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Review
Abstract
Since calcium phosphate cements were proposed, several formulations have been developed, some of them commercialised, and they have
proven to be very efficient bone substitutes in different applications. Some of their properties, such as the injectability, or the low-temperature
setting, which allows the incorporation of different drugs, make them very attractive candidates as drug carriers. In this article, the performance of
calcium phosphate cements as carriers of different types of drugs, such as antibiotics, analgesics, anticancer, anti-inflammatory, as well as growth
factors is reviewed.
2006 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Why calcium phosphate cements? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Calcium phosphate cements as drug carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Drug-release kinetics from calcium phosphate cements . . . . . . . . . . . . . . . . . . . . . . . .
Calcium phosphate cements as carriers for antibiotics. . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Effect of antibiotic incorporation on the physico-chemical properties of CPC . . . . . . . . .
5.2. Antibiotic release kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. In vivo performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Calcium phosphate cements as carriers for other drugs: anti-inflammatory, analgesic and anticancer .
7. Calcium phosphate cements as carriers for growth factors and other proteins . . . . . . . . . . . .
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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103
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Abbreviations: ACP, amorphous calcium phosphate; BMP, bone morphogenetic protein; CPC, calcium phosphate cement; DCP, dicalcium phosphate, CaHPO4;
DCPD, brushite, dicalcium phosphate dihydrate CaHPO42H2O; HA, hydroxyapatite, Ca10(PO4)6(OH)2; MCPM, monocalcium phosphate monohydrate Ca
(H2PO4)2H2O; MRSA, Staphylococcus aureus resistant to Meticilin-Cefem; PLGA, poly(lactic-co-glycolic acid); PMMA, poly(methyl methacrylate); rhTGF-1,
human recombinant-transforming growth factor-1; rhBMP-2, human recombinant-bone morphogenetic protein-2; SBF, simulated body fluid; -TCP, alphatricalcium phosphate, -Ca3(PO4)2; -TCP, beta-tricaclium phosphate, -Ca3(PO4)2; TTCP, tetracalcium phosphate, Ca4(PO4)2O; TGF, transforming growth factor;
TGF-SF, superfamily of transforming growth factor-beta.
Corresponding author. Tel.: +34 93 4011089; fax: +34 93 4016706.
E-mail address: maria.pau.ginebra@upc.edu (M.P. Ginebra).
0168-3659/$ - see front matter 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2006.04.007
1. Introduction
The increased life expectancy in the developed countries has
led to a serious rise in the number of musculoskeletal disorders,
such as osteoporosis and osteoarthritis. However, also the
number of medications to treat and even prevent these diseases
has expanded in recent years [1]. The development of new drugs
and active substances, allows treating some of these diseases
even in their initial stages.
A key issue in these treatments is to maximize the drug
access to specific bone sites, and to be able to control the
release of drugs, in order to maintain a desired drug
concentration level for long periods of time without reaching
a toxic level or dropping below the minimum effective level
[2]. For this reason, a major effort has been done focused on
the development of materials that are capable of releasing
drugs by a reproducible and predictable kinetics. Although
most of these drug carriers are polymers, in the specific field of
the pharmacological treatment of skeletal disorders, some
inorganic materials can also play a role. Indeed, calcium
phosphate based materials, which are bioactive, could have an
added value as drug carriers for the bone tissue. Moreover,
another relevant property of calcium phosphates is their unique
ability to adsorb different chemical species on their surfaces.
This property has been exploited for instance in the
hydroxyapatite (HA) chromatography, which has proved to
be very efficient for the purification and separation of proteins,
enzymes, nucleic acids and other macromolecules [3].
Especially relevant is the application of HA chromatography
to the purification of bone growth factors [4]. Indeed, the great
affinity of HA for these various active molecules can be
exploited within the field of the development of new matrixes
for drug delivery applications.
In this article we provide an insight in the application of one
family of calcium phosphate based materials, namely calcium
phosphate cements, as materials for controlled drug delivery.
2. Why calcium phosphate cements?
The possibility to obtain monolithic hydroxyapatite at
ambient or body temperature via a cementitious reaction was
put forward by LeGeros [5] and Brown and Chow [6] in the
early eighties. This was a significant step forward in the field of
bioceramics for bone regeneration, since it provided a material
which, in addition to being bioactive, was mouldable and had
the capacity of self-setting in vivo, within the bone cavity [7,8].
In addition, the development of injectable calcium phosphate
cement formulations established good prospects for minimally
invasive surgical techniques developed in recent years, less
aggressive than the classical surgical methods.
Since then, calcium phosphate cements have attracted much
attention and different formulations have been put forward
[6,913]. In general, all CPC are formed by a combination of
one or more calcium orthophosphates, which upon mixing with
a liquid phase, usually water or an aqueous solution, form a
paste which is able to set and harden after being implanted
within the body.
103
104
(c) The perfect fit to the implant site, which assures good
bonematerial contact, even in geometrically complex
defects. This allows for an optimum tissuebiomaterial
contact, necessary for stimulating the bone ingrowth,
(d) The fact that the setting reaction which takes place under
in vivo conditions is a dissolutionprecipitation process,
resulting in most cases in a precipitated hydroxyapatite
with a high and interconnected microporosity, chemically
and structurally similar to biological apatites. These
factors contribute to an increased reactivity of CPC as
compared to calcium phosphate ceramics.
(e) Lastly, as mentioned above, the low-temperature setting
allows incorporation of different drugs: from antibiotics
and anti-inflammatory drugs to growth factors which are
able to stimulate certain biological responses. This aspect
gives a great potential to this type of materials for the
controlled drug delivery in target sites of the skeletal
system.
3. Calcium phosphate cements as drug carriers
In general, a potential substrate to be used as drug carrier
must have the ability to incorporate a drug, to retain it in a
specific target site, and to deliver it progressively with time in
the surrounding tissues. Additional advantages are provided if
the material is injectable and biodegradable.
The possibility to use CPCs not only as bone substitutes but
also as carriers for local and controlled supply of drugs is very
attractive and can be useful in treatments of different skeletal
diseases, such as bone tumours, osteoporosis or osteomyelitis,
which normally require long and painful therapies.
Unlike calcium phosphate ceramics employed as drug
delivery systems, where the drugs are usually absorbed on the
surface, in CPCs the drugs can be incorporated throughout the
whole material volume, by adding them into one of the two
cement phases. This fact can facilitate the release of drugs for
more prolonged times.
The studies about incorporation of drugs into CPC cover
different aspects. In the first place, it is necessary to verify that
the addition of the drug (either to the liquid or the solid phases
of the cement) does not interfere in the setting reaction,
modifying the physico-chemical properties, not only in terms of
the setting and hardening mechanisms but also with respect to
the rheological behaviour. Secondly, it is necessary to
characterize the kinetics of drug release in vitro. Subsequently,
the effectiveness of the cement to act as carrier for drug delivery
in vivo, must be assessed. And finally, the clinical performance
of the drug delivery system must be evaluated.
During the last decade, several studies related to the
application of both commercial and experimental CPCs as
drug carriers have been published. Major attention has been
paid to antibiotics, due to their wide areas of application: either
as prophylactics to prevent infections produced during surgical
interventions, or in general in the treatment of bone infections.
However, also anti-inflammatory of anticancer drugs or even
hormones has been studied. In addition, in the last years the
incorporation in CPCs of some other substances or factors able
D Ve
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[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]