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Overview of drug delivery coatings

Michael Kuehler and B. BRAUN MELSUNGEN AG
INTRODUCTION
Implant surfaces are coated with drugs for several reasons. These agents can be
permanently bonded to an implant (e.g. covalent like heparin or temporary like
rapamycin for coronary stents). However, covalent fixed coatings only allow the action of
biological processes very close to the implant surface, and a drug carrier from the implant
surface to specific cell sites is frequently required. In order to fulfill the need for optimal
drug delivery, several important issues need to be considered.
If the drug is eluted over a defined time period a drug carrier is often necessary and
should be able to deliver an incorporated drug. Therefore, the release mechanism of the
carrier material must be coordinated with the characteristics of the drug itself (e.g. the
permeability of the carrier with the molecular weight of the drug). Furthermore, the
carrier should allow an adequate release rate, profile, and support drug transport to
specific cells.
Another issue is to ensure that there is a sufficient amount of the agent on the implant
surface. This is especially the case for small implants, such as stents, where the surface
area is limited. When developing a drug eluting surface, the structure of the implant and
drug-tissue pharmacokinetics also have to be considered.1
In this chapter an overview of drug release mechanisms for coated implants is
discussed.
DRUG RELEASE MECHANISMS
Implant drug delivery systems generally can be classified into those with an additional
carrier material (and without additional carrier material) (Figure 15.1). In systems
without an additional carrier diffusion of the agent will be controlled by the implants
surface topography (e.g. with holes, pores etc. on the surface hydrophobicity of the drug
and drug dispersion). Combinations of both groups are possible. Coating-based release
systems can be separated into three groups:
1. Diffusion controlled release
2. Swelling controlled release, and
3. Biodegradable systems.

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Diffusion controlled release systems

In the diffusion controlled system, the drug is dissolved or dispersed in the matrix (Figure
15.2). When it comes into contact with the implant site the agent will diffuse from the
carrier coating. Two release systems can be differentiated:

Fig. 15.1 Overview of different drug

release mechanisms.

Fig. 15.2 The matrix drug delivery

system (a), and reservoir system (b).2

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1. Matrix systems (Figure 15.2a) have a release rate that decreases over the time. But
continuous or so-called zero release profiles are often required.
2. Reservoir systems (Figure 15.2b) have a fairly stable diffusion rate. They comprise a
core that contains the concentrated agent within a polymer matrix and a shell, whereas
the shell is made of a rate controlling material. With regard to a stent strut this is
equivalent to a two-layer system with a drug in the first layer and a barrier coating in
the second layer.
Diffusion is driven by the concentration gradient between the core and the outside of the
shell or barrier coating.
Swelling controlled release systems2
Another option for drug release is the use of swelling controlled materials. The material
in the drug is compact in the dry state but swells during contact with liquids. Caused by
the swelling, which is often combined with a diffusion process, the incorporated drug is
released. Again, differences between matrix and reservoir systems can be differentiated.
Most of the compounds used in swelling controlled release systems are based on
hydrogels. These are polymers that can absorb a large amount of water without
dissolving. For some polymers, this property can be triggered by a change in the
environment surrounding the implant. If there is a change in pH, temperature or ionic
strength, the system can either shrink or swell (Figure 15.3).
Biodegradable release systems
When the carrier is biologically degraded the drug is released from the matrix. Depending
on the type and mesh size of the carrier, diffusion also plays a role. Depending on the
type of degradation, the systems are differentiated into bulk and surface degradable
systems (Figure 15.4). Surface degradable systems are favorable for drug delivery
systems in blood vessels because the risk of bulk fragments in the blood stream, and
therefore the risk of thrombosis caused by fragments is minimized.

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Fig. 15.3 The swelling controlled

release system: (a) reservoir (b)
matrix.2
RELEASE PROFILES
With conventional release systems like pills, considerable changes in drug concentration
occur, whereas the drug level varies between ineffective and toxic. Controlled drug
release coatings can deliver a drug continuously during a desired time frame. Very often,
a zero order pattern is desirable (Figure 15.5).
Coatings based on matrix systems will have a Fickian order for a constant source
(dispersed drug) or a mixed Fickian and first order release for a non-constant source (only
dissolved drug).

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Fig. 15.4 Biodegradable system: (a)

bulk and (b) surface erosion.2
Reservoir systems that have a constant source (pure liquid drug or dispersed drug)
provide a zero order release rate. A non-constant source (dissolved drug in solution)
provides a first order release rate.
MATERIALS FOR DRUG DELIVERY
Drug carriers can be made from lipids and, of course, polymers, which can be loosely
differentiated into permanent and degradable (Figure 15.6).

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Lipids and liposomes3,4

Lipids are amphipathic molecules (e.g. fatty acids, fats, and phospholipids). Lipids have a
dual structure that comprises a hydrophilic and a hydrophobic region. They are soluble in
organic solvents and form clusters in aqueous solutions. Monolayer, micelles, and
liposomes are the favored forms in aqueous solutions.

Fig. 15.5 Patterns of drug delivery.

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Fig. 15.6 Potential carrier materials for

drug delivery.

Fig. 15.7 Diagrammatic representation

of a liposome in which three

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phospholipid bilayers alternate with

aqueous compartments.3
Liposomes are spherical lipid clusters consisting of one or more lipid bilayers enclosing
one or more aqueous compartments (Figure 15.7). They can mimic several properties of
cell membranes (e.g. respond to osmotic forces, have a permeability barrier). Liposomes
are a suitable environment responsive system for drug delivery. Several chemical and
physical triggers for drug release exist (e.g. pH, heat, magnetic field, light,
polyelectrolytes).
In the aqueous layers of the liposome, water-soluble drugs can be entrapped by
intercalation while lipid-soluble drugs can be made soluble within the hydrocarbon
interiors of the lipid bilayers.
Polymers
Many polymers are known to have the potential for drug delivery coatings. Figure 15.8
shows some of the most common permanent polymers. If a polymer is degradable or not
depends on some chemical characteristics, such as molecular weight and hydrophobicity
In reality, everything degrades but the question is how fast it degrades. For drug delivery
applications, degradation in the human time scale is important.
Depending on the implantation site additional biocompatibility characteristics have to
be considered for polymers. For example, some of them may cause inflammation (e.g. in
blood vessels) but are well tolerated in other parts of the body. Other potential
disadvantages of polymer coatings are difficulties with mechanical behavior after
sterilization, and expansion if the implant undergoes high plastic deformations (e.g. like
stents).
Permanent polymers4
A number of more or less stable polymers with a potential for drug delivery are known
(Figure 15.8). Whereas hydrophobic or less hydrophilic polymers are suitable for
diffusion controlled coatings, very hydrophilic polymers, known as hydrogels, will form
swelling controlled coatings and are a group of polymers often used as drug delivery
matrices.
If a drug is mixed uniformly with the polymer the drug are dispersed in a homogenous
polymer matrix (matrix system). Some of the drug molecules dissolve into and saturate
the polymer matrix. These dissolved molecules can diffuse through the matrix into the
surrounding medium. The saturation of the matrix is lost and the dispersed molecules
have to re-dissolve to re-saturate the polymer matrix. After the drug is diffused out of the
polymer, pores remain and become filled with aqueous medium. The drug release
through the matrix and the pores is thus facilitated. Due to osmotic pressure generated by
the drug particles the polymer may fracture.
Depending on the hydrophobicity of the drug, the use of hydrophilic and hydrophobic
polymers or polymer blends allows the tailoring of release behavior.
A disadvantage of permanent polymers is that a rest content of the drug will remain

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Fig. 15.8 Permanent polymers.

in the polymer. Depending on the type of polymer, the mesh size and the size of the drug
molecule, a variable amount of drug will be encapsulated permanently. Late burst effects
due to a long term instability of the polymer could occur.
Hydrophilic polymers5,6
Hydrophilic polymers are soluble in and compatible with water. A wide range of
applications is known, such as in food, cosmetics, and medical implants.
Most hydrophilic polymers are based on acrylated and methacrylated composites. As
well as other monomeric species they possess polar dependent groups in the vinyl
position.
The side chain groups on the other carbon atoms contribute to the overall properties of
the hydrophilic polymer and they also create a large amount of free volume between
neighboring polymer molecules because of their size and flexibility. Their generally poor
mechanical properties can be enhanced by cross-linking them.
Hydrogels
Some materials, when placed in water, swell very rapidly and retain up to a multiple of
their own weight of aqueous fluid. These hydrogels usually comprise hydrophilic
polymer molecules that are cross-linked by chemical bonds or other cohesion forces, such
as ionic interaction, hydrogen bonding or hydrophobic interaction.
Because of their unique bulk and surface properties, hydrogels have favorable
biocompatibility and are ideal for several drug delivery applications. They have no

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Fig. 15.9 General structure of physical

(left) and chemical (right) gels.
interfacial tension with surrounding biological fluids and tissue, which minimizes the
driving force of protein adsorption and cell adhesion. Furthermore, hydrogels simulate
hydrodynamic properties of natural biological gels, cells, and tissue in many ways.
Types of hydrogels
The three-dimensional network of a hydrogel is held together by physical or chemical
bonds (Figure 15.9) and can be divided into two major categories: the physical hydrogels
and the chemical hydrogels.
Physical gel networks comprise an amorphous hydrophilic polymer phase, held
together by highly ordered aggregates of polymer chain segments arising from secondary
molecular forces in conjunction with other types of molecular interaction. They are
soluble in water or solvents and can be melted by heat.
Chemical gels are formed by the introduction of primary covalent cross-links. They do
not dissolve in water or organic solvents even on heating.
If two or more monomeric species are interwoven an interpenetrating network (IPN)
(Figure 15.10) is formed. They are used to modify properties that hydrogels normally
lack. If one or both phases are biodegradable the IPN can be used for drug delivery
applications. Semi-IPNs are IPNs with one cross-linked phase to immobilize the noncrosslinked phase. This technique is useful for implant coatings or drug release systems.
Through modification of the boundary conditions it is possible to alter the release
characteristics. In particular chemical configurations of some hydrogels are
biodegradable.

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Fig. 15.10 An interpenetrating network

(IPN) with two components.
Biodegradable polymers4,7
Biodegradable polymers have become increasingly important in the development of drug
delivery systems because they do not require removal after drugs are depleted.
Biodegradation can occur in many different structural levels (i.e. molecular,
macromolecular, microscopic, and macroscopic) depending on the mechanism. The
polymers become less complex through biodegradation; this occurs through four different
mechanisms: (1) solubilization, (2) charge formation followed dissolution, (3) hydrolysis,
and (4) enzyme-catalyzed degradation. In polymers, biodegradation undergoes four
stages: (i) hydration, (ii) strength loss, (iii) loss of mass integrity, and (iv) mass loss.
The evaluation of the biocompatibility of a degradable polymer also requires an
evaluation of the degradation products. A biocompatible polymer can degrade into toxic
degradation products. The number and size of fragments must be therefore specified.
Degradable polymers can undergo bulk or surface erosion. The nature of erosion
depends on the diffusion of water inside the matrix, the degradation rate of the polymers
functional groups, and matrix dimensions. For the matrix, a critical device dimension
Lcritical can be calculated. The polymer will undergo surface erosion if the matrix is larger
than Lcritical, if not it will undergo bulk erosion.7
If the polymer degrades in bulk, the rate of water penetration into the matrix is faster
than the rate of the polymer degradation. If the degradation rate occurs at a uniform rate
throughout the polymer matrix this process is homogeneous.
For a polymer that undergoes surface degradation, the rate of water penetration into
the matrix is slower than the rate of degradation. A heterogeneous process with
degradation of only a thin surface layer occurs.
Drug delivery matrices can be categorized in four different groups (Figure 15.11): (1)
cross-linked polymer network, (2) cleavable linear polymer, (3) insoluble linear polymer,
and (4) drug-conjugated polymer. The release of the drugs follows the mechanisms (i)

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diffusion, (ii) polymer degradation, (iii) osmosis, and (iv) labile covalent bonds cleavage
between drug and polymer.
The biodegradable polymers can be categorized as those with synthetic origins and
those with natural origins (Figures 15.12 and 15.13).
The degree of polymer degradability depends on different properties:
The higher the cristallinity of the polymer the slower the degradation.
The type of degradable bonds present on the polymer determines the rate of
degradation. It follows: AnhydrideEstersAmides.
Hydrophilics degrade faster than hydrophobic polymers.
Polymers with a high molecular weight degrade slower than polymers with a low
molecular weight.
Biodegradable polymers with synthetic roots
Biodegradable synthetic polymers often have advantages over the natural polymers with
regard to controlled release (e.g. they can be tailored for specific needs). In addition,
crystallinity, degradability, solubility, hydrophobicity, glass transition, and melting
temperature can be easily changed by the synthesis and recipe and condition.
Figure 15.12 presents some of the most common synthetic biodegradable polymers.
Each polymer possesses different crystallinity, degradability, solubility, processibility,
and stability.
A large group of polymers for drug delivery matrices are the polyesters. Poly(lactide
acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(-caprolactone), and
poly(lactid acid-co--caprolactone) are very common in controlled release systems. The
lactic/glycolic acid polymers have been extensively investigated for their potential as a
drug-containing matrix. Generally, they show little inflammatory response or other
harmful side effects, and the degradation products are non-toxic.
Degradable polymers with natural roots
The use of natural biodegradable polymers is limited by their lack of versatility: only
modification rather than synthesis of these is possible. Until now the modification is
limited to the effect that the resulting products may not meet controlled release
requirements.

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Fig. 15.11 Biodegradable polymers for

drug delivery. (a) Cross-linked
polymer, (b) cleavable linear polymer,
(c) insoluble linear polymer, and (d)
drug-conjugated polymer. (D, drug).4

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Fig. 15.12 Biodegradable polymers

with synthetic roots.

Fig. 15.13 Biodegradable polymers

with natural roots.

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REFERENCES
1. Hwang Chao-Wei AB, Wu D, Edelman ER. Physiological transport forces govern drug
distribution for stent-based delivery. Circulation 2001; 104:6005.
2. Brannon-Pepas L. Polymers in Controlled Drug delivery. Medical Plastics and Biomedical
Magazine archive 1997: http://www.devicelink.com/%20mpb/archive/97/11/003.html
3. Davis Colloidal drug delivery University of Nottingham, Faculty of Science 2001:
www.nottingham.ac.uk/~paz51/fage.html
4. Wu Xue Shen. Controlled drug delivery systems. Technomic: Lancaster, PA 1996.
5. Park K, Shalaby WSW. Park H. Biodegradable hydrogels for drug delivery. Technomic:
Lancaster, PA 1993.
6. LaPorte RJ. Hydrophilic polymer coatings for medical devices. Technomic: Lancaster, PA 1997.
7. Burkersroda F von, Schedl L, Gopferich A. Why degradable polymers undergo surface erosion
or bulk erosion. Biomaterials 2002; 23:442131.