phosphate, such as b-TCP, is provided in a particulate form of between about 1 pm and about 4 pm in size. In preferred embodiment, the calcium phosphate, such as b-TCP, is provided in a particulate form of about 2 pm in size. It is understood that the reference to the particle size is an average size of the largest diameter in a population of the particles.
Advantageously, the size of the encapsulated calcium phosphate, such as b-TCP, is optimised to be sufficiently avoid or reduce inadvertent release from the material and causing an immune reaction in vivo, and to also allow for extrusion.
In one embodiment, calcium phosphate pellets are provided as component A (i.e. calcium phosphate not encapsulated by polymer). Such calcium phosphate comprising pellets may comprise or consist of b-TCP. The calcium phosphate pellets, such as b- TCP pellets, may be between about 0.5mm and about 2.5mm in size. In a preferred embodiment, the calcium phosphate pellets, such as b-TCP pellets, are between about lmm and about 2mm in size. The size may refer to the largest diameter of the pellet and is understood to be the average size in a population of pellets. “Calcium phosphate pellets” may otherwise be termed “calcium phosphate granules” herein.
Advantageously, the size of the calcium phosphate pellets, such as b-TCP pellets, is optimised to be sufficiently large enough to provide macroporosity in the material but sufficiently small for malleability and to form an acceptable putty when mixed with the other components.
The calcium phosphate pellets, such as b-TCP pellets, may have macroporosity (having pores of >100pm in size) and/or microporosity (having pores of <10 pm in size). In a preferred embodiment, the calcium phosphate pellets, such as b-TCP pellets, may have interconnected porosity (for example, capable of wicking fluid therethrough).
The BMP-2 6
The BMP-2 may comprise recombinant BMP-2 (rBMP-2). The BMP-2 may comprise human BMP-2 (hBMP-2). In a preferred embodiment, the BMP-2 comprises or consists of recombinant human BMP-2 (rhBMP-2).
In one embodiment, the BMP-2 is provided in the BMP-2 encapsulating pellet (pellet B) in an amount of between about 0.01% and about 1% w/w. In another embodiment, the BMP-2 is provided in the BMP-2 encapsulating pellet (pellet B) in the amount of between about 0.01% and about 0.5% w/w. In another embodiment, the BMP-2 is provided in the BMP-2 encapsulating pellet (pellet B) in the amount of between about 0.1% and about 0.5% w/w. The BMP-2 may be provided in the BMP-2 encapsulating pellet (pellet B) in the amount of 0.19% w/w. In a preferred embodiment, the BMP-2 may be provided in the BMP-2 encapsulating pellet (pellet B) in the amount of about 0.2% w/w.
The Poloxamer 407
The BMP-2 encapsulating pellet (pellet B) may comprise or consist of between about 5% and about 15% poloxamer 407. In another embodiment, the BMP-2 encapsulating pellet (pellet B) may comprise or consist of between about 8% and about 12% poloxamer 407. In a preferred embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of about 10% poloxamer 407.
In one embodiment the poloxamer 407 is provided in powder form, for example prior to any addition of an aqueous carrier. The poloxamer 407 may be micronized powder. In one embodiment, the poloxamer is less than 105pm in size. At least 85% of the poloxamer 407 particles may be less than 60pm in size, preferably less than 53pm in size.
The poloxamer 407 may be encapsulated in the BMP-2 encapsulating pellets (pellet
B).
Advantageously, the poloxamer 407 aids the controlled release of the BMP-2 from the pellet and does not significantly reduce the pH, in contrast to some plasticiser additives such as PEG400. The level of poloxamer is optimised to a sufficient amount to increase release rate of the BMP-2, but not in an amount sufficient to interfere with 7 the hot melt extrusion process. Further advantageously, although poloxamer 407 can be classed as a plasticiser in the art, it has been demonstrated to not reduce the Tg of the polymer, such as PLGA.
The polymer
Polymer of the BMP-2 encapsulating pellet (pellet B)
In one embodiment the polymer of the BMP-2 encapsulating pellet (pellet B) comprises or consists of PLGA poly(lactide-co-glycolide). The PLGA of the BMP-2 encapsulating pellet (pellet B) may comprise or consist of PLGA 45:50 - 55:45. In a preferred embodiment, the PLGA is PLGA 50:50. The PLGA of the BMP-2 encapsulating pellet may be acid terminated PLGA, such as PLGA 50:50A.
In one embodiment, the PLGA of the BMP-2 encapsulating pellet may be PDIXGA. Alternatively, the PLGA may be only comprise the L-form of lactic acid.
The L:G (lactide to glycolide ) ratio is advantageously optimised for providing an appropriate BMP-2 release profile.
The BMP-2 encapsulating pellet (pellet B) may comprise or consist of between 60% and about 90% (w/w) of PLGA, such as PLGA 50:50. In another embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of between 70% and about 80% (w/w), such as PLGA50:50. The BMP-2 encapsulating pellet (pellet B) may comprise or consist of between 75% and about 76% (w/w), such as PLGA50:50. In a preferred embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of about 75.5% (w/w), such as PLGA50:50.
Advantageously, the amount of PLGA polymer, such as 60-90%, is optimised for an ability to be processed by hot melt extrusion, for example in the presence of other components, such as cyclodextrin.
The PLGA of the BMP-2 encapsulating pellet (pellet B) may have a molecular weight of between about 40kDa and about 80 kDa MWt. In another embodiment, the PLGA of 8 the BMP-2 encapsulating pellet (pellet B) may have a molecular weight of between about 60kDa and about 70 KDa MWt.
Advantageously, the molecular weight of the PLGA is optimised such that it degrades at a desired rate for providing a desired BMP-2 release profile.
Polymer of the calcium phosphate-encapsulating pellet (pellet A)
In one embodiment the polymer of the calcium phosphate-encapsulating pellet (pellet A) comprises or consists of PLGA poly(lactide-co-glycolide). The PLGA may comprise or consist of PLGA 75:25 to PLGA 95:5 (75-95:5-25). The polymer of the calcium phosphate-encapsulating pellet (pellet A) may comprise or consist of a PLGA 75:25 to PLGA 95:5. In another embodiment, the polymer of the calcium phosphate- encapsulating pellet (pellet A) may comprise or consist of a PLGA 93-97:7-3. In a preferred embodiment, the polymer of the calcium phosphate-encapsulating pellet (pellet A) comprises or consists of PLGA 95:5. The polymer of the calcium phosphate-encapsulating pellet (pellet A) may comprise or consist of ester terminated PLGA, such as PLGA 95: 5 A.
In one embodiment, the PLGA of the calcium phosphate-encapsulating pellet may be PDLLGA. Alternatively, the PLGA may be only comprise the L-form of lactic acid.
The L:G (lactide to glycolide ) ratio is advantageously optimised to prevent too rapid degradation, which can cause biocompatibility issues due to the acidity of the degradation products.
The calcium phosphate-encapsulating pellet (pellet A) may comprise or consist of between about 40% and about 60% (w/w) PLGA, such as PLGA 95:5. In another embodiment, the calcium phosphate-encapsulating pellet (pellet A) comprises or consists of between about 45% and about 55% (w/w) PLGA, such as PLGA 95:5. The calcium phosphate-encapsulating pellet (pellet A) may comprise or consist of between about 49% and about 51% (w/w) PLGA, such as PLGA 95:5. In a preferred embodiment, the calcium phosphate-encapsulating pellet (pellet A) comprises or consists of about 50% (w/w) PLGA, such as PLGA 95:5. 9
Advantageously, the amount of PLGA 95:5 polymer, such as 40- 60%, is optimised for a sufficient level of degradation and replacement by bone and the ability to be processed by hot melt extrusion.
The PLGA of the calcium phosphate-encapsulating pellet (pellet A) may have a molecular weight of between about 50kDa and about 90 kDa MWt.
Advantageously, the molecule weight of the PLGA is optimised such that it degrades at a desired rate in vivo.
In a preferred embodiment, the polymer of the BMP-2 encapsulating pellet (pellet B) comprises or consists of PDIXGA 50:50 and the polymer of the calcium phosphate- encapsulating pellet (pellet A) comprises or consist of PDIXGA 95 :5.
In a further preferred embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of about 75.5% (w/w) PLGA, such as PLGA 50:50, and the calcium phosphate-encapsulating pellet (pellet A) comprises or consist of about 50% (w/w) PLGA, such as PLGA 95:5.
The viscosity modifier
The BMP-2 encapsulating pellet (pellet B) may comprise between about 5% and about 15% w/w of the viscosity modifier. The viscosity modifier may comprise or consist of poloxamer 407. Therefore, in one embodiment, the BMP-2 encapsulating pellet (pellet B) may comprise between about 5% and about 15% w/w poloxamer 407. In another embodiment, the BMP-2 encapsulating pellet (pellet B) comprises between about 8% and about 12% w/w viscosity modifier, such as poloxamer 407. In a preferred embodiment, the BMP-2 encapsulating pellet (pellet B) comprises about 10% w/w of the viscosity modifier, such as poloxamer 407.
Advantageously, the viscosity modifier is provided for and optimised for increasing the BMP-2 release rate, whilst also not significantly interfering with the hot melt extrusion process. 10
The BMP-2 encapsulating pellet (pellet B) may not comprise a plasticiser. In one embodiment, the poloxamer 407 is not, and does not act as, a plasticiser (e.g. the poloxamer 407 does not and is not intended to significantly reduce the glass transition temperature (Tg) of the pellet).
In one embodiment the poloxamer 407 is provided in powder form, for example prior to any addition of an aqueous carrier. The poloxamer 407 may be micronized powder. In one embodiment, the poloxamer is less than 105pm in size. At least 85% of the poloxamer 407 particles may be less than 60pm in size, preferably less than 53pm in size.
2-Hydroxypropyl-P-cyclodextrin
The BMP-2 encapsulating pellet (pellet B) may comprise or consist of between about 10% and about 30% w/w 2-hydroxypropyl- -cyclodextrin. In one embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of between about 10% and about 20% w/w 2-hydroxypropyl- -cyclodextrin. In another embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of between about 12% and about 15% w/w 2-hydroxypropyl- -cyclodextrin. In a preferred embodiment, the BMP-2 encapsulating pellet (pellet B) comprises or consists of between about 14%, more preferably 14.3% w/w 2-hydroxypropyl- -cyclodextrin.
Advantageously, the 2-hydroxypropyl- -cyclodextrin is for protection of the BMP-2 during a hot melt extrusion process, and it can be optimised for sufficient protection of the BMP-2 and to not significantly interfere with the hot met extrusion process. The 2-hydroxypropyl- -cyclodextrin may advantageously aid the release of BMP-2, because of its high solubility, opening up pores and allowing water ingress.
Other characteristics of the BMP-2 encapsulating pellet (pellet A) and the b-TCP encapsulating pellet (pellet B)
In one embodiment, the BMP-2 encapsulating pellet (pellet B) and/or the calcium phosphate-encapsulating pellet (pellet A) is shaped as a hollow pellet, such as with an open hollow extending through the pellet, in accordance with those described in International Patent Application Publication No. W02018150166A1 (which is 11 incorporated herein by reference). The BMP-2 encapsulating pellet (pellet B) and/or the calcium phosphate-encapsulating pellet (pellet A) may be shaped as a hollow cylindrical pellet.
The hollow pellets may comprise an open hollow. For example, a hollow in a structure that is open at least at one end or side, i.e. not a hollow that is completely enclosed within the structure of the pellet. For example, the hollow pellets may have a tubular structure, with the hollow extending therethrough. The hollow tube may be open at one end or more preferably at both ends of the pellet structure. The hollow pellets may be substantially O-shaped in cross section. The invention also envisages a hollow in the form of a channel running through a pellet structure, whereby the channel may be open substantially along its length, i.e. as an alternative to a hollow tube structure having a generally O-shaped hollow cross section the hollow pellets may comprise a C-shaped or U-shaped cross-section such that the hollow channel is open substantially along its length. In one embodiment, the hollow pellets are tubular in structure and open at both ends. The hollow pellets may comprise substantially parallel walls (for example in the sense that opposite walls of a tube are generally parallel to each other). The hollow pellets may not be spherical. The hollow pellets may not comprise or consist of hollow microspheres (e.g. substantially spherical particles with a substantially hollow core).
The hollow pellets may be tubular. In one embodiment, the hollow pellets are tubular with a substantially circular cross-section. Alternatively, the hollow pellets may be any suitably shaped cross-section, such as circular, triangular, square, semi-circular, pentagonal, hexagonal, heptagonal, octagonal, or the like. In one embodiment wherein the hollow pellets are tubular, the outer surface of the hollow pellets may be substantially circular in cross-section and the inner surface of the hollow pellets may be substantially circular in cross-section. In another embodiment, the cross-sectional shape of the outer surface may be different to the cross-sectional shape of the inner surface. For example, the outer surface may be circular in cross-section, and the inner surface may be square in cross-section, or vice versa. In an example where the hollow pellets are formed by extrusion, the cross-sectional shape of the inner and outer surfaces of the tube-like structure may be determined by the shape of the extrusion die. 12
The hollow pellets may have a length that is equal to or greater than their diameter. In one embodiment, the length is greater than the diameter. The hollow pellets may have an aspect ratio of at least 0.5: 1, 1: 1, 1: 1.5, 1:2 or 1:3 length to diameter. The hollow pellets may have an aspect ratio of no more than 1:5, 1:4, 1:3 or 1:2 length to diameter. The hollow pellets may have an aspect ratio of between about 0.5: 1 and about 1:5 length to diameter. The hollow pellets may have an aspect ratio of between about 1: 1 and about 1:5 length to diameter. The hollow pellets may have an aspect ratio of between about 0.5: 1 and about 1:5 length to diameter.
The length of the hollow pellets may be uniform in the composition of hollow polymer pellets or a population of hollow polymer pellets in a composition may be irregular in length relative to each other.
The hollow pellets may have a size in their longest dimension of between about 300 pm and about 1300 pm. In another embodiment, the hollow pellets may have a size in their longest dimension of between about 300 pm and about 1000 pm. In another embodiment, the hollow pellets may have a size in their longest dimension of between about 300 pm and about 900 pm. The hollow pellets may have a size in their longest dimension of between about 600 pm and about 1300 pm.
The external diameter of the hollow pellets (i.e. the distance between opposing outer surfaces (e.g. external/outer diameter of a tube) may be between about 300 pm and about 900 pm. In another embodiment, the external diameter of the hollow pellets (i.e. the distance between opposing outer surfaces (e.g. external/outer diameter of a tube) may be between about 600 pm and about 900 pm. In another embodiment, the external diameter of the hollow pellets (i.e. the distance between opposing outer surfaces (e.g. external/outer diameter of a tube) may be between about 300 pm and about 700 pm.
The thickness of the walls of the hollow pellets may be between about 100 and 200pm. In a preferred embodiment, the thickness of the walls of the hollow pellets may be between about 120 pm and 170pm.
The internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 100 and about 300 pm. In another embodiment, the internal diameter of the hollow 13 polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 10 and about 300 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 20 and about 300 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 10 and about 200 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 20 and about 200 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 10 and about 100 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 20 and about 100 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be between about 20 and about 50 pm. In another embodiment, the internal diameter of the hollow polymer pellets may be about 200 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 20 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 40 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 50 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 800 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 100 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 150 pm. In another embodiment, the internal diameter of the hollow polymer pellets (i.e. the distance between opposing inner surfaces (e.g. internal diameter of a tube) may be at least about 200 pm. Such 14 hollow/lumen sizes allow for advantageous cell infiltration into the hollow polymer pellets.
In one embodiment, the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 400pm, but will pass through a sieve or filter with a pore size of about 500pm. In another embodiment, the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 400pm, but will pass through a sieve or filter with a pore size of about 600pm. In another embodiment, the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 400pm, but will pass through a sieve or filter with a pore size of about 800pm. In one embodiment, the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 300pm, but will pass through a sieve or filter with a pore size of about 500pm. In another embodiment, the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 300pm, but will pass through a sieve or filter with a pore size of about 600pm. In another embodiment, the hollow polymer pellets of the desired size may be unable to pass through a sieve or filter with a pore size of about 300pm, but will pass through a sieve or filter with a pore size of about 800pm.
In one embodiment, the hollow (or otherwise “lumen”) of the hollow polymer pellets may be at least 10% of the volume of the hollow polymer pellets. In another embodiment, the hollow of the hollow polymer pellets may be at least 20% of the volume of the hollow polymer pellets. In another embodiment, the hollow of the hollow polymer pellets may be at least 30% of the volume of the hollow polymer pellets. In another embodiment, the hollow of the hollow polymer pellets may be at least 40% of the volume of the hollow polymer pellets. In another embodiment, the hollow of the hollow polymer pellets may be at least 50% of the volume of the hollow polymer pellets. Such hollow/lumen volumes allow for advantageous cell infiltration into the hollow polymer pellets.
The hollow polymer pellets may be solid (with the exception of the hollow itself), that is the material of the hollow polymer pellet may be solid without a porous structure. Alternatively, the hollow polymer pellets may be comprised of porous material, such that the walls of the hollow polymer pellet structure are porous. 15
The BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length. The external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm. The external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm. In a preferred embodiment, the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm, and the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm.
The BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length, and the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm.
The BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length, and the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm.
In a preferred embodiment, the BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length, and the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm, and the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm. The BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length; and the thickness of the walls of the hollow pellets (pellet A and pellet B) may be between about 120 pm and 170pm. 16
The external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm. The external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm. In a preferred embodiment, the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm, and the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm; and the thickness of the walls of the hollow pellets (pellet A and pellet B) may be between about 120 pm and 170pm.
The BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length; the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm; and the thickness of the walls of the hollow pellets (pellet A and pellet B) may be between about 120 pm and 170pm.
The BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length; the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm; and the thickness of the walls of the hollow pellets (pellet A and pellet B) may be between about 120 pm and 170pm.
In a preferred embodiment, the BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate-encapsulating pellet (pellet A) may be between 600 pm and 1300 pm in length, and the external diameter of the BMP-2 encapsulating pellet (pellet B) may be between 600 pm and 900 pm, and the thickness of the walls may be between about 120 pm and 170pm; and the external diameter of the calcium phosphate-encapsulating pellet (pellet A) may be between 300 pm and 700 pm, and the thickness of the walls o may be between about 120 pm and 170pm.
The size, length, diameter, volume or thickness of the hollow polymer pellets, or features thereof, may refer to the average size of a population of hollow polymer pellets. In one embodiment, the size, length, diameter, volume or thickness of the hollow polymer pellets, or features thereof, may refer to the largest size, length, 17 diameter, volume or thickness of the hollow polymer pellet. The size of the hollow polymer pellets may be advantageously chosen by the skilled person for the intended application or type of osteoconductive implant material required. For example, the use of larger sized hollow polymer pellets may be for increased porosity, where the gaps between the hollow polymer pellets may be larger relative to the use of smaller hollow polymer pellets. Such size control can provide control over the agent release rate, whereby a faster release rate may be provided by the choice of larger hollow polymer pellets. For example when extruding the hollow polymer pellet material, the draw-off rate can be changed pull the hollow polymer pellets into thinner diameters. Additionally, morphology can be influenced by a change in temperature and thus cooling time.
Advantageously, the morphology and dimensions of the pellets A and/or B are optimised, such that they are large enough to allow for sufficient porosity of the resulting material and small enough to produce a good putty for handling and avoiding shedding of the pellets from the material.
The aqueous carrier
The aqueous carrier may be isotonic, for example relative to body fluid. In one embodiment, the aqueous carrier comprises or consist of saline. In a preferred embodiment, the aqueous carrier comprises or consists of physiological saline.
The saline may comprise or consist of about 0.9% w/v NaCl.
The aqueous carrier may be sterile/sterilised.
In one embodiment, the aqueous carrier does not comprise a plasticiser.
The composition
The osteoconductive implant material composition may be a composition for producing an osteoconductive scaffold. 18
The composition components (A), (B), (C) and optionally (D) may be mixed together into a single composition. In one embodiment the composition further comprises (D) an aqueous carrier. In embodiments with an aqueous carrier, the composition may be in the form of a putty.
The BMP-2 encapsulating pellets (B) may be provided in an amount of between about 10% and about 45% w/w of the composition (in the absence of the aqueous carrier (D). In another embodiment, the BMP-2 encapsulating pellets (B) may be provided in an amount of between about 10% and about 30% w/w of the composition (in the absence of the aqueous carrier (D). In one embodiment, the BMP-2 encapsulating pellets (B) are provided in an amount of between about 20% and about 30% w/w of the composition (in the absence of the aqueous carrier (D). In a preferred embodiment, the BMP-2 encapsulating pellets (B) are provided in an amount of about 20% w/w of the composition (in the absence of the aqueous carrier (D). In one embodiment, for example wherein calcium phosphate pellets are provided as component (A), the BMP- 2 encapsulating pellets (B) may be provided in an amount of about 23% w/w of the composition (in the absence of the aqueous carrier (D).
Advantageously, the proportion of BMP-2 encapsulating pellets (B) is optimised for sufficient dosing and release profile of BMP-2 relative to the acid degradation of the PLGA.
The calcium-phosphate-encapsulating pellets (A) may be provided in an amount of between about 10% and about 52% w/w of the composition (in the absence of the aqueous carrier (D). In another embodiment, the calcium -phosphate-encapsulating pellets (A) may be provided in an amount of between about 25% and about 50% w/w of the composition (in the absence of the aqueous carrier (D). In another embodiment, the calcium -phosphate-encapsulating pellets (A) are provided in an amount of between about 35% and about 45% w/w of the composition (in the absence of the aqueous carrier (D). In a preferred embodiment, the calcium -phosphate-encapsulating pellets (A) are provided in an amount of about 40% w/w of the composition (in the absence of the aqueous carrier (D).
The calcium-phosphate pellets (A) may be provided in an amount of between about 25% and about 50% w/w of the composition (in the absence of the aqueous carrier 19
(D). In another embodiment, the calcium -phosphate pellets (A) are provided in an amount of between about 30% and about 40% w/w of the composition (in the absence of the aqueous carrier (D). In a preferred embodiment, the calcium -phosphate pellets (A) are provided in an amount of about 35% w/w of the composition (in the absence of the aqueous carrier (D)
Advantageously, the relative proportion of calcium phosphate pellets or calcium phosphate-encapsulating pellets (A) is optimised to provide a putty with sufficient handling characteristics.
In one embodiment a mixture of calcium phosphate pellets and calcium phosphate- encapsulating pellets are provided as component (A).
The viscosity modifier (C) (e.g. poloxamer 407) may be provided in an amount of between about 25% and about 50% w/w of the composition (in the absence of the aqueous carrier (D). In another embodiment, the viscosity modifier (C) is provided in an amount of between about 35% and about 45% w/w of the composition (in the absence of the aqueous carrier (D). In a preferred embodiment, the viscosity modifier
(C) is provided in an amount of about 40% w/w of the composition (in the absence of the aqueous carrier (D). In one embodiment, for example wherein calcium phosphate pellets are provided as component (A), the viscosity modifier (C) may be provided in an amount of about 42% w/w of the composition (in the absence of the aqueous carrier
(D). In a preferred embodiment, for example wherein calcium phosphate pellets are provided as component (A), the viscosity modifier (C) may be provided in an amount of about 40.5% w/w of the composition (in the absence of the aqueous carrier (D).
Advantageously, the relative proportion of viscosity modifier is optimised to gel at room temperature (e.g. about 24°C) to form a putty, but also at a level to be soluble.
Preferably the composition is suitable for forming an osteoconductive implant material in a subject when mixed with the aqueous carrier (D).
The composition may form a putty when mixed with the aqueous carrier (D). 20
The aqueous carrier (e.g. physiological saline) (component D) may be provided at a ratio of between 0.3 and about 0.8 parts to 1 part powder mixture (v/w) of the calcium phosphate pellets and/or calcium phosphate-encapsulating pellets (A), the BMP-2 encapsulating pellets (B) and the viscosity modifier (C). In one embodiment, the aqueous carrier (e.g. physiological saline) (component D) may be provided at a ratio of between 0.5 and 0.6 parts to 1 part powder mixture (v/w) of the calcium phosphate pellets and/or calcium phosphate-encapsulating pellets (A), the BMP-2 encapsulating pellets (B) and the viscosity modifier (C). In one embodiment, the aqueous carrier (e.g. physiological saline) (component D) may be provided at a ratio of 0.6 parts to 1 part powder mixture (v/w) of the calcium phosphate pellets and/or calcium phosphate- encapsulating pellets (A), the BMP-2 encapsulating pellets (B) and the viscosity modifier (C). In another embodiment, the aqueous carrier (e.g. physiological saline) (component D) may be provided at a ratio of 0.4 parts to 1 part powder mixture (v/w) of the calcium phosphate pellets and/or calcium phosphate-encapsulating pellets (A), the BMP-2 encapsulating pellets (B) and the viscosity modifier (C).
Advantageously, the relative proportion of the aqueous carrier to the dry powder components is optimised to fully wet the composition and form a putty, but to avoid too low viscosity and poor handling characteristics.
The composition may be sterile/sterilised.
The composition may or may not set into a solid non-malleable scaffold.
In an embodiment wherein the composition is in putty form, or solidified form, the composition may be filled within a cage, such as an anterior lumbar cage. The anterior lumbar cage may comprise an El Capitan Anterior Lumbar Interbody Fusion (ALIF) System, or a Transforaminal Lumbar Interbody Fusion (TLIF) system. The composition may be used for any bone fusion procedure, e.g. Anterior cervical discectomy and fusion (ACDF), Transforaminal Lumbar Interbody Fusion (TLIF), extreme lateral interbody fusion (XLIF), Anterior Lumbar Interbody Fusion (ALIF), Oblique Lateral Interbody Fusion (OLIF), Posterior Lumbar Fusion (PLF), Occipitocervical Fusion (OCF), or posterior cervical fusion.
In one embodiment, the composition comprises or consists of: 21
(A) calcium phosphate pellets or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
-40-60% w/w PLGA having an L:G ratio of 75-95:5-25, and
-40-60% w/w calcium phosphate, wherein the calcium phosphate is encapsulated within the PLGA;
(B) BMP-2 encapsulating pellets comprising or consisting of:
-60-90% w/w PLGA having an L:G ratio of 45-55:55-45,
-10-30% w/w 2-hydroxypropyl- -cyclodextrin,
-5-15% w/w poloxamer 407, and
-0.01-0.1% w/w BMP-2, wherein the BMP-2 is encapsulated within the PLGA; and
(C) a viscosity modifier comprising poloxamer 407; and optionally
(D) an aqueous carrier.
In one embodiment, the composition comprises or consists of:
(A) calcium phosphate pellets;
(B) BMP-2 encapsulating pellets comprising or consisting of:
-60-90% w/w PLGA having an L:G ratio of 45-55:55-45,
-10-30% w/w 2-hydroxypropyl- -cyclodextrin,
-5-15% w/w poloxamer 407, and
-0.01-0.1% w/w BMP-2, wherein the BMP-2 is encapsulated within the PLGA; and
(C) a viscosity modifier comprising poloxamer 407; and optionally
(D) an aqueous carrier.
In another embodiment, the composition comprises or consists of:
(A) 40% w/w of calcium phosphate-encapsulating pellets comprising or consisting of:
-PLGA 95:5 (50% w/w), and
- calcium phosphate (50% w/w) wherein the calcium phosphate is encapsulated within the PDIXGA 95:5;
(B) 20% w/w of rhBMP-2 encapsulating pellets comprising or consisting of:
-PLGA 50:50 (poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), -2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
-poloxamer 407 (micronized) (10% w/w), and 22
-rhBMP-2 (0.19% w/w) and excipients, wherein the rhBMP-2 is encapsulated within the PDIXGA 50:50; and
(C) a viscosity modifier comprising 40% w/w poloxamer 407 (powder); and optionally
(D) an aqueous carrier.
In another embodiment, the composition comprises or consists of:
(A) 35% w/w of calcium phosphate pellets;
(B) 23% w/w of rhBMP-2 encapsulating pellets comprising or consisting of:
-PLGA 50:50 (poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), -2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
-poloxamer 407 (micronized) (10% w/w), and
-rhBMP-2 (0.19% w/w) and excipients, wherein the rhBMP-2 is encapsulated within the PDIXGA 50:50; and
(C) a viscosity modifier comprising 42% w/w poloxamer 407 (powder); and optionally
(D) an aqueous carrier.
In another embodiment, the composition comprises or consists of:
(A) 37% w/w of calcium phosphate pellets;
(B) 22% w/w of rhBMP-2 encapsulating pellets comprising or consisting of:
-PLGA 50:50 (poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), -2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
-poloxamer 407 (micronized) (10% w/w), and
-rhBMP-2 (0.19% w/w) and excipients, wherein the rhBMP-2 is encapsulated within the PDIXGA 50:50; and
(C) 41% w/w poloxamer 407 (powder); and optionally
(D) an aqueous carrier.
Other Aspects
According to another aspect of the present invention, there is provided an anterior lumbar cage containing the osteoconductive implant material according to the invention herein. 23
According to another aspect of the present invention, there is provided a method of spinal fixation of a patient, for example with degenerative disc disease, the method comprising the steps of filling a lumbar cage with the osteoconductive implant material according to the invention herein and implanting the lumbar cage into the patient.
The lumbar cage may be implanted between two adjacent vertebrae of the patient. The method or use in treatment may comprise an Anterior Lumbar Interbody (ALIF) fusion procedure. The method or use in treatment may comprise any spinal fusion procedure, such as Anterior cervical discectomy and fusion (ACDF), Transforaminal Lumbar Interbody Fusion (TLIF), extreme lateral interbody fusion (XLIF), Anterior Lumbar Interbody Fusion (ALIF), Oblique Lateral Interbody Fusion (OLIF), Posterior Lumbar Fusion (PLF), Occipitocervical Fusion (OCF), or posterior cervical fusion. The method or use may be in spinal fusion procedures in adult patients with degenerative disc disease (DDD) at one level from L4-S1.
According to another aspect of the present invention, there is provided the osteoconductive implant material according to the invention herein for use in bone repair or in an Anterior Lumbar Interbody (ALIF) fusion procedure.
The osteoconductive implant material of the invention may be used for fixing a screw or rod into bone, or fixing a plate onto bone. According to another aspect of the present invention, there is provided the osteoconductive implant material according to the invention herein for use in bone grafting.
The use in bone grafting or repair may be to augment the grafting of natural bone from the subject or from a donor. In another embodiment, the bone grafting may be to fill a void in a subject’s bone, such as a damaged bone, with the material of the invention. The invention may be used in any bone grafting fusion procedure. 24
According to another aspect of the present invention, there is provided the osteoconductive implant material according to the invention herein for use in spinal fusion, such as Transforaminal Lumbar Interbody Fusion (TLIF).
According to another aspect of the present invention, there is provided the osteoconductive implant material according to the invention herein for use as a bone void filler, such as in an Anterior Lumbar Interbody (ALIF) fusion procedure.
According to another aspect of the present invention, there is provided the use of the osteoconductive implant material according to the invention herein in a lumbar cage for spinal fixation.
The invention may be used in the treatment of idiopathic scoliosis, neuromuscular scoliosis, degenerative disc disease, spondylosis, spondylolisthesis, or any other condition that may be treated by bone repair, bone grafting, or bone replacement.
According to another aspect of the present invention, there is provided the use of 2- hydroxypropyl- -cyclodextrin for protecting BMP-2 from heat-mediated denaturation in a process of hot melt extrusion of a polymer, which is encapsulating the BMP-2.
The 2-hydroxypropyl- -cyclodextrin may be co-encapsulated with the BMP-2 in the polymer.
According to another aspect of the present invention, there is provided a kit for forming an osteoconductive implant material, the kit comprising:
(A) calcium phosphate pellets or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
-polymer, and
-b-TCP, wherein the b-TCP is encapsulated within the polymer;
(B) BMP-2 encapsulating pellets comprising or consisting of:
-polymer,
-2-hydroxypropyl-beta-cyclodextrin,
-poloxamer 407, and
-BMP-2, wherein the BMP-2 is encapsulated within the polymer; and 25
(C) a viscosity modifier comprising poloxamer 407; and
(D) an aqueous carrier.
The components (A), (B) and (C) may be retained in separate packets, such as sachets. Two, or all of, components (A), (B) and (C) may be retained in the same packets, such as sachets. The aqueous carrier (D) may be kept separate, for example in a sachet or bottle, until it is used to mix with the components.
The kit may comprise an oxygen scavenger and/or desiccant. The skilled person will be familiar with suitable oxygen scavengers sufficient to maintain substantially oxygen free environment. The oxygen scavenger may at least absorb more than 20 ml oxygen within 7 days under 25±2°C. Alternatively, the oxygen scavenger may at least absorb more than 40 ml oxygen within 7 days under 25±2°C. Example oxygen scavengers may comprise one or more, or all of, silicide, carbon hydride compound, resin powder, activated carbon, silica gel, and inorganic additives.
The skilled person will be familiar with suitable desicants sufficient to maintain low moisture content. The desiccant may have an adsorption capacity of at least = > 16.5% at 25 °C, 80% relative humidity. Desiccant material may comprise a molecular sieve.
The kit may comprise or consist of:
(A) calcium phosphate pellets or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
-40-60% w/w PLGA having an L:G ratio of 75-95:5-25, and -40-60% w/w calcium phosphate, wherein the calcium phosphate is encapsulated within the PLGA;
(B) BMP-2 encapsulating pellets comprising or consisting of:
-60-90% w/w PLGA having an L:G ratio of 45-55:55-45,
-10-30% w/w 2-hydroxypropyl- -cyclodextrin,
-5-15% w/w poloxamer 407, and
-0.01-0.1% w/w BMP-2, wherein the BMP-2 is encapsulated within the PLGA; and
(C) a viscosity modifier comprising poloxamer 407; and optionally
(D) an aqueous carrier. 26
In another embodiment, the kit may comprise or consist of:
(A) 40% w/w of calcium phosphate pellets or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
-PLGA 95:5 (50% w/w), and
-calcium phosphate (50% w/w) wherein the calcium phosphate is encapsulated within the PDIXGA 95:5;
(B) 20% w/w of rhBMP-2 encapsulating pellets comprising or consisting of:
-PLGA 50:50 (poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), -2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
-poloxamer 407 (micronized) (10% w/w), and
-rhBMP-2 (0.19% w/w) and excipients, wherein the rhBMP-2 is encapsulated within the PDIXGA 50:50; and
(C) a viscosity modifier comprising 40% w/w poloxamer 407 (powder); and optionally
(D) an aqueous carrier.
In another embodiment, the kit may comprise or consist of:
(A) 35% w/w of calcium phosphate pellets;
(B) 23% w/w of rhBMP-2 encapsulating pellets comprising or consisting of:
-PLGA 50:50 (poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), -2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
-poloxamer 407 (micronized) (10% w/w), and
-rhBMP-2 (0.19% w/w) and excipients, wherein the rhBMP-2 is encapsulated within the PDIXGA 50:50; and
(C) a viscosity modifier comprising 42% w/w poloxamer 407 (powder); and optionally
(D) an aqueous carrier.
According to another aspect of the present invention, there is provided a method of forming an osteoconductive implant material comprising the mixture of (A) calcium phosphate pellets or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
-40-60% w/w PLGA having an L:G ratio of 75-95:5-25, and
-40-60% w/w calcium phosphate, wherein the calcium phosphate is encapsulated within the PLGA; 27
(B) BMP-2 encapsulating pellets comprising or consisting of:
-60-90% w/w PLGA having an L:G ratio of 45-55:55-45,
-10-30% w/w 2-hydroxypropyl- -cyclodextrin,
-5-15% w/w poloxamer 407, and
-0.01-0.1% w/w BMP-2, wherein the BMP-2 is encapsulated within the PLGA; and
(C) a viscosity modifier comprising poloxamer 407; with
(D) an aqueous carrier.
Components (A), (B) and (C) may be provided as a dry mix prior to mixing with (D) the aqueous carrier. Components (A), (B) and (C) may be sterilised prior to mixing with (D) the aqueous carrier. The mixture may be manipulated into a putty consistency.
According to another aspect of the present invention, there is provided a process of manufacture of an osteoconductive implant material in accordance with the invention herein, the method comprising the provision of and mixing of components (A), (B) and (C), and optionally (D).
Components (A), (B) and (C) may be sterilized prior to mixing with (D) the aqueous carrier.
Sterilization may be by irradiation. In one embodiment, sterilisation is carried out by irradiation of a sealed packaging comprising one or more, or all components (A), (B), (C) and (D). Preferably, the sealed packaging is gas-impermeable. The sealed packaging preferably comprising an oxygen scavenger and/or desiccant. The oxygen scavenger and/or desiccant may be provided in one or more gas-permeable packaging, such as a porous polyethylene, which may be sealed together with one or more, or all components (A), (B), (C) and (D) within the gas-impermeable packaging. Preferably at least the BMP-2 encapsulating pellets are protected from oxygen and/or free radicals during irradiation by such packaging.
The sealed packaging may be sealed in a low- or zero-oxygen environment, such as in a nitrogen environment. The sealed packaging may not comprise oxygen. The sealed 28 packaging may comprise nitrogen gas (instead of air). The sealed packaging may be sealed by vacuum packing, for example, drawn to about 2mbar of pressure. In one embodiment, the sealed packaging comprises an oxygen scavenger and/or a desiccant.
The BMP-2 encapsulating pellets (B) may be formed by hot melt extrusion (HME).
In one embodiment, the BMP-2 encapsulating pellets (B) are formed by combining -60-90% w/w PLGA having an L:G ratio of 45-55:55-45,
-10-30% w/w 2-hydroxypropyl- -cyclodextrin,
-5-15% w/w poloxamer 407, and -0.01-0.1% w/w BMP-2, to form a mixture, and extruding the mixture in a hot melt extrusion process.
The hot melt extrusion process for the b BMP-2 encapsulating pellets may have a feed rate of 1-4%. The feed rate for the BMP-2 encapsulating pellets may be about 2%. In a preferred embodiment, the feed rate for the BMP-2 encapsulating pellets is about 2.2%. The skilled person will recognise that the hot melt extrusion and pelletisation parameters such as the feed rate, screw speed and pelletiser settings may be adjusted for providing the required pellet consistency and size in accordance with the invention herein.
The hot melt extrusion process for the BMP-2 encapsulating pellets may have a screw speed of 10-30 rpm. In a preferred embodiment, the screw speed for the BMP-2 encapsulating pellets is about 20 rpm.
The hot melt extrusion process for the BMP-2 encapsulating pellets may have a feed rate of 1-4% and a screw speed of 10-30 rpm. The feed rate for the BMP-2 encapsulating pellets may be about 2% and the screw speed may be 10-30 rpm, or more preferably about 20 rpm. In a preferred embodiment, the feed rate is about 2.2% and the screw speed is about 20 rpm.
The hot melt extrusion process for the BMP-2 encapsulating pellets may comprise the use of a pelletiser with the settings of 1-6 m/min and 0.1-2 mm, more preferably 3 m/min and 0.6 mm. 29
The hot melt extrusion process for the BMP-2 encapsulating pellets may have a feed rate of 1-4% and a screw speed of 10-30 rpm with pelletiser settings of 1-6 m/min and 0.1-2 mm, more preferably 3 m/min and 0.6 mm. The feed rate for the BMP-2 encapsulating pellets may be about 2% and the screw speed may be 10-30 rpm, or more preferably about 20 rpm, with pelletiser settings of 1-6 m/min and 0.1-2 mm, more preferably 3 m/min and 0.6 mm. In a preferred embodiment, the feed rate for the BMP-2 encapsulating pellets is about 1.8% and the screw speed is about 20 rpm, and with pelletiser settings of 1-6 m/min and 0.1-2 mm, more preferably 3 m/min and 0.6 mm.
The hot-melt extrusion process for the BMP-2 encapsulating pellets may comprise heating and extruding the composition through the temperatures steps of about 50- 90°C, 70-110°C, 70-110°C, 70-110°C (each temperature representing a different step/section of extruder as the material passes through) optionally with a total time of 10 minutes or less. In one embodiment, the hot-melt extrusion process may comprise heating and extruding the composition through the temperatures steps of about 60°C, 80°C, 80°C, 80°C (each temperature representing a different step/section of extruder as the material passes through) optionally with a total time of 10 minutes or less. The hot-melt extrusion process may not exceed 110°C and/or may not exceed 10 minutes.
The hot-melt extrusion process advantageously provides conditions where extrusion of the material is possible at a sufficient temperature, whilst avoiding significant heat damage to the BMP-2.
The calcium phosphate-encapsulating pellets (A) may be formed by hot melt extrusion (HME). In one embodiment, the calcium phosphate-encapsulating pellets (A) may be formed by combining 40-60% w/w PLGA having an L:G ratio of 75-95:5-25, and 40- 60% w/w calcium phosphate to form a mixture and extruding the mixture in a hot melt extrusion process.
The hot melt extrusion process for the calcium phosphate-encapsulating pellets may have a feed rate of 1-3%. The feed rate may be about 2%. In a preferred embodiment, the feed rate for the calcium phosphate-encapsulating pellets is about 1.8%. 30
The hot melt extrusion process for the calcium phosphate-encapsulating pellets may have a screw speed of 10-20 rpm. In a preferred embodiment, the screw speed for the b-TCP encapsulating pellets is about 15 rpm.
The hot melt extrusion process for the calcium phosphate-encapsulating pellets may have a feed rate of 1-3% and a screw speed of 10-20 rpm. The feed rate for the calcium phosphate-encapsulating pellets may be about 2% and the screw speed may be 10-20 rpm, or more preferably about 15 rpm. In a preferred embodiment, the feed rate is about 1.8% and the screw speed is about 15 rpm.
The hot melt extrusion process for the calcium phosphate-encapsulating pellets may comprise the use of a pelletiser with the settings of 0.5-5 m/min and 0.2-2 mm, more preferably 1.4 m/min and 1.3 mm.
The hot melt extrusion process for the calcium phosphate-encapsulating pellets may have a feed rate of 1-3% and a screw speed of 10-20 rpm with pelletiser settings of 0.5-5 m/min and 0.2-2 mm, more preferably 1.4 m/min and 1.3 mm. The feed rate for the calcium phosphate-encapsulating pellets may be about 2% and the screw speed may be 10-20 rpm, or more preferably about 15 rpm, with pelletiser settings of 0.5-5 m/min and 0.2-2 mm, more preferably 1.4 m/min and 1.3 mm. In a preferred embodiment, the feed rate for the calcium phosphate-encapsulating pellets is about 1.8% and the screw speed is about 15 rpm, and with pelletiser settings of 0.5-5 m/min and 0.2-2 mm, more preferably 1.4 m/min and 1.3 mm.
The hot melt extrusion process for the calcium phosphate-encapsulating pellets may comprise heating and extruding the composition through the temperatures steps of about 70-100°C, 100-150°C, 100-150°C, 100-150°C (each temperature representing a different step/section of the extruder as the material passes through). In one embodiment, the hot melt extrusion process for the calcium phosphate-encapsulating pellets may comprise heating and extruding the composition through the temperatures steps of about 80°C, 120°C, 120°C, 120°C (each temperature representing a different step/section of the extruder as the material passes through). 31
The extrusion process advantageously provides temperatures sufficient to extrude polymer material containing calcium phosphate, such as b-TCP, but not such that the polymer material is damaged.
The method may further comprise the insertion of the osteoconductive implant material into a lumbar cage.
In one embodiment, the osteoconductive implant material of the invention, such as the putty, may be mixed with autologous bone fragments prior to use. For example, autologous bone fragment may be mixed with the osteoconductive implant material of the invention and placed outside the lumbar cage.
Therefore, one embodiment, the osteoconductive implant material of the invention may further comprise autologous bone fragments from a subject to be treated.
Definitions
“Autologous bone” is considered to be donor bone taken from a patient/subject to be treated and re-implanted back into another site of the same patient/subject.
Poloxamer 407 is a hydrophilic non-ionic surfactant of the more general class of copolymers known as poloxamers. Poloxamer 407 is a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol (PEG).
Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by a-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzymatic conversion. Typical cyclodextrins are constituted by 6-8 glucopyranoside units. These subunits are linked by 1,4 glycosidic bonds. The cyclodextrins have toroidal shapes, with the larger and the smaller openings of the toroid exposing to the solvent secondary and primary hydroxyl groups respectively b (beta)-cyclodextrin has 7 glucose subunits.
BMP-2 (bone morphogenetic protein 2), like other bone morphogenetic proteins, plays an important role in the development of bone and cartilage. It is involved in the 32 hedgehog pathway, TGF beta signalling pathway, and in cytokine-cytokine receptor interaction. It is also involved in cardiac cell differentiation and epithelial to mesenchymal transition.
A “putty” is understood to be a solid material with high plasticity, similar in texture to clay or dough. Putty is a malleable solid material, for example malleable by hand. The putty may be manipulated into a shape, which is retained.
The term “room temperature” is intended to refer to a temperature of from about 15°C to about 25°C, such as from about 20°C to about 25°C.
The terms “encapsulated”, “encapsulating” or “encapsulated within” is intended to refer to one substance (such as BMP-2 or calcium phosphate) being substantially mixed within and throughout the material of another substance, such as the polymer described herein. The encapsulation may be by extrusion, preferably hot-melt extrusion. Encapsulation does not describe substances/agents that have been surface loaded into the other substance, such as a polymer. The loading of an agent/substance into and through the pores of a porous substance such as a polymer is also not considered to be encapsulation within that substance. In particular, an encapsulated substance will form part of the same material with the encapsulating substance.
The skilled person will understand where two or more ranges of percentage components are provided in a given composition, the provided percentage of one component will be balanced by the percentage of the other component(s) such that in combination they amount to no more than 100%.
The skilled person will understand that optional features of one embodiment or aspect of the invention may be applicable, where appropriate, to other embodiments or aspects of the invention.
Embodiments of the invention will now be described in more detail, by way of example only, with reference to the accompanying drawings.
Figure 1. Pictorial summary of the three components that comprise LDGraft. 33
Figure 2. Pictorial summary of the preparation of LDGraft at the point of use for spinal fusion. Figure 3. Morphology of b-TCP structural pellets manufactured by hot melt extrusion having [A] 50% w/w b-TCP content and [B] 60% w/w content.
Figure 4. [A] Morphology of hollow pellets in close association with each other. [B] Demonstration of interconnected porosity caused by pellet lumen. Note - there is no poloxamer 407 present for this demonstration.
Figure 5. pH measurements to demonstrate differential degradation rates of PLGA 5050 and PLGA 955 in an in-vitro degradation study.
Figure 6. Rheological traces for PLGA5050, PLGA5050+PEG400 and PLGA5050 + PEG400 + P407 showing [A] phase shift angle and [B] loss modulus versus temperature. Oscillatory rheology test 0.1% strain/1 Hz. Figure 7. Impact of cyclodextrin HPB on structure of BMP-2 after lyophilisation and heating to mimic the manufacturing process of LDGraft.
Figure 8. BMP-2 structural pellets manufactured by HME containing [A] 100 mM cyclodextrin HPB and [B] 50 mM cyclodextrin as an excipient to protect the BMP-2 structure.
Figure 9. Activity of BMP-2 measured by ALP expression in C2C12 cells. [A] is data achieved from active BMP-2 released by the feedstock [B] is data achieved from active BMP-2 released from the BMP-2 scaffold pellets.
Figure 10. Sub-optimal pellets caused by incorrect manufacturing parameters. [A] Incomplete cutting of thin strands comprising of PLGA5050 based material [B] Shattered pellets comprising of PLGA955^- 34
TCP based material [C] Split pellets comprising of PLGA5050 based material.
Figure 11. Optimal pellet morphology for [A] BMP-2 scaffold pellets and [B] b-TCP scaffold pellets
Figure 12. Overview of pellet manufacture method for LDGraft.
Figure 13. Overview of packaging for LDGraft.
Figure 14. Three packaging configurations to protect the BMP-2 protein during processing by X-ray to terminally sterilise. 20200202YF is the BMP- 2 protein as supplied. LOCBAT0115 is the BMP-2 extracted from a batch after hot melt extrusion. As is: This BMP-2 sample underwent the sterilisation process without protectants. LCl-3 are the lead configurations for packaging.
Figure 15. b-TCP Granules. Demonstration of macro and micro porosity.
Light and scanning electron microscope images of: A: b-TCP Granules; B: b- TCP Granules: xlO; C: b-TCP Granules xlOO; D: b-TCP Granules x2000 (showing surface morphology).
Examples 1. Composition, manufacture and parameter testing of osteoconductive implant material “LDGraft”
Table la - Example of b-TCP scaffold pellets composition 35
Table lb. ALTERNATIVE COMPONENT A 36
Table 2 - formation of b-TCP scaffold pellets composition
Table 3 - composition of BMP-2 scaffold pellets composition 37 38
Table 4 - formation of BMP-2 scaffold pellets
Table 5 composition of viscosity modifier 39
Table 6 composition of liquid carrier
Table 7 Combination of components A, B, C and D for LDGraft product The skilled person will recognise that the percentage of components provided for mixture is relative to the amount in the dry mixture (e.g. components A, B and C) prior to addition to the aqueous carrier (e.g. component D).
Morphology and Porosity 40
Figure 3 shows the morphology of b-TCP structural pellets manufactured by hot melt extrusion having [A] 50% w/w b-TCP content and [B] 60% w/w content. There is a clear difference in the appearance of the pellets, the higher b-TCP content has caused the pellets to crumble during the pelletisation process resulting in small shards of material as well as roughly cut pellets which are not satisfactory for the final product as porosity would be reduced as small pieces would block open pores. The pellets manufactured with 50% w/w b-TCP [Fig. 3A] do not crumble and have a lumen to maximise porosity.
Figure 4 further demonstrates the porosity of the material when the pellets are closely associated with each other as within the LDGraft putty. The LDGraft will be packed into an interbody spinal fusion cage and the poloxamer 407 will leach away from the site, the remaining pellets will provide good porosity and have a structure which is similar to that shown in Fig. 4A. The material readily wicks fluid through the interconnected open pores [Fig. 4B] pH drop caused by PLGA degradation (PLGA 5050 vs PLGA 955) For this study, pre-formed scaffolds were prepared by allowing the closely associated pellets manufactured from PLGA50:50 based materials and PLGA95:5 based materials sinter at a temperature slightly higher than their glass transition temperature. For each scaffold, 200 mg of sterilised pellets were mixed with 140 pi of aqueous carrier (l%w/v F127. 0.5%w/v in 0.9%w/v saline) in an open bore syringe to make a paste.
The paste was injected into individual pre-drilled open cell Sawbone™ defects measuring 6 mm in diameter and 10 mm in depth. All the materials were allowed to sinter overnight (50 °C- check) in a humid environment. The Sawbone samples having filled defects were transferred to 20 ml of sterile phosphate buffered saline (PBS) and the pH value was measured. On a weekly basis, the pH was re-measured and the PBS replaced with fresh.
As PLGA degrades in a sealed environment, acid degradation products will build up leading to a drop in pH. Figure 5 clearly shows that the PLGA that comprises the BMP-2 structural pellets (PLGA5050) degrades at a much faster rate than the PLGA 41 that comprises the b-TCP structural pellets (PLGA955). This ensures the active BMP- 2 is released at a faster rate than the degradation of the whole scaffold.
Effect of poloxamer407 on glass transition temperature
Figure 6 shows two rheology plots [A] is the phase shift angle against temperature and [B] the loss modulus against temperature. The test was an oscillatory test having 0.1% strain and a speed of 1 Hz. The temperature ramp was set at 10 to 80 °C with an interval of 30 seconds.
The data shows that the P407 has little effect on the glass transition temperature (Tg) of PLGA5050 over the effect of PEG400. As a single plasticiser, PEG400 has a major effect in the reduction of Tg. Tg is indicated a number of ways, the peak loss modulus gives a single value whereas the peak phase shift angle tends to overestimate and therefore the onset of phase shift to peak is quoted in table 8 below. The Tg stated on the certificate of analysis for the PLGA5050 is 48 oC which gives confidence in the data achieved. Table 8. Measurement of glass transition temperature by loss modulus and phase shift angle.
Cyclodextrin concentration required for HME process and BMP-2 protection Active BMP-2 is a protein which is sensitive to heat, moisture and oxygen radicals and therefore it must be afforded as much protection as possible in the formulation, the manufacturing process and the packaging. Figure 7 show the impact of cyclodextrin at different concentrations within the formulation on the structure of the BMP-2 molecule where the material was subjected lyophilisation (part of the 42 manufacturing process prior to hot melt extrusion) and heat (during hot melt extrusion). The BMP-2 was solubilised in 1% v/v acetic acid ± hydroxypropyl beta cyclodextrin between 0 and 100 mM. One sample was snap frozen in liquid nitrogen, lyophilised for 72 hours and then heated for 10 minutes to 90 °C to simulate the HME conditions. Control samples were not heated or lyophilised. Samples were prepared for non-reducing SDS-PAGE and gels stained with silver stain.
Figure 7 shows although 1 mM cyclodextrin HPB offers some protection for the BMP- 2 molecule, maximum protection (as shown by an absence of a band at approximately 35 kDa) is achieved at 50 mM and maintained at 100 mM.
Although it may be considered to use cyclodextrin HPB at 100 mM for protection of the molecule, this level of excipient interferes with the manufacturing process for LDGraft resulting in poorly formed and broken pellets which would not be suitable for the final product. (Figure 8).
BMP-2 Release data
Although BMP-2 can be detected by ELISA methods, this does not determine whether the molecule remains active and therefore a study was performed to determine activity through alkaline phosphatase expression in C2C12 cells.
Some of the lyophilised feedstock for HME was retained and this was tested for BMP- 2 release alongside the manufactured BMP-2 scaffold pellets. In each case a 100 mg sample of feedstock or pellets was placed into a transwell which was suspended within a culture well containing C2C12 cells. At regular intervals, the transwell containing the test samples was transferred to fresh C2C12 cells. An ALP assay was then performed on the cells to determine activity.
The data in Figure 9 has been normalised to the ALP activity of a standard amount of BMP-2 (0.2 pg/ml) the activity of which was determined at each time point. The activity of the BMP-2 within the feedstock dropped off after 11 days whereas activity of BMP-2 release from the PLGA material could be detected for up to 74 days in culture. This indicates the role that encapsulation of the BMP-2 into the PLGA has in 43 prolonging the release and activity over entrapment of the BMP-2 within the feedstock.
Data for manufacturing parameters
Hot melt extrusion is a continuous process and parameters/settings were altered ‘in process’ to achieve optimum pellet shape and size.
All of the parameters to produce the LDGraft pellets are inter-related and can impact on each other. Some of these inter-relationships are shown below in Table 9. Figure 10 shows examples of pellet morphologies where the manufacturing parameters were not optimal.
Figure 11 shows the optimal pellet morphology for b-TCP scaffold pellet and BMP-2 scaffold pellet morphology.
Table 9 Interdependency of parameters during hot melt extrusion. 44
Manufacture Overview
Figure 12 gives an overview of the manufacturing processes for LDGraft pellets and Figure 13 shows an overview of the packaging process.
The addition of oxygen scavengers and desiccant into the packaging has been shown to further protect the material during the sterilisation process which is performed using X-ray. BMP-2 protein needs to be protected throughout the manufacturing process including terminal sterilisation. The addition of cyclodextrin provides protection especially during the manufacturing process, but it has been found that packaging configurations 45 incorporating desiccants and oxygen scavengers are also advantageous against the effects of irradiation required for terminal sterilisation.
A number of different configurations have been trialled with three lead configurations (LC) shown in Figure 14. These are described briefly as follows:
LC1: The LDGraft material is packaged in a porous polyethylene (HPDE) pouch (Tyvek® pouch) with two oxygen scavenger pouches, one either side of the Tyvek pouch. A desiccant pouch is included and all four components are further packaged in a laminated foil pouch under nitrogen.
LC2: This has the same packaging configuration as LC1 but, the LDGraft and oxygen scavengers are re-packaged without the desiccant into a fresh foil pouch under nitrogen just prior to sterilisation by X-ray.
LC:3 This configuration has the same four components but, the desiccant is separated away from the LDGraft material. Again, it is packaged into a foil pouch under nitrogen.
Oxygen scavenger used was PharmaKeep KD-20™ (Mitsubishi Gas Chemical Company Inc.), comprising silicide, carbon hydride compound, resin powder, activated carbon, silica gel, and inorganic additives. Each one packet absorbs oxygen more than 20 ml within 7 days under 25±2°C.
Desiccant used was MOLSIEVEPHARMA 32G G2 68X100 1K/D (Airnov Healthcare Packaging). Material includes molecular sieve, non-woven polyester and polyolefin ink. Adsorption Capacity = > 16.5% at 25 °C, 80% relative humidity.
Figure 16: This Figure shows the results for non-reducing SDS-PAGE for the following samples:
20200202YF is the BMP-2 protein as supplied. LOCBAT0115 is the BMP-2 extracted from a batch after hot melt extrusion (i.e the cyclodextrin is providing the protection from the heat of the HME process).
As is: This sample underwent the sterilisation process without any oxygen scavengers or desiccant. The data shows that all three packaging configurations are advantageous in protecting the protein. 46
Use of the osteoconductive implant material
The present invention may be used for treatment in any of the following diseases/conditions, procedures or forms provided in the following table.

Claims

47 CLAIMS
1. An osteoconductive implant material composition comprising or consisting of:
(A) calcium phosphate pellets and/or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
-40-60% w/w PLGA having an L:G ratio of 75-95:5-25, and
-40-60% w/w calcium phosphate, wherein the calcium phosphate is encapsulated within the PLGA;
(B) BMP-2 encapsulating pellets comprising or consisting of:
-60-90% w/w PLGA having an L:G ratio of 45-55:55-45,
-10-30% w/w 2-hydroxypropyl- -cyclodextrin,
-5-15% w/w poloxamer 407, and
-BMP-2, wherein the BMP-2 is encapsulated within the PLGA; and
(C) a viscosity modifier optionally comprising or consisting of poloxamer 407; and optionally
(D) an aqueous carrier.
2. The osteoconductive implant material composition according to claim 1, wherein the calcium phosphate comprises or consists of b-tricalcium phosphate (b-TCP).
3. The osteoconductive implant material composition according to claim 1 or 2, wherein the calcium phosphate is provided in a particulate form in the calcium phosphate-encapsulating pellets of between about 0.5 pm and about 20 pm in size; or wherein pellet component (A) consists of calcium phosphate pellets between about 0.5mm and about 2.5mm in size.
4. The osteoconductive implant material composition according to any preceding claim, wherein the BMP-2 is provided in the BMP-2 encapsulating pellet (pellet B) in an amount of between about 0.01% and about 1% w/w.
5. The osteoconductive implant material composition according to any preceding claim, wherein the polymer of the BMP-2 encapsulating pellet (pellet B) comprises or consists of PDLLGA 50:50 and the polymer of the calcium phosphate-encapsulating pellet (pellet A) comprises or consist of PDLLGA 95:5. 48
6. The osteoconductive implant material composition according to any preceding claim, wherein the BMP-2 encapsulating pellet (pellet B) comprises or consists of about 75.5% (w/w) PLGA, and the calcium phosphate-encapsulating pellet (pellet A) comprises or consist of about 50% (w/w) PLGA.
7. The osteoconductive implant material composition according to any preceding claim, wherein the BMP-2 encapsulating pellet (pellet B) and/or the calcium phosphate-encapsulating pellet (pellet A) are shaped as a hollow cylindrical pellet.
8. The osteoconductive implant material composition according to any preceding claim, wherein the BMP-2 encapsulating pellet (pellet B) and/or calcium phosphate- encapsulating pellet (pellet A) are between 600 pm and 1300 pm in length.
9. The osteoconductive implant material composition according to any preceding claim, wherein the composition components (A), (B), (C) and optionally (D) are mixed together into a single composition in the form of a putty.
10. The osteoconductive implant material composition according to any preceding claim, wherein the BMP-2 encapsulating pellets (B) are provided in an amount of between about 10% and about 30% w/w of the composition.
11. The osteoconductive implant material composition according to any preceding claim, wherein the calcium-phosphate-encapsulating pellets (A) are provided in an amount of between about 25% and about 50% w/w of the composition.
12. The osteoconductive implant material composition according to any preceding claim, wherein the calcium-phosphate pellets (A) are provided in an amount of between about 25% and about 50% w/w of the composition.
13. The osteoconductive implant material composition according to any preceding claim, wherein the poloxamer 407 is provided in an amount of between about 25% and about 50% w/w of the composition. 49
14. The osteoconductive implant material composition according to any preceding claim, wherein the aqueous carrier (component D) is provided at a ratio of between 0.3 and about 0.8 parts to 1 part powder mixture (v/w) of the calcium phosphate pellets and/or calcium phosphate-encapsulating pellets (A), the BMP-2 encapsulating pellets (B) and the viscosity modifier (C).
15. A lumbar cage, such as an anterior lumbar cage, containing the osteoconductive implant material according to any one of the preceding claims.
16. A method of spinal fixation of a patient, for example with degenerative disc disease, the method comprising the steps of filling a lumbar cage with the osteoconductive implant material according to claims 1-14 and implanting the lumbar cage into the patient.
17. An osteoconductive implant material according to any one of claims 1-14 for use in bone repair, bone fusion, bone grafting or as a bone void filler in a bone grafting procedure, such as a procedure selected from Anterior cervical discectomy and fusion (ACDF), Transforaminal Lumbar Interbody Fusion (TLIF), extreme lateral interbody fusion (XLIF), Anterior Lumbar Interbody Fusion (ALIF), Oblique Lateral Interbody Fusion (OLIF), Posterior Lumbar Fusion (PLF), Occipitocervical Fusion (OCF), or posterior cervical fusion.
18. Use of the osteoconductive implant material composition according to any of claims 1-14 in a lumbar cage for spinal fixation, or for fixing a screw or rod into bone, or fixing a plate onto bone.
19. Use of 2-hydroxypropyl- -cyclodextrin for protecting BMP-2 from heat-mediated denaturation in a process of hot-melt extrusion of a polymer, which is encapsulating the BMP-2.
20. A kit for forming an osteoconductive implant material, the kit comprising:
(A) calcium phosphate pellets or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
-40-60% w/w PLGA having an L:G ratio of 75-95:5-25, and 50
-40-60% w/w calcium phosphate, wherein the calcium phosphate is encapsulated within the PLGA;
(B) BMP-2 encapsulating pellets comprising or consisting of:
-60-90% w/w PLGA having an L:G ratio of 45-55:55-45,
-10-30% w/w 2-hydroxypropyl- -cyclodextrin,
-5-15% w/w poloxamer 407, and
-BMP-2, wherein the BMP-2 is encapsulated within the PLGA; and
(C) a viscosity modifier optionally comprising or consisting of poloxamer 407; and optionally
(D) an aqueous carrier.
21. The kit according to claim 20, wherein the kit further comprises an oxygen scavenger and/or a desiccant.
22. The kit according to claim 20 or 21, wherein the kit comprises:
(A) 40% w/w of calcium phosphate pellets or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
-PLGA 95:5 (50% w/w), and
-calcium phosphate (50% w/w) wherein the calcium phosphate is encapsulated within the PDIXGA 95:5;
(B) 20% w/w of rhBMP-2 encapsulating pellets comprising or consisting of:
-PLGA 50:50 (poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), -2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
-poloxamer 407 (micronized) (10% w/w), and
-rhBMP-2 (0.19% w/w) and excipients, wherein the rhBMP-2 is encapsulated within the PDIXGA 50:50; and
(C) about 40% w/w poloxamer 407 (powder) as a viscosity modifier; and optionally
(D) an aqueous carrier.
23. The kit according to any one of claims 20-22, wherein the kit comprises:
(A) 35% w/w of calcium phosphate pellets;
(B) 23% w/w of rhBMP-2 encapsulating pellets comprising or consisting of:
-PLGA 50:50 (poly(DL-lactic acid-co-glycolic acid) (75.5% w/w), 51
-2-hydroxypropyl-beta-cyclodextrin (14.30% w/w),
-poloxamer 407 (micronized) (10% w/w), and
-rhBMP-2 (0.19% w/w) and excipients, wherein the rhBMP-2 is encapsulated within the PDIXGA 50:50; and
(C) 42% w/w poloxamer 407 (powder) as a viscosity modifier; and optionally
(D) an aqueous carrier.
24. A method of forming an osteoconductive implant material comprising the mixture of
(A) calcium phosphate pellets or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
-40-60% w/w PLGA having an L:G ratio of 75-95:5-25, and
-40-60% w/w calcium phosphate, wherein the calcium phosphate is encapsulated within the PLGA;
(B) BMP-2 encapsulating pellets comprising or consisting of:
-60-90% w/w PLGA having an L:G ratio of 45-55:55-45,
-10-30% w/w 2-hydroxypropyl- -cyclodextrin,
-5-15% w/w poloxamer 407, and
-BMP-2, wherein the BMP-2 is encapsulated within the PLGA; and
(C) a viscosity modifier optionally comprising or consisting of poloxamer 407; with
(D) an aqueous carrier.
25. the method according to claim 24, wherein components (A), (B) and (C) are provided as a dry mix prior to mixing with (D) the aqueous carrier.
26. The method according to claim 24 or 25, wherein components (A), (B) and (C), and optionally (D) are sterilised by irradiation, optionally prior to mixing with (D) the aqueous carrier.
27. The method according to any one of claims 24-26, wherein the mixture is manipulated into a putty consistency. 52
28. A process of manufacture of an osteoconductive implant material, the method comprising the provision of:
(A) calcium phosphate pellets or calcium phosphate-encapsulating pellets, wherein the calcium phosphate-encapsulating pellets comprise or consist of:
-40-60% w/w PLGA having an L:G ratio of 75-95:5-25, and
-40-60% w/w calcium phosphate, wherein the calcium phosphate is encapsulated within the PLGA;
(B) BMP-2 encapsulating pellets comprising or consisting of:
-60-90% w/w PLGA having an L:G ratio of 45-55:55-45,
-10-30% w/w 2-hydroxypropyl- -cyclodextrin,
-5-15% w/w poloxamer 407, and
-BMP-2, wherein the BMP-2 is encapsulated within the PLGA;
(C) a viscosity modifier optionally comprising or consisting of poloxamer 407; and
(D) an aqueous carrier; and optionally mixing of components (A), (B) and (C), and further optionally mixing with
(D).
29. The process according to claim 28, wherein one or more or all of components (A), (B), (C) and (D) are provided in sealed packaging comprising an oxygen scavenger and/or desiccant.
30. The process according to claim 28 or 29, wherein the sealed packaging is sealed in a nitrogen environment.
31. The method according to any of claims 24-27 or the process according to any of claims 28-30, wherein the BMP-2 encapsulating pellets (B) are formed by hot melt extrusion (HME).
32. The method according to any of claims 24-27 or the process according to any of claims 28-30, wherein the BMP-2 encapsulating pellets (B) are formed by combining
-60-90% w/w PLGA having an L:G ratio of 45-55:55-45,
-10-30% w/w 2-hydroxypropyl- -cyclodextrin,
-5-15% w/w poloxamer 407, and -0.01-0.1% w/w BMP-2, to form a mixture, and 53 extruding the mixture in a hot melt extrusion process.
33. The method according to any of claims 24-27, 31-32 or the process according to any of claims 28-32, wherein the calcium phosphate-encapsulating pellets (A) are formed by hot melt extrusion (HME).
EP22723746.8A 2021-05-14 2022-05-13 Osteoconductive implant material with bmp-2 delivery Pending EP4337273A1 (en)

Applications Claiming Priority (2)

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GBGB2106973.7A GB202106973D0 (en) 2021-05-14 2021-05-14 Osteoconductive implant material with BMP-2 delivery
PCT/GB2022/051221 WO2022238718A1 (en) 2021-05-14 2022-05-13 Osteoconductive implant material with bmp-2 delivery

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JP (1) JP2024518085A (en)
CN (1) CN117980013A (en)
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GB0307011D0 (en) 2003-03-27 2003-04-30 Regentec Ltd Porous matrix
ITMI20061538A1 (en) * 2006-08-02 2008-02-03 Mediolanum Pharmaceuticals Ltd SUBCUTANEOUS PLANTS ABLE TO RELEASE THE ACTIVE PRINCIPLE FOR A PROLONGED PERIOD OF TIME
GB0701896D0 (en) 2007-02-01 2007-03-14 Regentec Ltd Composition
GB201702475D0 (en) * 2017-02-15 2017-03-29 Locate Therapeutics Ltd Tissue scaffold and scaffold composition

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WO2022238718A1 (en) 2022-11-17
CN117980013A (en) 2024-05-03
JP2024518085A (en) 2024-04-24

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