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WO2007012841A2 - Composition - Google Patents

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Publication number
WO2007012841A2
WO2007012841A2 PCT/GB2006/002778 GB2006002778W WO2007012841A2 WO 2007012841 A2 WO2007012841 A2 WO 2007012841A2 GB 2006002778 W GB2006002778 W GB 2006002778W WO 2007012841 A2 WO2007012841 A2 WO 2007012841A2
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WO
WIPO (PCT)
Prior art keywords
bone
monobutyrin
growth factor
osteoporosis
pharmaceutical composition
Prior art date
Application number
PCT/GB2006/002778
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English (en)
Other versions
WO2007012841A3 (fr
Inventor
Andrew Harrison
Ed Margerrison
Robert Morgan
Original Assignee
Smith & Nephew, Plc
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 Smith & Nephew, Plc filed Critical Smith & Nephew, Plc
Publication of WO2007012841A2 publication Critical patent/WO2007012841A2/fr
Publication of WO2007012841A3 publication Critical patent/WO2007012841A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders

Definitions

  • the invention relates generally to the field of musculo-skeletal biology and is concerned with the provision of methods, pharmaceutical compositions/ medicaments and devices for promoting musculo-skeletal tissue regeneration, repair and formation which comprise such compositions.
  • Bone healing is required in situations of traumatic injury (e.g. fracture), total joint arthroplasty and where bone has been compromised as a result of surgical procedure. In many situations, the healing either does not take place leading to, for example, a non union, or occurs at a sub optimal rate resulting in a loss of function. Additionally, there are many comorbidities known to impair bone healing including diabetes and osteoporosis. Certain drug therapies such as steroids are also known to impair bone repair when it is needed. It is also apparent that the functioning of many currently used orthopaedic implants is sub-optimal. An example is a cementless tibial tray used in total knee arthroplasty, wherein the bone ingrowth to allow fixation of the implant is often insufficient to allow joint stability.
  • Vertebrate bone as a tissue providing mechanical support for the body, undergoes constant remodelling through the formation and resorption of bone mediated, it is widely thought, by the activities of osteoblasts and osteoclasts respectively.
  • Bone remodelling comprises a complex and highly organised interaction between cells and the extracellular matrix (ECM).
  • ECM extracellular matrix
  • the remodelling process is, however, adaptive in response to requirements of growth or habitual activity.
  • the rate of bone formation approximates with the rate of bone resorption, through a process known as remodelling.
  • Bone resorption or formation is not, though, a generalised feature of the entire skeleton simultaneously but occurs in discrete sites which may be surrounded by areas of quiescent bone. Where resorption occurs excessively, several clinical problems can occur either at a specific locality or more extensively throughout the skeleton.
  • osteoporosis is a disease that is characterised by abnormalities in the amount and architectural arrangement of bone tissue. Osteoporosis is a major clinical condition that can lead to fractures of bone following only minimal trauma. Osteoporosis results from a shift in the balance of bone resorption and formation towards resorption so that there is net bone loss. In addition to the distress to sufferers, the direct hospital costs of osteoporosis have been estimated, in the U.S. only, to approach $13 billion and in the UK to approach £750 million.
  • the term Osteoporosis' in fact refers to a group of conditions that are associated with loss of bone tissue and an accompanying architectural abnormality that occurs in cancellous bone space.
  • postmenopausal osteoporosis When the condition develops in post-menopausal women it is referred to as postmenopausal osteoporosis. Fractures occur commonly in the hip, spine and distal radius and are considered in many countries to be a major public health problem (Lindsay R (1993), Clinical Rheumatology Osteoporosis; V.7, No.3). While genetics, diet and life-style appear to be factors in the pathogenesis of the disease, loss of ovarian function is an important determinant, at least in postmenopausal osteoporosis.
  • osteoporotic-associated disease states include steroid induced osteoporosis, idiopathic juvenile osteoporosis, and posttransplantation osteoporosis where bone resorption is a secondary indication of disorder.
  • Paget's disease In the disease known as Paget's disease, there is excessive osteoclastic resorption of bone which results in excessive osteoblastic bone formation leading to disorganised bone structure.
  • Tumour-induced osteolysis may also lead to pathologically raised serum calcium levels, which are believed to increase significantly morbidity in cancer patients.
  • Oestrogen and other hormone replacements have a history of use for postmenopausal osteoporosis, either alone or in combination with other therapeutics.
  • suggestions of an increased risk of endometrial and breast cancer, as well as the continuation of menstrual bleeding, which is often unwelcome in the elderly female section of the population who form the majority of sufferers of osteoporosis, has provided a need for an alternative approach.
  • the most well established method for bone repair is the mechanical one, and this typically involves hard implants and hardware, such as plates, pins and screws.
  • hard implants Within the category of hard implants, there exist an array of plastics, organic-based synthetic cements and metal prostheses.
  • mechanical hardware and implants There are two major considerations and concerns in using mechanical hardware and implants. The first relates to the effectiveness of the physiological integration of the hardware into the body systems, while the second is that of the long-term durability of the non-biological material which has been implanted.
  • mechanical implants are very popular, and, while not comprising living bone tissue, make significant contributions assisting in the bone reconstruction.
  • Allogeneic bone sources These are widely used in orthopaedic surgery and come in a variety of forms (including demineralised bone matrix). Concern has been raised in the use of such material owing to, for example, the potential for disease transmission, and also the efficacy of the material following processing which may include, for example, freeze drying which is believed to reduce the potential for host bone integration.
  • Synthetic bone grafts These materials generally do not suffer from the limitations described above, although their use has been limited by their inability to overcome a biological impairment to bone healing. In this capacity, they represent a largely inert scaffold over/ through which bone can regenerate in certain limited indications.
  • BMPs bone morphogenic proteins
  • osteogenic stimuli which can overcome specific biological obstacles to bone healing, without the potential for associated morbidity of autograft, lack of efficacy of allograft and synthetic scaffolds, and potential super-physiological doses of other osteogenic stimuli.
  • Cartilage has a limited capacity for self repair.
  • the cartilage of the body can be damaged by physical knocks. Damaged cartilage is prone to further degeneration, i.e. osteoarthritis.
  • OA osteoarthritis
  • a major constituent of cartilage is collagen.
  • Collagen is one of the most abundant animal proteins in nature. It is present in all types of multicellular animals, including humans, where it is estimated to account for about 30% of the total human body protein. Collagen constitutes the fibrillar component of the soft connective tissues (e.g., skin, ligament, and tendon) and is the major component of the organic matrix of calcified tissues such as bone and dentine. In addition to its structural significance, collagen plays an important role in development and wound healing, and has been implicated in ageing and some disease processes.
  • soft connective tissues e.g., skin, ligament, and tendon
  • Type Il collagen is the major collagen of cartilage. It is synthesised by chondrocytes as a procollagen molecule with noncollagenous aminopropeptide and carboxypeptide extensions. These two extensions are removed by specific peptideases before type Il collagen is incorporated into fibrils.
  • cartilage we mean any cartilage of the animal or human body including but not limited to: articular, hyaline, meniscal and yellow-elastic cartilage.
  • musculo-skeletal tissue such as bone and cartilage
  • monobutyrin acts as a stimulus for promoting musculo-skeletal tissue repair, regeneration and formation.
  • Monobutyrin has surprisingly been found to be osteogenic.
  • Monobutyrin has surprisingly been found to be chondrogenic.
  • EINECS 209-165-5 Glycerol-alpha-mono-n-butyrate, NSC 8451 , alpha-Monobutyrin, 2,3-Dihydroxypropyl butyrate, Butanoic acid, 2,3-dihydroxypropyl ester.
  • Monobutyrin exists in three isomeric forms, having the chemical structures as illustrated in Figures 1-3. Monobutyrin spontaneously isomerises into these forms. For example at ambient room temperature monobutyrin isomerises to approximately 45%:10%:45% of R-l-monobutyrin: 2- monobutyrin:S-1- monobutyrin
  • Monobutyrin has been previously described as being pro- angiogenic, and has been used for the treatment of tumours and some other disorders.
  • composition for promoting musculo-skeletal tissue repair, regeneration and/or formation, the composition comprising;
  • the active compound monobutyrin is an ester composed of glycerol and butyric acid, and can be made simply in a laboratory setting by known means to the skilled person.
  • Embodiments of the invention include where the musculoskeletal tissue is bone, cartilage, synovium, muscle, tendon, ligament or meniscus.
  • the present invention can be used to treat bone repair, or induce bone growth without a large concentration of monobutyrin.
  • concentration of monobutyrin in the composition is preferably from about 100 ⁇ g/ml to 5mg/ml and even more preferably from about 10 ⁇ g/ml to 100 ⁇ g/ml.
  • the present invention can be used to treat cartilage repair, or induce cartilage growth without a large concentration of monobutyrin.
  • concentration of monobutyrin in the composition is preferably from about 100 ⁇ g/ml to 5mg/ml and even more preferably from about 10 ⁇ g/ml to 100 ⁇ g/ml.
  • Embodiments of the invention include where the composition stimulates osteogenesis in cells selected from the group consisting of embryonic stem cells, adult stem cells, osteoblastic cells, preosteoblastic cells and skeletal progenitor cells derived from bone, bone marrow or blood.
  • Embodiments of the invention include where the composition stimulates chondrogenesis in cells selected from the group consisting of embryonic stem cells, adult stem cells, chondrocytes, fibroblasts and skeletal progenitor cells derived from bone, bone marrow or blood.
  • the tissue to be repaired, formed or regenerated may be in vivo or in vitro.
  • the second agent is a bone anabolic agent.
  • the second agent is selected from the group consisting of bone morphogenetic factors, cartilage derived morphological protein, epidermal growth factor, fibroblast growth factor, platelet derived growth factor, parathyroid hormone, insulin-like growth factor, sodium fluoride, bisphosphonates, calcium carbonate, prostaglandins, vitamin D, vitamin K, oestrogen and mixtures thereof.
  • Embodiments of the invention include where the second agent and the pharmaceutically acceptable carrier are the same.
  • the second agent and the pharmaceutically acceptable carrier are the same.
  • calcium phosphate is the second agent and the pharmaceutically acceptable carrier.
  • bone fracture repair such as, non-union fractures, osteoporotic fractures
  • this invention may be used to treat other clinical conditions and diseases where the tissue healing response has been impaired by physiological abnormalities or injury.
  • Clinical conditions and diseases characterised by musculo- skeletal tissue loss which may benefit from this invention include, but are not restricted to; osteoporosis, arthritis, diabetes, cancer, Paget's disease, Sch ⁇ llers disease, renal bone dystrophy, brachypodism,
  • Embodiments of the invention include where osteoporosis is steroid-induced osteoporosis, idiopathic juvenile osteoporosis, postmenopausal osteoporosis, post-traumatic osteoporosis, senile osteoporosis.
  • Embodiments of the invention include where the arthritis is osteoarthritis or rheumatoid arthritis.
  • Embodiments of the invention include where the cancer is osteosarcoma or myeloma.
  • Embodiments of the present invention include where bone loss is induced by steroid use.
  • compositions of the invention can be prepared according to methods well known and called for by accepted pharmaceutical practice.
  • compositions suitably comprise the composition of the invention together with a pharmaceutically acceptable carrier and are suitably in unit dosage form.
  • Pharmaceutical compositions of the invention are suitable for administration either locally or systemically.
  • compositions of the invention are suitable for administration via the oral, parenteral, topical or intravenous routes.
  • Embodiments of the invention include where the pharmaceutical compositions are delivered from both aqueous and solid media.
  • Formulations will include dip coating of solid substrates with the pharmaceutical composition, mixing the pharmaceutical composition with aqueous solutions, powder coating and integration of the pharmaceutical composition into resorbable substrates among others.
  • Embodiments of the invention include where the pharmaceutical composition additionally comprises excipients, preservatives, solubilisers, buffering agents, albumin, lubricants, fillers, stabilisers and mixtures thereof.
  • composition is formulated in a form selected from the group consisting of a liquid solution, liquid emulsion, liquid suspension, coated capsules, pills, tablets, suppositories, lyophilized powders, transdermal patches, gels, ointments, lotions, creams and sprays.
  • the composition is provided as a liquid solution, emulsion or suspension encapsulated within a biodegradable vesicle selected from liposomes, microspheres and nanospheres, thereby enabling temporally- controlled release of the composition.
  • the composition is formulated in a biodegradable film, biodegradable coating or biodegradable matrix.
  • suitable pharmaceutical carriers include, for example, but are not restricted to, synthetic bone grafts (such as ceramic calcium phosphates), allogeneic bone grafts (such as demineralised bone matrix), autogenic bone grafts, gels (e.g. Hyaluranon), both injectable and non-injectable forms, synthetic polymers (such as polyhydroxyacids) and natural polymers (such as collagen), surgical fixation means (such as surgical screws, surgical pins, surgical rods or surgical plates).
  • composition can be mixed with or onto the surface of an appropriate carrier, or could be covalently linked to a carrier to allow specific release kinetics into the site of action.
  • monobutyrin and/or the second agent will be released from carrier over a time period that spans a minimum of the first 3 days of fracture up to 14 days post fracture.
  • the first 24-48 hours of fracture repair involve harsh conditions of tissue breakdown and turnover to prepare the fracture site. These conditions are likely to catabolise any active agent present at this time.
  • monobutyrin By releasing monobutyrin at beyond 3 days post fracture, where there is a proliferation and differentiation of the fracture repair cell types, proliferation and differentiation will be enhanced during the early stages of fracture repair.
  • compositions comprising monobutyrin can be formulated into/onto a number of different carriers, including:
  • Ceramics can be spray dried with a composition comprising monobutyrin, and the resultant ceramic can be dry powder compacted into an appropriate shape for implantation.
  • the compositions comprising monobutyrin can also been adsorbed onto the surface of tricalcium phosphate ceramics for subsequent implantation.
  • compositions comprising monobutyrin can be admixed to hyaluronic acid to provide an injectable formulation.
  • compositions comprising monobutyrin can be admixed into a polymer with an appropriate solvent, or could be covalently linked to a polymer to allow sustained/ delayed release of the active ingredient.
  • compositions comprising monobutyrin can be admixed with saline or other similar liquids/ solutions.
  • the monobutyrin and/or the second agent is coupled to a "bone-seeking" substance such as a tetracycline or bisphosphonates to improve target specificity as known by those skilled in the art.
  • a "bone-seeking" substance such as a tetracycline or bisphosphonates
  • Function manipulating agents of the invention may be manufactured according to any appropriate method of choice.
  • compositions of the invention can comprise a composition of the present invention in the form of a pro-drug which can be metabolically converted to the active form of the invention agent by the recipient host.
  • compositions of the present invention may also be used in conjunction, e.g. simultaneously, sequentially or separately with other therapies.
  • an implantable orthopaedic device comprising a composition comprising monobutyrin and/or derivatives, fragments and/or analogues thereof.
  • Embodiments of the invention include, for example where the implantable orthopaedic device is a prosthetic implant (such as an endoprosthesis e.g a hip implant), surgical screw (such as a bone screw), surgical nail (such as a intramedullary nail), surgical pin (such as a cartilage anchor pin), surgical rod, surgical plate, bone filler, autologous tissue graft, allogenic tissue graft or a scaffold.
  • a prosthetic implant such as an endoprosthesis e.g a hip implant
  • surgical screw such as a bone screw
  • surgical nail such as a intramedullary nail
  • surgical pin such as a cartilage anchor pin
  • surgical rod surgical plate, bone filler, autologous tissue graft, allogenic tissue graft or a scaffold.
  • compositions further comprises a second agent capable of promoting musculoskeletal tissue repair, regeneration and/or formation.
  • the second agent capable of promoting musculoskeletal tissue repair, regeneration and/or formation is preferably selected from the group consisting of bone morphogenetic factors, cartilage derived morphological protein, epidermal growth factor, fibroblast growth factor, platelet derived growth factor, parathyroid hormone, insulin-like growth factor, sodium fluoride, bisphosphonates, calcium carbonate, prostaglandins, vitamin D, vitamin K, oestrogen and mixtures thereof.
  • the composition is applied to a surface of the device, for example a bone-contacting surface or a cartilage-contacting surface.
  • the pharmaceutical composition of the invention is present as a layer, for example as a coating on a surface (e.g the bone- contacting surface or cartilage-contacting surface) of the device.
  • a surface e.g the bone- contacting surface or cartilage-contacting surface
  • medical devices according to the invention may be prepared by absorbing the composition onto, for example, the titanium oxide or other surface of a metallic surface or of a polymer surface, e.g. bone screw, by incorporating the composition into a carrier material and coating the carrier onto the medical device.
  • the pharmaceutical composition can be powder coated onto calcium sulphate powder and compacted into bone graft substitute materials, for example JAXTM (Smith & Nephew Inc, Community Trade Mark No. E2052611) to allow delivery of the composition into bone voids.
  • Calcium phosphate can also be dipped coated into the pharmaceutical composition to achieve the same end.
  • the bone- contacting surface or the cartilage-contacting surface has been 'derivatised' or modified such that the composition of the invention is directly bonded, aptly by covalent bonds, to the surface.
  • composition is impregnated within the device.
  • an artificial scaffold material for promoting musculo-skeletal tissue formation, the scaffold having operatively coupled thereto the composition of the invention.
  • an artificial scaffold material for promoting bone formation the scaffold having operatively coupled thereto the composition of the present invention.
  • an artificial scaffold material for promoting cartilage formation the scaffold having operatively coupled thereto the composition of the present invention.
  • the scaffold of the invention may in the form of a three dimensional matrix or layer, for example, a continuous film, or gel.
  • the matrix structure may be manufactured from fibres or a suitable material which is then textile processed (e.g. braided, knitted, woven or non-woven, melt-blown, felted, hydro-entangled) and further manipulated into a desired three dimensional shape.
  • the matrix structure may also assume other forms, e.g. sponges or foams.
  • Suitable scaffold materials are preferably biodegradable/resorbable and are not inhibitory to cell growth or proliferation. Typically the materials should not elicit an adverse reaction from the patients' body and should be capable of sterilisation by for example ethylene oxide treatment.
  • the material is osteoconductive.
  • Suitable materials therefore include, for example, biodegradable polyesters such as polylactic acid (PLA), polyglycolic acid (PGA), polydioxanone, polyhydroxyalkanoates, e.g. poly hydroxbuty rate (ICI) and hyaluronic acid derivatives, e.g. HYAFF (Fidia), hydrophilic polyurethanes, polyetherpolyester, polyethylene oxide, polyetherpolyamide, carboxymethylcellulose, ethylene-vinyl acetate copolymers, polybutadiene, styrene-butadiene-styrene block copolymers and the like.
  • Other scaffold materials are collagen based e.g.
  • cross-linked collagen/elastin material cross-linked collagen/elastin material
  • cross-linked collagens manufactured from acid-soluble type I bovine collagen sources collagen gels, (for example those sold under the trade names COLLASTAT and COLETICA).
  • Collagen from natural or recombinant sources may be used.
  • Modified or chimeric recombinant fibrillar collagens are also provided which incorporate a composition from the present invention and features that promote its assembly, stability and use as a biomaterial.
  • the modified collagen may be used as a scaffold material described supra.
  • Approaches include use of the C-terminal globular domain from type I collagen to promote triple helix formation; the removal or alteration of the collagenase cleavage site to suppress degradation; the inclusion of additional lysines to promote cross-linking and the alternation of N- terminal globular domain cleavage site to promote the retention of the N-terminal domain in the mature fibre.
  • the chordin/SOG sequence of collagen Ha could be substituted for the protein/polypeptide function manipulating agent.
  • Analogous domain shuffling approaches may be used to incorporate a composition of the present invention into other extracellular matrix components (e.g. fibronectin link protein or collagen IV) or ECM binding molecules or sequences (e.g. heparin binding domains). See, for example, WO 97/08311, the entire content of which are incorporated herein by reference.
  • extracellular matrix components e.g. fibronectin link protein or collagen IV
  • ECM binding molecules or sequences e.g. heparin binding domains.
  • a bone substitute material for example a bone void filler, comprising a composite material comprising any one of the above scaffold materials and a crystalline phase (e.g. an apatite such as hydroxyapatite) incorporating the composition of the invention.
  • the crystalline phase is an osteoinductive or osteoinductive phase.
  • a cartilage substitute material comprising a composite material comprising any one of the above scaffold materials and a crystalline phase (e.g. an apatite such as hydroxyapatite) incorporating the composition of the invention.
  • a crystalline phase e.g. an apatite such as hydroxyapatite
  • composition of the present invention is delivered as a scaffold in the form of a gel.
  • the gel will comprise thrombin, fibrinogen and Factor XIII or another transglutaminase to cross-link the gel.
  • composition is bound to a solid matrix and implanted to the desired orthopaedic site.
  • composition of the present invention preferably bound to a solid matrix, has the advantage over the prior art that excess monobutyrin produced naturally in the body are not wasted. Excess monobutyrin may be utilised or excreted from the body.
  • Allogeneic bone sources As a synthetic material, there is no potential for disease transmission • Synthetic bone grafts: We have demonstrated in a critical sized segmental defect that the bone repair is enhanced over and above that which can be attained with the use of a synthetic void filler. Specifically, we can demonstrate improved cortical bridging, a greater linear bone growth rate, and a higher bone density.
  • Another advantage of this therapy is that it takes advantage of a dual mode of action: the direct osteogenic effect of monobutyrin has been described above, but it also has a known angiogenic effect which will assist in the repair of bone tissue where there is vascular compromise for example in diabetes.
  • Bone may form through a process of endochondral ossification through which cartilage is laid down first and is then mineralised. In this way bone forms through cartilage formation and therefore any treatment that is found to heal bone can be presumed to stimulate cartilage formation and it can also be assumed that the converse is true.
  • the present invention can be used to treat cartilage repair, or induce cartilage growth without a large concentration of the growth factor being needed.
  • Using large concentrations of growth factors has been a problem to date as this suffers from the disadvantage that large concentration of the growth factor as noted above, can cause a shift in biological equilibrium possibly making the growth factor less potent.
  • composition comprising monobutyrin or derivatives, fragments and/or analogues thereof and a second agent capable of promoting musculo-skeletal tissue repair, regeneration and/or formation for use as a medicament.
  • the present invention can be used to treat bone repair, or induce bone growth without a large concentration of monobutyrin.
  • concentration of monobutyrin in the composition is preferably from about 100 ⁇ g/ml to 5mg/ml and even more preferably from about 10 ⁇ g/ml to 100 ⁇ g/ml.
  • Embodiments of the invention include where the musculo- skeletal tissue is bone, cartilage, synovium, muscle, tendon, ligament or meniscus.
  • the present invention can be used to treat cartilage repair, or induce cartilage growth without a large concentration of monobutyrin.
  • concentration of monobutyrin in the composition is preferably from about 100 ⁇ g/ml to 5mg/ml and even more preferably from about 10 ⁇ g/ml to 100 ⁇ g/ml.
  • Embodiments of the invention include where the second agent is selected from the group consisting of bone morphogenetic factors, cartilage derived morphological protein, epidermal growth factor, fibroblast growth factor, platelet derived growth factor, parathyroid hormone, insulin-like growth factor, sodium fluoride, bisphosphonates, calcium carbonate, prostaglandins, vitamin D, vitamin K, oestrogen and mixtures thereof.
  • the second agent is selected from the group consisting of bone morphogenetic factors, cartilage derived morphological protein, epidermal growth factor, fibroblast growth factor, platelet derived growth factor, parathyroid hormone, insulin-like growth factor, sodium fluoride, bisphosphonates, calcium carbonate, prostaglandins, vitamin D, vitamin K, oestrogen and mixtures thereof.
  • a method to promote musculoskeletal tissue repair, regeneration and/or formation in a subject comprising the step of administering to the subject a composition comprising monobutyrin and/or derivatives, fragments and/or analogues thereof.
  • bone fracture repair such as, non-union fractures, delayed fractures, mal- union fractures or osteoporotic fractures
  • this invention will benefit bone fracture repair (such as, non-union fractures, delayed fractures, mal- union fractures or osteoporotic fractures) it may be used to treat other clinical conditions and diseases where the tissue healing response has been impaired by physiological abnormalities or injury.
  • Clinical conditions and diseases characterised by musculoskeletal tissue loss which may benefit from this invention include, but are not restricted to; osteoporosis, arthritis, diabetes, cancer, Paget's disease, Sch ⁇ llers disease, renal bone dystrophy, brachypodism, Hunter-Thompson chondrodysplasia, a spinal deformation, bone dysplasia, scoliosis, peridonatal disease, osteomalacia or fibrous osteitis,
  • Embodiments of the invention include where osteoporosis is steroid-induced osteoporosis, idiopathic juvenile osteoporosis, post- menopausal osteoporosis, post-traumatic osteoporosis, senile osteoporosis.
  • Embodiments of the invention include where the arthritis is osteoarthritis or rheumatoid arthritis.
  • Embodiments of the invention include where the cancer is osteosarcoma or myeloma.
  • Embodiments of the present invention include where bone loss is induced by steroid use.
  • animal models useful in the investigation of musculo-skeletal tissue disorders For example, the role of monobutyrin in the skeletal system may be investigated using non-human mammalian, e.g. mouse.
  • Figure 1 shows a chemical structure of monobutyrin - the R-I- monobutyrin (chemical structure 1).
  • Figure 2 shows a chemical structure of monobutyrin - the 2- monobutyrin (chemical structure 2).
  • Figure 3 shows a chemical structure of monobutyrin - the S-1- monobutyrin (chemical structure 3).
  • Figure 4 shows a significant increase in alkaline phosphatase expression at day 3 only in primary human osteoblasts stimulated with 500 and 100O u g/ml monobutyrin.
  • Figure 5 illustrates the bone graft substitute JAXTM.
  • Example 1 ⁇ G-63 cells (osteoblast-like cells)
  • MG-63 cells were cultured in Eagle's minimal essential media with 10% foetal calf serum at 37 0 C and 5% CO 2 .
  • cells were seeded at 5x10 3 cells per well in 96 well plates. All cells were cultured with ascorbic acid (50 ⁇ g/ml) as standard. Cells were stimulated with either monobutyrin or BMP-2. Monobutyrin was dosed at 0.1%, 0.05% or 0.01 %v/v, either once at day 1 or daily for up to 5 days. BMP was dosed once only on day 0 at 100ng/well.
  • Cells were lysed at 1 , 3 and 5 days after the first dose and assayed for alkaline phosphatase using a standard 96 well format p-nitrophenyl phosphate (pNPP) assay. Briefly, cells were lysed in 200 ⁇ l of 0.2M carbonate buffer containing 0.1% Triton X-100 and freeze thawed three times. 50 ⁇ l of each cell lysate was added to 50 ⁇ l of pNPP working solution (40mg pNPP in 9ml 0.2M carbonate buffer pH10.2, 1ml 10OmM MgCI 2 , 20ml H 2 O).
  • pNPP p-nitrophenyl phosphate
  • dexamethasone as standard at 37°C and 5% CO 2 .
  • cells were seeded into 96 well plates at 5x10 3 cells per well. Cells were stimulated once with a dose range of monobutyrin (100, 500 and 1000 g/ml) or BMP-2 at 1 g/ml. Cells were subsequently cultured for 3, 7 or 9 days further before lysis for assaying for alkaline
  • Monobutyrin has been formulated onto both calcium sulphate JaxTM and collagen sponge for in-vivo delivery purposes.
  • Calcium sulphate was dry spray powder coated with monobutyrin before pressing into JaxTM.
  • Collagen sponge was soaked in an aqueous solution of monobutyrin.
  • a known dose range of monobutyrin was used in both studies.
  • a critical size (15mm) segmental defect was performed in the rabbit ulna and packed with either the monobutyrin formulated JAXTM granules or the monobutyrin formulated collagen sponge. Carrier only acted as negative controls. Animals were returned to normal load bearing and assessment of bone filling was performed at 12 weeks.
  • Table 2 Individual scores for each animal from each scorer
  • Figure 5 illustrates the bone graft substitute JAXTM, which is an example of an implantable orthopaedic device according to the present invention.
  • a bone graft is a procedure whereby material is placed in a bone void to provide an environment for and/or induce new bone growth.

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Abstract

L'invention concerne des compositions/médicaments, dispositifs et procédés de traitement de tissus squeletto-musculaires.
PCT/GB2006/002778 2005-07-28 2006-07-25 Composition WO2007012841A2 (fr)

Applications Claiming Priority (2)

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