Controlled release composite

Details Controlled release composite Controlled release composite

2001-11-01

2004-06-22

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S489000

Reexamination Certificate

active

06753007

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to controllably dissolving a composite.
Controlled release of medication in vivo is the subject of much research. Various methods and release agents have been suggested, tested and marketed. Calcium sulfate has been utilized as filler for bone cavities as it is capable of being spontaneously adsorbed and replaced by bone. Calcium sulfate, formed from the hemihydrate, has been used as a controlled release agent alone for the filling of bone cavities and in combination with additives such as medicaments and pesticides. As a carrier for medicaments, it has been useful in vivo because it is biocompatible and is progressively resorbed by the body, thereby eliminating the need for secondary surgical procedures.
One application for a calcium sulfate controlled release agent is the local delivery of medicaments in vivo. The ideal characteristics of a local medicament delivery system are (1) biodegradability, (2) biocompatibility, (3) prolonged pharmaceutical release (e.g., over a period of at least 4 to 6 weeks), (4) reproducibility, (5) predictable pharmacokinetics, and (6) controllability.
One of the disadvantages to the use of calcium sulfate as a carrier is that, for some medicaments, the medicament is eluted from the calcium sulfate matrix at too rapid of a rate.
SUMMARY OF THE INVENTION
In general, the invention features a composite having a controlled rate of dissolution. The composite includes at least two regions, each of which includes a composition that includes calcium sulfate. A first region of the composite exhibits a rate of dissolution that is different from a second region of the composite. These composites are useful for filling bone voids and for delivering calcium and medicaments in vivo for sustained periods of time. In one embodiment, the regions are in the form of layers. In another embodiment, the first region surrounds the second region.
The preferred calcium sulfate is selected from the group consisting of alpha-calcium sulfate hemihydrate, beta-calcium sulfate hemihydrate, calcium sulfate dihydrate prepared from alpha-calcium sulfate hemihydrate, calcium sulfate dihydrate prepared from beta-calcium sulfate hemihydrate, and combinations thereof.
In one embodiment, the first composition further includes a medicament, preferably a medicament selected from the group consisting of tetracycline hydrochloride, vancomycin, tobramycin, gentamicin, cephalosporin, cis-platinum, ifosfamide, methotrexate, doxorubicin hydrochloride, transforming growth factor beta, bone morphogenic protein, demineralized bone matrix (“DBM”), basic fibroblast growth factor, platelet-derived growth factor, polypeptide growth factors, lidocaine hydrochloride, bipivacaine hydrochloride, ketorolac tromethamine, or a combination thereof. In another embodiment, the second composition also includes a medicament.
In one embodiment, the first composition includes calcium sulfate dihydrate prepared from alpha-calcium sulfate hemihydrate, and preferably, the second composition includes calcium sulfate dihydrate prepared from beta-calcium sulfate hemihydrate.
Preferred compositions are prepared by contacting with an aqueous liquid an alpha-calcium sulfate hemihydrate having a mean particle size of from about 12 &mgr;m to about 23.5 &mgr;m. In one embodiment, at least 80% of the alpha-calcium sulfate hemihydrate has a particle size of from about 12 &mgr;m to about 22 &mgr;m more preferably from about 16 &mgr;m to about 22 &mgr;m. In preferred composites, from about 0.1% to about 2.0% of the alpha-calcium sulfate hemihydrate has a particle size of less than about 2 &mgr;m. In one embodiment, the alpha-calcium sulfate hemihydrate has a density of from about 2.6 to about 2.9 g/cm
3
. In other embodiments, the alpha-calcium sulfate hemihydrate has a purity greater than 98 wt. % calcium sulfate hemihydrate. The preferred range for the BET surface area of the alpha-calcium sulfate hemihydrate is from about 0.2 m
2
/g to about 1.0 m
2
/g.
Preferably the calcium sulfate is prepared from alpha-calcium sulfate hemihydrate having a purity greater than 98 weight % (“wt. % ”) calcium sulfate hemihydrate, a BET surface area in the range of from about 0.35 m
2
/g to about 0.9 m
2
/g, a density in the range of from about 2.73 to about 2.80 g/cm
3
, and a mean particle size of about 16 &mgr;m to about 22 &mgr;m. Preferably from about 90 to about 95 wt. % of the alpha-calcium sulfate hemihydrate has a particle size distribution from about 1 &mgr;m to about 45 &mgr;m.
In one embodiment, the first composition is prepared by contacting with an aqueous liquid calcium sulfate consisting essentially of beta-calcium sulfate hemihydrate having a mean particle size in the range of from about 10 &mgr;m to about 15 &mgr;m. In other embodiments, the beta-calcium sulfate hemihydrate has a purity greater than 98 wt. % calcium sulfate hemihydrate. The beta-calcium hemihydrate can also have a BET surface area of from about 4.5 m
2
/g to about 7.5 m
2
/g, more preferably from about 5 m
2
/g to about 6 m
2
/g, and a density of from about 2.5 g/cm
3
to about 2.6 g/cm
3
. In another embodiment, the first composition is prepared by contacting with an aqueous liquid calcium sulfate consisting essentially of beta-calcium sulfate hemihydrate having a purity greater than 98 wt. % calcium sulfate hemihydrate, a BET surface area in the range of from about 4.5 m
2
/g to about 7.5 m
2
/g, a density in the range of from about 2.5 g/cm
3
to about 2.6 g/cm
3
, and a mean particle size in the range of from about 13 &mgr;m to about 14 &mgr;m.
In another aspect, the invention features a method of delivering medicament in vivo. The method includes implanting the above-described composite into a mammal.
The composite of the invention permits the controlled dissolution of regions that include a calcium sulfate composition, as well as the controlled release of additives such as, e.g., medicaments and pesticides.
Other features and advantages of the invention will be apparent form the following description of the preferred embodiments thereof, and from the claims.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The composite includes two regions that exhibit different rates of dissolution with respect to each other. The regions of the composite are macroscopic and can exist in a variety of forms in the composite such as, e.g., layers and geometrical shapes, e.g., spheres. The regions can be continuous or discontinuous, and one or more regions can exist within another region or regions.
The regions consist of compositions that include calcium sulfate and, optionally, an additive. Examples of sources of calcium sulfate suitable for use in preparing the compositions include alpha-calcium sulfate hemihydrate powder, beta-calcium sulfate hemihydrate powder, calcium sulfate dihydrate powder made from calcium sulfate hemihydrate powders including alpha-calcium sulfate hemihydrate and beta-calcium sulfate hemihydrate, and combinations thereof.
A preferred alpha-calcium sulfate hemihydrate powder has a purity greater than 98 wt. % calcium sulfate hemihydrate, a BET surface area of from about 0.2 m
2
/g to about 1.0 m
2
/g (preferably from about 0.35 m
2
/g to about 0.9 m
2
/g, more preferably from about 0.35 m
2
/g to about 0.7 m
2
/g), a density of about 2.6 g/cm
3
to about 2.9 g/cm
3
(more preferably from about 2.73 g/cm
3
to about 2.80 g/cm
3
), and a mean particle size of from about 12 &mgr;m to about 23.5 &mgr;m. Preferably from about 0.1% to about 2.0% of the alpha-calcium sulfate hemihydrate has a particle size of less than about 2.0 &mgr;m. Preferably at least 80% of the alpha-calcium sulfate hemihydrate has a particle size of from about 12 &mgr;m to about 22 &mgr;m, more preferably from about 16 &mgr;m to about 22 &mgr;m.
A preferred beta-calcium sulfate hemihydrate powder has a purity greater than 98 wt. % calcium sulfate hemihydrate, a BET surface area of from about 4.5 m
2
/g to about 7.5 m
2
/g (more preferably from about 5 m
2
/g to about 6 m
2
/g), a density of from about 2.5 g/cm
3
to about 2.6 g/cm
3
,

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