INTRODUCTION TO DELIVERY MECHANISM OF POLYMER MATRICES

Julia Nofadini (1306370972), Teknologi Bioproses

Regenerative therapies mostly are cell-based concepts; however, a prolonged local release of bioactive molecules including small
chemical entities as well as more complex substances such as growth factors or chemokines may be desired and is addressed in present
research. Additionally, also for the long-term treatment of chronical diseases, intense research activities can be expected in the
pharmaceutical industry to provide controlled release formulations as successors of initial oral dosage forms. This may be possible when
new intellectual property is generated by new controlled release formulations. This goal can be achieved by embedding the drug into
polymeric matrices, which govern the release rates of encapsulated drugs. These matrices typically consist of degradable polymers, which
slowly degrade under physiological conditions and thus avoid accumulation of exhausted drug carriers in the body or the need of a second
surgery for explantation.
1.1 Factor Influencing Drug Release from Degradable Polymer Matrices
A central goal in controlled drug delivery is to establish the desired release kinetics of a certain drug for a specific application.
Several factors may affect drug release rates, and the most important aspects of these are summarized in Figure 1. In general, factors
controlling drug release behavior can be classified into two major groups, i.e., (1) physical processes and chemical/physicochemical
molecular properties associated with the involved materials and (2) the environmental conditions as well as properties related to the
engineered shape of the drug carrier

1.1.2

Figure 1. Scheme of major factors that may influence drug release rates from drug carriers based on
degradable
Indication and Required Release Rates Define Preferred Carrier Type

At the starting point of any project aiming to design controlled release carriers, two things will typically be known the drug and
its clinical application. Against the background of the drugs pharmacokinetics (e.g., minimal effective concentration, clearance), the
specific application will define several requirements such as (1) the desired release rates, duration of release and total dose, (2) the route
of administration, (3) type of drug carrier (e.g., particles or implants), (4) specific shapes or dimensions of the carrier (e.g., particle size
distribution or shape of implants such as polymeric stents), and (5) other design criteria. Depending on these application-dictated
requirements, a specific drug carrier may be selected that fits the indication of interest. Obviously, the three dimensional geometry of the
carrier is of major importance.
1.1.3

Effect of Environmental Conditions on Release

The drug release rates that finally can be realized from a specific carrier are largely affected by environmental or physiological
conditions, drug physicochemical properties, matrix ultrastructure and shape, contributions of osmotically driven mechanisms, and,
importantly, biodegradation and erosion pathways of the polymeric matrix. While release assays may not in all cases be designed to fully
display in vivo conditions, modifications in experimental conditions certainly can alter drug release. Typically, standard conditions will be
at 37C in a suitable buffer at physiological pH value. However, particularly for hydrophobic drugs with low solubility, the set up of the
assay, the volume of release medium, the presence of solubilizing surfactants, and the intensity of agitation may play a significant role.
Physiological or pathological environmental conditions during in vivo studies may sometimes result in a faster drug release than in vitro,
e.g. due to the presence of enzymes, which in some cases are known accelerators of polymer degradation.
1.1.4

Impact of Drug Properties

The physicochemical properties of the drug molecules are another key factor when discussing release rates. For example, low
solubility drugs are typically characterized by lower diffusion rates due to a lower concentration gradient of the drug from the inside to the

outside the matrix. The diffusion of encapsulated substances may also depend strongly on the drugs hydrodynamic radii, or more simply,
their molecular weights. Large substances such as proteins do often not show release by diffusion through a dense, nonporous polymer
matrix. This is because proteins do not generally partition in the polymer phase and because their molecular size may be substantially
larger than the physically entangled mesh of the matrix polymer. Noncovalent binding between drug and polymer may reduce release rates
or cause incomplete release until complete erosion of the polymer.
1.1.5

Contributions of Osmotically Mediated Mechanisms

In the polymer matrix, osmotic pressure builds up by encapsulated highly water-soluble compounds, resulting in water influx. Such
water penetration through the polymer phase and/or pore network can result in rupture of pore walls for rapid release out of the polymer
and/or release by osmotic convective mass transfer. On the one hand, swelling of the matrix material could facilitate movement of
dissolved drug out of large inter-connective pores. Also, a higher swellability of the particle core compared to the shell may result in
osmotically driven breakage of the particles. On the other hand, substantial swelling that first occurs at the particle surface may lead to
closure of micropores and a swelling-controlled release mechanism from polymer matrices of relative hydrophilicity.
1.2 Principles of Polymer Degradation and Erosion
1.2.1 Principles of Polymer Degradation
The degradation, i.e., the molecular breakdown of polymers is governed by both their chemical composition, architecture and
morphology as well as a complex interplay of environmental conditions and device properties. For example, in hydrolytically degrading
(co)polymers, the uptake of water into the matrix is an essential precondition for chain cleavage and is affected by the matrix
hydrophilicity as a function. In principle, three concepts of polymer degradation with relevance for controlled drug release can be
differentiated. First, linear polymers as most often used for controlled drug release matrices can degrade into mono- or oligomers by
random or selective scission of bonds in the polymer main chain. Second, linear polymers may contain side chains that, after cleavage,
convert into hydrophilic or charged groups attached to the polymer backbone, which enable aqueous solubility of the polymer. Third,
polymer networks may disintegrate into water-soluble linear polymer chains by selective degradation of net points. The three dimensional
architecture of the polymer molecules should also be taken into account when discussing degradation properties. Typically, a faster
degradation and mass loss can be observed for branched compared to linear polymers of a similar molecular weight. A faster degradation
of branched molecules may be explained by a faster gain of the critical oligomer size for aqueous solubility due to the shorter initial length
of each arm.
1.2.2

Principles of Erosion Triggering Mass Loss

Polymer erosion, i.e., the release of degraded or non-degraded polymeric material, resulting in mass loss of the sample, may in
principle derive from degradation induced by exposure to different factors including, e.g., heat, light, or oxidative stress. For polymer
erosion that relies on aqueous hydrolysis, four different steps can be differentiated, i.e., (1) wetting of the polymer surface including a
possible internal porous structure, (2) water uptake with a material-specific rate into the polymer bulk, (3) degradation of the polymer
following a characteristic pathway with a material and possibly geometry dependent rate, and (4) if possible, diffusion controlled removal
of degradation products. A major aspect in this context is the speed and extent of water uptake compared to the degradation rate and water
consumption during hydrolysis. When devices are characterized by a geometry and/or microstructure that allows easy diffusion of
degradation products out of the matrix, the decrease of molecular weight during bulk degradation may be homogeneous throughout the
matrix. In this context, it is important to consider (1) differences in the analytical techniques to determine average molecular weights, (2)
the polydispersity, PD, of the polymer, (3) the solubility of the endcapping moiety, and (4) that discussing Mn values might be more
relevant in view of the initiation of matrix mass loss by aqueous solubility of degradation products. As described above, the
degradation/erosion pathway can also be a function of environmental conditions, which include in vivo the presence of enzymes and cells.
1.2.3

Drug Effects on Polymer Degradation

The incorporation of any substances including drugs into a polymer matrix may change the polymers degradation behavior. The
free carboxyl groups of the drug may have contributed to polymer degradation by acidic catalysis. Moreover, water uptake resulted in a Tg
reduction, i.e., plasticization with increased chain flexibility and in turn higher water and drug diffusion coefficients. For basic drugs, e.g.,
thioridazine, an amine catalyzed hydrolysis of the polymer matrix during the particle preparation and a faster release were observed,
which could be reduced by performing the o/w emulsification at lower temperatures or erasing the drugs basicity by the formation of
salts.
1.3 Drug Release Characteristics of Degradable Polymeric Carriers
1.3.1 Microparticles
Microencapsulation Techniques
A summary of the most commonly employed microencapsulation techniques is provided in Figure 3.

Figure 2. Summary of the principles of the most common techniques for the
microencapsulation of drugs

Drug Release from Microparticles

For drugs that are suitable to diffuse through a totally hydrated microparticle matrix, short diffusion pathways may result in release
over days to months depending on the microparticle morphology and the physicochemical properties of the drug. By contrast, molecules
that cannot permeate through a compact polymer matrix such as proteins above a certain hydrodynamic radius may, after initial burst,
not be further released until breakdown of the dense matrix. The effective surface for a diffusion-controlled drug release from the top
layers of the microparticles is much larger than the outer particle surface. In theory, when considering the properties of a single carrier,
i.e., one microparticle compared to one preformed implant, there is a reduced risk for microparticles that failure in the integrity of one
individual carrier unit could have toxic effects by dose dumping in a patient.

1.3.2 Preformed Implants

Preparation Techniques
Implants from solid polymers are typically prepared either in a rod-like shape for subcutaneous injection or as disks/wafers for
implantation such as during open surgery. Some commonly employed methods are summarized in Figure 3.

Figure 3. Summary of the principles of some common preparation

techniques for implants
Drug Release from Preformed Implants
Very often, the percentaged drug release from implants will be slower due to longer diffusion lengths. Therefore, in addition to the
properties of the matrix polymer, the surface area/volume ratio and the porosity, which are both associated with the implant shape and
method of processing shape, may be major contributors to the observed release pattern. Generally, the incorporation of additives may
serve multiple goals. Larger molecules such as proteins cannot diffuse through dense polymer matrices as for instance created by melt
extrusion processes. According to the theory of pure surface erosion, the molecular weight of the bulk material should be constant for an
extended period of time, while degradation-induced mass loss from the implant surface should occur in a linear manner upon contact
with water. For larger devices such as implants, an erosion zone at the implant surface can be distinguished where degradation occurs at
much higher rates than in the bulk due to the presence of larger quantities of water. As a consequence, large molecules such as proteins,
which previously were entrapped in the polymer, can be released from the surface erosion zone. Overall, the presented examples of
biodegradable implants stress that the feasibility for a controlled drug release cannot solely be discussed in the light of matrix material
properties such as prevalence to surface or bulk erosion, but also involves numerous aspects of polymer processing.
1.3.3 In Situ Forming Drug Depots
Strategies to form In Situ Drug Depots
In situ forming gels, i.e., solvent rich matrices consisting of hydrophilic or amphiphilic molecules, may employ various
mechanisms of intermolecular binding including (1) thermosensitive materials gelling upon decrease in temperature; materials range
from block copolymers studied in water to small molecules evaluated in different solvents including biocompatible vegetable oils, (2)

thermosensitive materials, which gel upon increase in temperature; gelation occurs, (3) covalent crosslinking of network precursors, e.g.
by enzymatic reactions, (4) ionic crosslinking, e.g. of charged polymers or nanoparticles, or (5) pH changes. Theoretically, polymers
that can be handled as a liquid at temperatures (slightly) above physiological temperatures and solidify when cooled to body
temperature by phase transition to a glassy or semicrystalline state could also be used for in situ forming depots. By combining the
concepts of microparticulate carriers and in situ forming depots, in situ forming microparticles were proposed to overcome issues
associated with conventional microparticle formulations such as the cost intensive preparation, drying, and potentially difficult
resuspension. Also, in contrast to in situ forming implants, in situ forming microparticles showed lower myotoxicity, easier injectability
depending on the type of solvent and suspension medium, and a more reproducible surface area as opposed to the irregular shape
obtained for in situ implants.

In Situ Depot Formation by LiquidLiquid Phase Separation and Drug Release Characteristics
Mechanistically, the liquidliquid phase separation process and the properties of an obtained polymeric device from drug loaded
polymer solutions is based on the following two aspects. First is the thermodynamic state of the initial system as determined by the
ternary composition containing polymer, solvent, and nonsolvent. Second, the kinetics of mass transfer during solvent exchange and
polymer precipitation is crucial, and involves the following process that is, (1) diffusion of water into to polymer solution, (2) solvent
removal from the polymer solution into the nonsolvent bath or, in vivo, into the tissue, (3) polymer precipitation to form solid implants
solvents characterized by a high water miscibility, (4) drug distribution between the phases. NMP as the standard solvent for in situ
forming implants is freely miscible with water and, therefore, may be exchanged at high rates.

1.5 Strategies to Control Drug Release Rates from Degradable Polymers Toward Zero Order Profiles
1.5.1 Relevance of In Vitro Zero Order Release and Common Limitations
This is particularly important for drugs that are characterized by a narrow therapeutic window between the minimum effective
concentration and the minimum toxic concentration. Particularly for hydrophobic drugs, accumulation in deep compartments such as the
fatty tissue may occur. As a consequence, (1) the determined plasma concentration may not reflect the true amount of the released drug,
(2) a possible release of the correct dose may not result in efficacy, and (3) the drug may be available for pharmacological effects even
after exhaustion of the drug carrier due to a gradual distribution from the deep compartment into other compartments. A strong liberation
of drug is observed in the initial hours of release. This burst release may be a consequence of several factors such as (1) poor embedding
of drug particles in the matrix, (2) poor solubility of many drugs in the matrix polymer, (3) drug transport to the matrixs surface caused
by solvent diffusion during preparation of the carrier, and (4) dynamic pore formation and closure, which transiently controls diffusion
paths.
1.5.2 Timely Separation of Diffusion-Controlled Drug Release and Collapse of Bulk-degrading Matrices.
Depending on the drugs physicochemical properties and the characteristics of the respective polymer matrix, drugs with and
without capacity for matrix diffusion have to be differentiated. When the initial drug concentration is higher than the drug solubility and
when the accessible surface area of the drug carrier does not change, constant release rates may be obtained only the case of certain
geometries. Importantly, for degradable polymers, material properties, properties of the prepared carrier matrix, and in many cases also
microenvironmental conditions dynamically change over time. Therefore, by selecting a combination of a hydrophilic, diffusible drug and
a bulk degrading material with low degradation rates, a timely separation of drug release and degradation may be achieved and late state
dose dumping linked to polymer degradation/ matrix erosion may be avoided.
1.5.3 Blending Approaches for Bulk Degrading Carriers
Most commonly, the lag phase is considered as a slow release or even as an absence of reasonable drug release due to poor drug
diffusion in an initially dense matrix. Upon degradation-driven increase in matrix porosity, the lag phase may be followed by a rapid
release phase. An alternative explanation for the beginning of the lag phase for initially porous materials involves spontaneous pore
closing as driving mechanism. Typically, lag phases in diffusion controlled release systems are observed for larger molecules or
hydrophobic drugs, which require the access of larger volumes of water for drug solubilization or larger pore diameters for drug diffusion.
Therefore, blending of high average molecular weight polymer with a small portion of a low average molecular weight polymer was one
of the first methods identified to ensure continuous release of peptides and hydrophobic drugs. By blending preformed, uniformly sized
polymer microparticles of different radii and drug diffusion lengths, linear release profiles can be established.
1.5.4 Employing Surface Eroding Carriers
For drugs that do not easily diffuse in bulk degrading materials or at least for carriers from these materials that do not have a porous
microstructure, a zero order drug release will unlikely be found. Particularly for protein drugs with sensitivity to acidic microenvironment,
prolonged exposure to acidic products of polymer degradation such as present inside bulk eroding poly(a-hydroxy esters) may induce
protein instability in many cases. Therefore, surface eroding polyorthoesters or polyanhydrides are often believed to be a guarantee for
zero order release profiles, since degradation products are not accumulated and drug diffusion is not the controlling mechanism of release.

Reference : Juergen Siepmann et al. (ed.) Fundamental and Applications of Controlled Release Drug
Delivery, Springer.