Apatite-coated solid composition

Details Apatite-coated solid composition Apatite-coated solid composition

1999-10-20

2002-02-05

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S457000, C424S462000, C424S486000, C424S489000, C424S490000, C424S463000, C514S772300, C514S963000

Reexamination Certificate

active

06344209

ABSTRACT:

This application is the National Stage of International Application No. PCT/JP98/01870, filed Apr. 23, 1998.
TECHNICAL FIELD
The present invention provides an apatite-coated solid composition containing a biodegradable polymer, an apatite-coated solid composition containing a biodegradable polymer and a medicinal substance, and a method for producing the solid composition.
BACKGROUND ART
The bone and teeth of vertebrates are composed of 70% of a mineral phase and 30% of an organic matrix, with the constitution of the mineral phase closely resembling that of hydroxyapatite. Therefore, investigations into the possible utilization of apatite as a biological material began around 1970. As substitutes for bone, metallic materials such as stainless steel, cobalt-chromium alloy, titanium alloys, etc. and organic compounds such as high density polyethylene, polymethyl methacrylate, etc. had been used for some time. However, since those materials are incapable of being fused directly to the bone tissue, loosening and breakage of the implants occur with a high incidence, inducing adverse responses such as chronic inflammation of the surrounding tissue. To secure a firmer fusion to bone, a technology comprising coating the surface of such a material with hydroxyapatite by, for example, sputtering or plasma spray coating has been developed and is in practice.
Various contrivances were made for securing a firm fusion of biochemical materials to bone, and it was discovered that when SiO
2
—Na
2
O—CaO—P
2
O
5
type glass is implanted in bone, an intimate chemical coupling takes place. Further improvements led to the development of an alkali metals-free glass ceramic comprising apatite and wollastonite crystals (the A—W glass ceramic) starting with a powder of SiO
2
—CaO—P
2
O
5
—MgO—CaF
2
glass via sintering and crystallization. The research into the mechanism of fusion of this material to bone is well-documented and in view of its high mechanical strength, this material has been clinically applied with success as bone graft substitutes for iliac bone and vertebrae.
It was confirmed that between the A—W glass ceramic and bone, there exists a layer of fine poorly oriented apatite crystals formed from the ions released from the A—W glass ceramic and the body fluid components, so that the bone and the implant are intimately bound through this layer. The mechanisms of formation of such an apatite layer have been analyzed using a buffer solution called “simulated body fluid” (SBF) which is free of high molecular components such as proteins and has been prepared to match the body fluid only in the concentrations of ions (Manual of Materials for Orthopaedic Materials, Kanehara & Co., Ltd.). It is reported that by taking advantage of such properties of the A—W glass ceramic, an apatite layer could be formed on an organic polymer such as poly(ethylene terephthalate) by immersing the polymer and A—W glass ceramic together in a simulated body fluid (Journal of Biomedical Materials Research, 29, 349-357, 1995). In connection with this technology, it has been recommended that the surface of the polymer be pretreated by glow discharge.
Regarding the exploitation of biodegradable-absorbable polymers in the development of injectable bone substitutes, it has been reported that in an implantation experiment, new bone formation took place in line with the degradation and absorption of a polylactic acid (PLA)-hydroxyapatite (HA) complex, suggesting the possibility of clinical application of such polymers as bone implants (Collection of Papers on Polymers, 42 (11), 771-776, 1985).
Bone remodelling has been confirmed with an implant material comprising either PLA or poly (DL-lactide-co-glycolide) (PLGA) as a carrier and an osteoinductive factor (bone morphogenetic protein, BMP) or a material comprising a complex of said polymer and hydroxyapatite as a carrier and BMP (Abstract of Lectures at the 24th Medical Polymer Symposium, pages 65-66).
Furthermore, it has been reported that in an experiment involving the implantation of a PLA-polyethylene glycol (PEG) block copolymer-BMP complex or a ternary complex containing hydroxyapatite in addition to the above combination at sites of osseous defect they regenerate bone tissues (Clinical Orthopaedics and Related Research, No. 294, pp. 333-343, 1993), thus suggesting their clinical applicability as bone implants.
Powders containing pharmacologically active substances having an activity of promoting bone formation are useful for the therapy of various diseases of bone (e.g. osteoporosis and bone fracture) by injecting or implanting the powder containing such a pharmacologically active substance. Furthermore, applicability of such powders can be expanded in scope and the effect improved by adding new functions such as sustained release and biodegradability to such powders. Meanwhile, it is known that apatite is composed of calcium phosphate just as is bone, thus having a very high affinity for bone and that, therefore, when administered to a host body, apatite does not induce foreign-body reactions such as immune responses, thus being of great utility. However, pharmacologically active substances and powder materials are generally incapable of withstanding the tortuous conditions of sputtering, plasma spray coating, and other coating operations but undergo degradation in their course.
DISCLOSURE OF INVENTION
The inventors of the present invention thought it possible to effectively exploit the pharmacologic action of a powder containing a drug substance by covering the surface of the powder with apatite and did intensive investigations. As a result, they found that when a powder is immersed in an aqueous solution containing various ions, an apatite coating layer is formed on the surface of the particles with good efficiency under mild conditions. The finding was followed by further research which has culminated in the present invention.
The present invention is:
(1) An apatite-coated solid composition containing a biodegradable polymer,
(2) A solid composition according to item (1), which contains a medicinal substance,
(3) A solid composition according to item (2), which comprises a sustained release preparation,
(4) A solid composition according to item (1), wherein the biodegradable polymer is polylactic acid, polyglycolic acid, or a copolymer of polylactic acid and polyglycolic acid,
(5) A solid composition according to item (2), wherein the medicinal substance is hardly soluble in water,
(6) A solid composition according to item (2), wherein the medicinal substance is a medicine for prophylaxis or treatment of bone diseases, an antibiotic, an anti-inflammatory agent or an anti-tumor agent,
(7) A solid composition according to item (1), wherein the apatite is a crystalline mineral substance which has (1) at least one cation selected from the group consisting of Na
+
, K
+
, H
+
, Ca
2+
, Sr
2+
, Ba
2+
, Pb
2+
, Zn
2+
, Cd
2+
, Mg
2+
, Fe
2+
, Mn
2+
, Ra
2+
, Al
3+
, Y
3+
, Ce
3+
, Nd
3+
, La
3+
and Dy
3+
, and (2) at least one anion selected from the group consisting of SO
4
2−
, CO
3
2−
, HPO
4
2−
, PO
3
F
2−
, PO
4
3−
, AsO
4
3−
, VO
4
3−
, BO
3
3−
, CrO
4
3−
, SiO
4
3−
, GeO
4
3−
, (CO
3
F)
3−
and BO
4
5−
,
(8) A solid composition according to item (1), wherein the apatite is hydroxyapatite,
(9) A solid composition according to item (1), wherein the apatite is phosphate apatite,
(10) A solid composition according to item (1), which is in a microcapsule preparation,
(11) A solid composition according to item (1), wherein the apatite layer has a honeycomb structure,
(12) A solid composition according to item (1), wherein the apatite layer is about 1 nm to 50 &mgr;m,
(13) A method for producing an apatite-coated solid composition containing a biodegradable polymer, which comprises subjecting a substrate of a solid composition containing a biodegradable polymer to immersion in an aqueous ion solut

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