GB2559761A - Composition for improved bone fracture healing - Google Patents
Composition for improved bone fracture healing Download PDFInfo
- Publication number
- GB2559761A GB2559761A GB1702549.5A GB201702549A GB2559761A GB 2559761 A GB2559761 A GB 2559761A GB 201702549 A GB201702549 A GB 201702549A GB 2559761 A GB2559761 A GB 2559761A
- Authority
- GB
- United Kingdom
- Prior art keywords
- parathyroid hormone
- formulation according
- derivative
- delivery
- bone
- 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.)
- Withdrawn
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- 239000000203 mixture Substances 0.000 title claims abstract description 37
- 208000010392 Bone Fractures Diseases 0.000 title claims abstract description 30
- 230000035876 healing Effects 0.000 title description 12
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- 229960001319 parathyroid hormone Drugs 0.000 claims abstract description 26
- 239000000199 parathyroid hormone Substances 0.000 claims abstract description 26
- 238000009472 formulation Methods 0.000 claims abstract description 25
- 239000000463 material Substances 0.000 claims abstract description 20
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims abstract description 16
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 12
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- XXUPLYBCNPLTIW-UHFFFAOYSA-N octadec-7-ynoic acid Chemical compound CCCCCCCCCCC#CCCCCCC(O)=O XXUPLYBCNPLTIW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims abstract description 12
- 239000004926 polymethyl methacrylate Substances 0.000 claims abstract description 12
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- 101001135770 Homo sapiens Parathyroid hormone Proteins 0.000 claims abstract description 8
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims abstract description 6
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Classifications
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Abstract
A formulation comprising (i) an osteoclast inhibitor; and (ii) a parathyroid hormone or derivative thereof wherein the osteoclast inhibitor and parathyroid hormone or derivative thereof are combined with a delivery material for delivery in a solid or liquid paste to a subject; and wherein the delivery material is selected from calcium sulphate, or mono-, di- or tri-calcium phosphate, calcium carbonate, an autograft bone material, an allograft, a synthetic allograft, a ceramic, a bioglass, a collagen sponge, carboxymethylcellulose or a polymethyl methacrylate (PMMA) bone cement, or a combination of any two or more thereof, is provided. Preferably the osteoclast inhibitor is selected from a RANKL antagonist, an osteoprotegerin (OPG) antagonist, a bisphosphonate such as zoledronic acid and/or alendronic acid, osteoprotegerin, calcitonin, minocycline, or combinations of any two or more thereof. Preferably the derivative of parathyroid hormone is selected from parathyroid hormone-related protein (PTHrP), 1-34 recombinant human parathyroid hormone (1-34 rhPTH), 1-84 recombinant human parathyroid hormone (1-84 rhPTH), H05AA03 parathyroid hormone, teriparatide, and abaloparatide, or combinations of any two or more thereof. Preferably the formulation is for use in the treatment of bone fractures and is delivered via injection.
Description
(54) Title of the Invention: Composition for improved bone fracture healing Abstract Title: Composition for improved bone fracturing healing (57) A formulation comprising (i) an osteoclast inhibitor; and (ii) a parathyroid hormone or derivative thereof wherein the osteoclast inhibitor and parathyroid hormone or derivative thereof are combined with a delivery material for delivery in a solid or liquid paste to a subject; and wherein the delivery material is selected from calcium sulphate, or mono-, di- or tri-calcium phosphate, calcium carbonate, an autograft bone material, an allograft, a synthetic allograft, a ceramic, a bioglass, a collagen sponge, carboxymethylcellulose or a polymethyl methacrylate (PMMA) bone cement, or a combination of any two or more thereof, is provided. Preferably the osteoclast inhibitor is selected from a RANKL antagonist, an osteoprotegerin (OPG) antagonist, a bisphosphonate such as zoledronic acid and/or alendronic acid, osteoprotegerin, calcitonin, minocycline, or combinations of any two or more thereof. Preferably the derivative of parathyroid hormone is selected from parathyroid hormone-related protein (PTHrP), 1-34 recombinant human parathyroid hormone (1-34 rhPTH), 1-84 recombinant human parathyroid hormone (1-84 rhPTH), H05AA03 parathyroid hormone, teriparatide, and abaloparatide, or combinations of any two or more thereof. Preferably the formulation is for use in the treatment of bone fractures and is delivered via injection.
Composition for Improved Bone Fracture Healing
The present invention relates to a composition for use i) in acute bone fractures at high risk of non-union, whether due to fracture-specific factors (i.e. the location of the fracture; or whether it is open or closed), or patient-specific factors; and ii) in chronic bone injuries that have already developed a delayed or non-union.
The total economic impact of musculoskeletal conditions represents $126 billion in the US alone, with approximately 6.8 million fractures requiring orthopaedic input annually. Of these 6.8 million fractures, approximately 300,000 per year will go on to develop slow (delayed) or incomplete (non-union) healing. Nonunion is a term generally used to refer to a fracture that has failed to heal within 9 months. In the UK, there are approximately 850,000 new fractures seen each year, of which the majority heals without any significant complication. Rates of non-union of 5-10% of fractures have been suggested. A proportion of these will be accounted for by fragility fractures due to poor bone density in elderly patients, as with an increasing global population and aging society, an ever-increasing number of fragility fractures occur worldwide. An estimated 200 million people worldwide suffer from osteoporosis, of which 40% of female sufferers and 15-30% of men will sustain one or more fragility fractures in their remaining lifetime. Typically, these patients demonstrate impaired fracture healing, with consequent increases in operative intervention, increased risk of complications and incidence of delayed and non-union healing. In addition, certain fractures are known for their poor healing potential; for example, scaphoid fractures carry an associated risk of non-union approaching 50%. As well as the fracture type (location, blood supply, open/closed), patient factors also determine fracture-healing potential, with, for example, diabetic patients, or those on long-term steroid and immunosuppressant therapy also demonstrating impaired fracture healing.
Delayed fracture healing and non-union present a particularly challenging problem for care providers and patients, and therefore the health system and social services supporting them. Their management typically requires large assets and longlasting therapies with often unsuccessful results.
Several studies have analysed the health economics of non-union, all demonstrating major increases in length of hospital stays, number of operations, and the lengths of follow up treatments. A 2007 paper by Kanakaris et al found that on average the cost of treatment for non-union ranged from £15,660 to £17,200, dependent upon the location of the fracture and treatment modality used. A separate paper by Dahabreh et al analyzed 25 fractures with non-union, and their economic analysis focused on the direct medical costs of in-hospital and outpatient treatments from the time of initial injury. A total of 127 hospital admissions, a mean hospital stay of 34.08 days and a mean of 5.36 operations per fracture were recorded. The average total cost of treatment per fracture that develops a non-union was found to be £21,183.05. This was in contrast to the same fractures if treated successfully, with an uncomplicated clinical course, costing from £3,003 to £3,119. Patil et al published a paper focusing on tibial and femoral non-unions treated with an Ilizarov frame. The mean number of operations undergone prior to the surgical intervention of the authors was 3. The estimated costs were derived from the 2004-2005 assessment of the Finance Department of their hospital, and were limited to the final phase of treating these 41 complicated cases with an Ilizarov frame. The average expenses reached the sum of £29,204 and represented the direct medical costs of this treatment option alone.
The cost to the UK National Health Service (NHS) of treating non-union has been reported to range between £7,000 and £79,000 per person. However, this does not take into account the morbidity and loss of earnings of the individual, nor any long-term health burden, so the cost to society will in fact be far greater than this. The overall burden in the UK on the National Health Service is therefore significant. Extrapolating up from an estimated 85,000 non-unions per annum in the UK would give a financial cost of £595 million to £6.7 billion based on available data, notwithstanding the patient burden of pain, associated depression, disability and time off work, with the resulting negative impact upon productivity and therefore economic impact on the nation as a whole.
The majority of health systems in Europe are tax-based government funded systems. As a result, a reduction in this burden by up to 50% would provide a significant health budget saving and improvement in quality of life. A best-case scenario of a reduction in incidence of 50% would deliver savings of £297.5 million to £3.6 billion per year.
Delayed and non-union fractures are typically managed with a combination of surgery and biological methods. Surgery involves either debridement of the non-union site and internal fixation such as plate fixation or over-reaming and intramedullary nailing, or external fixation systems such as Ilizarov circular frames. Biological methods revolve around filling osseous defects and encouraging the fracture repair process, either in the form of autologous bone graft, or bone graft substitutes - both allogenic or synthetic. Allogenic bone graft is available from cadaveric tissue donors, or commercially. Platelet rich plasma and bone marrow aspirate are also used in combination with a bone graft to enhance fracture healing, but are harvested from the patient, or donors, usually sourced from national tissue banks in the UK rather than commercial sources. In addition, orthobiologics are also starting to be used; chiefly the bone morphogenetic proteins (BMP) 2 and 7, with several studies demonstrating their ability to create ectopic bone formation by recruiting stem cells from distant sites and inducing osteoblast and chondrocyte differentiation at the fracture site. However, they have failed to become as pervasive as anticipated due to their relatively high cost, with one vial of BMP-7 costing £3000. Despite this, the benefit of orthobiologics in the treatment of fracture non-unions is emerging, with one study reporting a cost saving of 47% when treating non-unions with BMP-7 compared to traditional treatment methods alone.
It would therefore be desirable to develop a composition which is able to aid in the treatment of chronic bone injuries and fractures that have developed a delayed or non-union, and which are able to reduce the incidence of surgical methods in the treatment thereof. Ideally, such a composition would also be able to shorten the duration of fracture healing.
Therefore, in accordance with the invention, there is provided a formulation comprising:
i) an osteoclast inhibitor; and ii) a parathyroid hormone or a derivative thereof;
wherein the osteoclast inhibitor and parathyroid hormone or the derivative thereof are combined with a delivery material for delivery in a solid or liquid phase to a subject; and wherein the delivery material is selected from calcium sulphate, or mono-, di-, and tricalcium phosphates, calcium carbonate, an autograft bone material, an allograft, a synthetic allograft, a ceramic, a bioglass, a collagen sponge, carboxymethylcellulose or a polymethyl methacrylate (PMMA) bone cement, or a or combination of any two or more thereof.
The parathyroid hormone, or a derivative thereof, used in the formulation of the invention may be produced in, or derived from, any form.
Examples of osteoclast inhibitors that may be used in the formulation of the invention include, but are not limited to, a RANKE antagonist, such as osteoprotegerin, an osteoprotegerin (OPG) antagonist, a bisphosphonate (such as zoledronic acid or alendronic acid); calcitonin; or minocycline; or combinations or any two or more thereof.
The use of parathyroid hormone (PTH) acts two-fold in the composition of the invention; firstly, as a mesenchymal stem cell recruiter, increasing the number of cell substrate for use in the fracture repair process; and secondly, in increasing the longevity of osteoblasts involved in the fracture repair process. These effects have been demonstrated in animals exposed to high systemic doses of PTH, with emerging evidence in humans; however few studies to date have used topically applied PTH, and none have applied PTH via the preferred delivery method of the invention, which is discussed further below.
Examples of derivatives of parathyroid hormone which may be used in the formulation of the invention include, but are not limited to, parathyroid hormonerelated protein (PTHrP), 1-34 recombinant human parathyroid hormone (1-34 rhPTH), 1-84 recombinant human parathyroid hormone (1-84 rhPTH), H05AA03 parathyroid hormone, teriparatide, and abaloparatide, or combinations of any two or more thereof.
In summary, the composition of the invention acts in two ways. PTH increases the number of cells available at the fracture site for the fracture repair process; and the osteoclast inhibitors prevent unwanted osteoclast activity at this stage.
Also envisaged within the invention is that the formulation may further comprise one or more additives selected from vitamin D and its derivatives or isomers thereof, hydroxyapatite and its derivatives, vitamin E, selenium, zinc, magnesium, phosphate, or collagen. Examples of derivatives of vitamin D include 1,25(OH)2 vitamin D3 and its synthetic derivatives 1,24(OH)2 vitamin D3 and calcipotrio.
According to a further aspect of the invention, the formulation may further be combined with stem cells, such as mesenchymal stem cells.
The formulation of the invention may be administered to an affected area of the patient by any method apparent to a medical professional. However, according to one embodiment of the invention, the composition is mixed with a calcium sulphate paste for direct injection into a fracture site. In acute fractures, a percutaneous technique under fluoroscopic guidance could be used, whereas in a chronic injury, a small incision and osteotomy or drilling to access the fracture site may be needed. Once injected into a bony space its setting time is approximately 8 minutes, followed by a complete absorption time of 2-3 weeks, over which it elutes any added compounds. After this period, the product is absorbed entirely, leaving no trace either clinically or radiographically.
However, any of the other delivery material defined hereinabove may also be used to deliver the formulation to the body of a subject.
According to a further aspect of the invention, there is provided a method of manufacturing a formulation comprising an osteoclast inhibitor, and a parathyroid hormone or a derivative thereof, the method comprising combining amounts of an osteoclast inhibitor, and a parathyroid hormone or a derivative thereof, with an amount of a delivery material for delivery in a solid or liquid phase to a subject, wherein the delivery material is selected from calcium sulphate, or mono-, di-, and tri-calcium phosphates, calcium carbonate, an autograft bone material, an allograft, a synthetic allograft, a ceramic, a bioglass, a collagen sponge, carboxymethylcellulose or a polymethyl methacrylate (PMMA) bone cement, or a or combination of any two or more thereof.
According to a further aspect of the invention, there is provided a use of a formulation as defined hereinabove in the treatment of bone fractures. The treatment typically involves administering the composition to a patient in combination with a material comprising calcium sulphate, typically via injection.
According to a further aspect of the invention, there is provided a method of delivering a formulation as defined hereinabove into a human or animal body.
It is of course to be understood that the present invention is not intended to be restricted to the foregoing examples which are described by way of example only.
Claims (11)
1. A formulation comprising:
i) an osteoclast inhibitor; and ii) a parathyroid hormone or a derivative thereof;
wherein the osteoclast inhibitor and parathyroid hormone or the derivative thereof are combined with a delivery material for delivery in a solid or liquid phase to a subject; and wherein the delivery material is selected from calcium sulphate, or mono-, di-, and tri-calcium phosphates, calcium carbonate, an autograft bone material, an allograft, a synthetic allograft, a ceramic, a bioglass, a collagen sponge, carboxymethylcellulose or a polymethyl methacrylate (PMMA) bone cement, or a or combination of any two or more thereof.
2. A formulation according to claim 1, wherein the osteoclast inhibitor is selected from a RANKL antagonist, an osteoprotegerin (OPG) antagonist, a bisphosphonate, osteoprotegerin, calcitonin, minocycline, or combinations of any two or more thereof.
3. A formulation according to claim 1 or claim 2, wherein the bisphosphonate is zoledronic acid and/or alendronic acid.
4. A formulation according to any preceding claim, wherein the derivative of the parathyroid hormone is selected from parathyroid hormone-related protein (PTHrP), 1-34 recombinant human parathyroid hormone (1-34 rhPTH), 1-84 recombinant human parathyroid hormone (1-84 rhPTH), H05AA03 parathyroid hormone, teriparatide, and abaloparatide, or combinations of any two or more thereof.
5. A formulation according to any preceding claim, further comprising one or more additives selected from vitamin D and its derivatives or isomers thereof, hydroxyapatite and its derivatives, vitamin E, selenium, zinc, magnesium, phosphate, or collagen.
6. A formulation according to any preceding claim, further comprising stem cells.
7. A formulation according to claim 6, wherein the stem cells are mesenchymal stem cells.
8. A method of manufacturing a formulation according to any preceding claim, the method comprising combining amounts of an osteoclast inhibitor, and a
5 parathyroid hormone or a derivative thereof with an amount of a delivery material for delivery in a solid or liquid phase to a subject, wherein the delivery material is selected from calcium sulphate, or mono-, di-, and tri-calcium phosphates, calcium carbonate, an autograft bone material, an allograft, a synthetic allograft, a ceramic, a bioglass, a collagen sponge,
10 carboxymethylcellulose or a polymethyl methacrylate (PMMA) bone cement, or a or combination of any two or more thereof.
9. Use of a formulation according to any of claims 1-7 in the treatment of bone fractures.
10. A method of delivering a formulation according to any of claims 1-7 into a
15 human or animal body.
11. A method according to claim 10, wherein the composition is delivered via injection.
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| CN113880474A (en) * | 2021-02-08 | 2022-01-04 | 武汉理工大学 | High-strength injectable magnesium phosphate bone cement and preparation method thereof |
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| GB2587744A (en) * | 2019-12-24 | 2021-04-07 | Corthotec Ltd | Composition for improved bone fracture healing |
| WO2021130479A1 (en) * | 2019-12-24 | 2021-07-01 | Corthotec Ltd | Composition for improved bone fracture healing |
| GB2590692A (en) * | 2019-12-24 | 2021-07-07 | Corthotec Ltd | Composition for improved bone fracture healing |
| GB2587744B (en) * | 2019-12-24 | 2021-08-25 | Corthotec Ltd | Composition for improved bone fracture healing |
| US20220111122A1 (en) * | 2019-12-24 | 2022-04-14 | Corthotec Ltd | Composition for improved bone fracture healing |
| CN114929297A (en) * | 2019-12-24 | 2022-08-19 | 科索泰克有限公司 | Composition for improving fracture healing |
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| Publication number | Publication date |
|---|---|
| GB201702549D0 (en) | 2017-04-05 |
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