Patent Application
20110189296
The present invention relates to a new chemical composition for a bone substitute, composed of a mixture of porous bioglass and calcium sulfate.
Bone defects encountered in orthopedic surgery and in dentistry have been treated with bone grafting for some time. The graft is either taken from the patient (autograft), which involves an additional surgical intervention, or obtained from a human tissue bank (allograft), which is associated with higher costs and risks of contamination. There have also been endeavors to use chemical bone substitutes in surgery for some time.
For more than a century, calcium sulfate (“plaster of Paris”) has been used to correct bone defects (for filling osteitis cavities and vertebral abscesses in osseous tuberculosis, etc.) with noteworthy results. Calcium sulfate supplies the necessary material (Ca++) and scaffold for new bone growth. Nevertheless, it has two disadvantages: it is too rapidly resorbed and does nothing to stimulate bone growth.
There are other chemical substitutes currently in use, for example:
HAP (hydroxyapatite)
Biphasic HAP
HAP carbonate
Beta-TCP (biphasic calcium phosphate)
DCPD (dicalcium phosphate dihydrate)
HAP+silicon
HAP+collagen
Calcium sulfate
Calcium sulfate+PLLA
Bioglass (“Bioglass”®)
Porous bioglass
and possible combinations of these products.
Some of these products and chemical compounds (HAP, beta-TCP, and DCPD) have the disadvantage of being very slowly resorbed by the body and thus their presence prevents new bone growth.
Bioglass is resorbable. The resorption time varies inversely with the contact surface. Hence porous bioglass, which exhibits a substantial contact surface with body fluids, will be rapidly resorbed compared to unrefined bioglass.
Of the 47 commercially available bone substitutes surveyed by the AAOS (American Academy of Orthopedic Surgeons, January 2008), none correspond to the ideal bone substitute.
Other reference articles in this field include:
Kelly, C. M. et al., “The Use of a Surgical Grade Calcium Sulfate as a Bone Graft Substitute,” Clin. Orthop. Rel. Res. 382, 2001, pp. 42-50.
Peltier, L. F., “The Use of Plaster of Paris to Fill Defects in Bone,” Clin. Orthop. Rel. Res. 21, 1961, pp. 1-31.
Alexander, D. et al., “Efficacy of Calcium Sulfate Plus Decompression Bone in Lumbar and Lumbosacral Spinal Fusion: Preliminary Results in 40 patients,” Can. J Surg. 44(4), 2001, pp. 262-266.
It can thus be stated that the required characteristics of an ideal bone substitute are:
Of the chemical products suitable for implantation in the body of a mammal (human being, among others), mention can be made of:
Medical grade calcium sulfate (CaSO4, “plaster of Paris”) has been in use for over a century as a bone substitute for correcting bone defects, with noteworthy results. It provides the calcium needed for reconstructing bone, it is osteoconductive, malleable, and injectable, provides rapid mechanical anchoring (sets rapidly), and is rapidly resorbed (in 4 to 8 weeks). It is currently in widespread use and sold as a bone substitute under the trade names
Theoretically, the two chemical products (bioglass and calcium sulfate) are complementary; hence mixing them should give rise to an ideal bone substitute as defined above. However, the mixing and preparation of unrefined bioglass granules and plaster of Paris turns out to be unsuitable because CaSO4 will not set in the presence of unrefined bioglass.
In contrast, it has been shown that porous bioglass obtained from unrefined bioglass as defined in the document WO 2006/018531 A2, in granular form and under certain conditions, is capable of forming a mixture with calcium sulfate that is injectable, sets rapidly, and provides excellent mechanical resistance.
The present invention relates to such a composition of porous bioglass granules and calcium sulfate, and more particularly to a powdery composition for a bone substitute comprising powdery or granular porous bioglass and powdery calcium sulfate alpha-hemihydrate.
According to a preferred characteristic of the invention, the composition comprises 0.25 to 5 parts by weight of calcium sulfate alpha-hemihydrate per 1 part of bioglass.
According to another preferred particularity of the invention, the particle size distribution of the porous bioglass is in the range of between 0 and 1,000 microns (more particularly between 1 and 1,000 microns).
The first material, porous bioglass (such as that supplied by the company “Noraker”), may be present in the form of granules of variable sizes, namely:
According to the invention, the size of the porous bioglass granules is critical.
Granules from 1 to 90μ in size result in too slow a setting of the mixture. On the other hand, granules 900μ in size result in good setting of the mixture, but detract from injectability due to their excessively large size.
According to a preferred characteristic of the invention, the ideal size is in the range of between 100 and 300μ.
The second material, calcium sulfate hemihydrate, is present in the form of a fine powder which, when mixed with water, chemically reacts to form calcium sulfate dihydrate, which exhibits particularly high mechanical resistance.
Calcium sulfate hemihydrate occurs in two crystalline forms: alpha-hemihydrate and beta-hemihydrate. When mixed with water, the alpha form will produce a more solid dihydrate than the beta form and will be resorbed more slowly in vivo (around 30 days for the beta form vs. 50 days for the alpha form).
Hence it is imperative to choose an alpha-hemihydrate for the composition of the invention. The latter may be obtained from the dihydrate either by a special heating process or by a chemical process (dehydration of the dihydrate by heating in diluted sulfuric acid solution).
An alpha-hemihydrate powder is sold under the trade name CAPSET® by the company Lifecore (Chaska, Minn.).
In order for setting to occur rapidly, it is highly preferable to add a set accelerator. According to a preferred characteristic of the invention, the composition thus comprises at least one set accelerator chosen from among:
Preference is given to the calcium sulfate dihydrate having a particle size distribution ranging from 10 to 100 microns.
The company Lifecore (Chaska, Minn.) markets a pre-loaded alpha-hemihydrate under the trade name of CAPSET®.
The powdery composition of the invention preferably comprises 1 to 15 wt % calcium sulfate dihydrate in proportion to calcium sulfate alpha-hemihydrate, and more particularly
The porous bioglass used preferably has a porosity (measured by a geometric method) of 50 to 80%, with macropores having a mean diameter of 100 to 1250 microns and micropores having a mean diameter ≦5 microns, and preferably has a content of 40 to 55 wt % SiO2, 15 to 25 wt % CaO, 15 to 25 wt % Na2O, and 1 to 9 wt % P2O5.
A preferred powdery composition of the invention comprises:
The mixture can be prepared as follows: the CaSO4 alpha-hemihydrate and CaSO4 dihydrate powders and the porous bioglass granules are dry-mixed in a vessel at ambient temperature. NaCl and/or hydroxypropyl methylcellulose is optionally added to the mixture.
The invention also relates to a composition for an injectable bone substitute comprising a powdery composition as described above, mixed with deionized water, at ambient temperature. Preference is given to mixing the preparation for thirty seconds.
A preferred composition for an injectable bone substitute of the invention comprises:
The setting of the CaSO4 alpha-hemihydrate/CaSO4 dihydrate/porous bioglass granules/deionized water mixture, with or without added NaCl and/or hydroxypropyl methylcellulose, takes place in three phases:
The optionally added hydroxypropyl methylcellulose acts as a plasticizer capable of improving the injectability of the mixture. The NaCl can be used as a supplementary set accelerator.
The bone substitute compositions according to the invention are injectable, osteoconductive, osteoinductive, resorbable, and exhibit a mechanical resistance comparable to that of bone.
A composition for an injectable bone substitute according to the invention is achievable with:
The first three materials are dry-mixed, and then added to the water and mixed for 30 seconds. The mixture remains injectable for 4 minutes (until the IST). The final setting time (FST) is 10 minutes.
Another composition for an injectable bone substitute according to the invention is achievable with:
The mixture remains injectable for 6 minutes and final setting occurs after 17 minutes.
A composition for an injectable bone substitute according to the invention is achievable as in example 2, with 1 gram of hydroxypropyl methylcellulose added.
The viscosity of the mixtures of examples 1-3 during the preparation phase prior to the initial setting (IST) is such that said mixtures are injectable with a syringe or capable of being manipulated like finishing putty.
The weak exothermic reaction (<40° C.) that takes place as the mixture sets allows the incorporation of pharmaceutical agents in the mixture. Examples thereof include antibiotics (gentamicin, tobramycin, cephalosporins, vancomycin, etc.), chemotherapeutic agents (cis-platinum, methotrexate, isofosfamide, etc.), analgesics (lidocaine, etc.).
The two main constituents of the composition will exhibit different resorption rates after implantation in the body of a mammal (human being, among others).
Calcium sulfate is resorbed first, disappearing in approximately 50 days, and this resorption gradually allows the porous bioglass to come into contact with the tissues. Bioglass is more slowly resorbed, thus allowing it to exert its osteostimulation effect. The graduated resorption of the two constituents thus takes place at a rate corresponding to the speed of new bone growth.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2008/0474 | Aug 2008 | BE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP09/60874 | 8/24/2009 | WO | 00 | 4/19/2011 |
