degradable polymeric carriers for parenteral controlled drug delivery
Carriers for Parenteral
• Factors influencing drug release from
degradable polymer matrices
• Principles of polymer degradation and erosion
• Drug release characteristics of degradable
• Strategies to control drug release rates from
degradable polymers toward zero order profiles
• Microencapsulation concepts developed in the 1980s
and 1990s of the last century led to injectable particulate
depot formulations, e.g., for leuprolide acetate (Lupron®
Depot, Enantone®, Trenantone®) and goserelin acetate
• 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 ex-
• Degradability is often a strong benefit in terms of
patients’ convenience, marketing, and hospitalization
• The term degradation (or biodegradation if
driven by contributions of living cells)
usually refers to a breakdown of polymers
at the molecular level, i.e., chain cleavage
that leads to degradation products that are
safely eliminated by the body.
• In contrast, the term erosion refers to the
process of polymer mass loss, which
includes not only degradation but several
other processes, such as water uptake
leading to microscopic or macroscopic
changes of the structural integrity of the
drug carrier and eventual removal of
degraded or nondegraded material to the
• In principle, drug release from hydrophobic
polymers can be controlled by diffusion and/or
degradation of the matrix, typically by
• The uptake of distinct quantities of water into the
matrix is required to enable drug diffusion and
hydrolytic cleavage of polymer chains.
• If the extent of water uptake is rather low, in this
case, the type of erosion mechanism may largely
depend on the involved rates of two mechanisms,
water uptake and hydrolytic degradation, and which
of them is dominating over the other.
• In this chapter, temporal controlled injectable and
implantable delivery systems are reviewed, which
involve degradation and erosion of the polymer
Factors Influencing Drug Release from
Degradable Polymer Matrices
• 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.
Fig. 8.1 Scheme of major factors that may
influence drug release rates from drug
carriers based on degradable polymers
• Other important parameters or processes that
contribute to the release profile are
• Indication and Required Release Rates Define
Preferred Carrier Type
• Effect of Environmental Conditions on Release
• Impact of Drug Properties
• Contributions of Osmotically Mediated Mechanisms
Indication and Required Release Rates
Define Preferred Carrier Type
• The desired release rates, duration of release and
• The route of administration (e.g., sc, im, ip, or site of
• Type of drug carrier (e.g., particles or implants),
• Specific shapes or dimensions of the carrier (e.g.,
particle size distribution or shape of implants such
as polymeric stents).
• Depending on these application-dictated
requirements, a specific drug carrier may be
selected that fits the indication of interest
Effect of Environmental Conditions on
• The drug release rates from a specific carrier are
largely affected by,
• environmental or physiological conditions,
• drug physicochemical properties,
• matrix ultrastructure and shape,
• osmotically driven mechanisms,
• biodegradation and erosion pathways of the
Impact of Drug Properties
• 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
• Large substances such as proteins do often not
show release by diffusion through a dense,
nonporous polymer matrix.
• Noncovalent binding between drug and polymer
may reduce release rates or cause incomplete
release until complete erosion of the polymer.
• Molecular weights and hydrodynamic radii.
Contributions of Osmotically Mediated
• 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
• Moreover, polymer properties have a very
important impact on drug release rates from
degradable matrices. This includes several
• polymer hydrophilicity/hydrophobicity,
• drug–polymer interactions,
• polymer mesh width,
• drug diffusibility, polymer morphology and physical
• polymer degradation and erosion behavior.
Principles of Polymer Degradation and
• Principles of Polymer Degradation:
• The degradation i.e. the molecular breakdown of
polymers is governed by
• chemical composition,
• architecture and morphology,
• environmental conditions and device properties.
• e.g. , 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
• Three concepts of polymer degradation with
relevance for controlled drug release can be
• 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.
• All commercialized drug loaded implants and
microparticle products based on polyesters or
polyanhydrides follow this pathway.
• 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.
Besides other pathways.
• This mechanism is discussed as the major pathway
in polyalkyl-cyanoacrylate degradation.
• Third, polymer networks may disintegrate into water-
soluble linear polymer chains by selective
degradation of netpoints.
• Polyacrylate-based networks crosslinked with
hydrolytically cleavable copolyester segments are
examples for hydrophobic matrices. 19
• Principles of Erosion Triggering Mass Loss:
• Polymer erosion, i.e., the release of degraded or
nondegraded polymeric material, resulting in mass
loss of the sample.
• Degradation induced by exposure to different factors
including, e.g., heat, light, or oxidative stress.
• copolymers synthesized from dilactides and
diglycolide (PLGA) is the example of controlled
• For polymer erosion that relies on aqueous
hydrolysis, four different steps can be differentiated,
• (1) wetting of the polymer surface including a
possible internal porous structure,
• (2) water uptake with a material-specific rate into the
• (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
• For instance, incorporation of acidic substances into
the matrix acting as catalysts can increase the
degradation rate, thus changing degradation pattern
and drug release to a surface erosion controlled
mechanism for certain polymers.
• However, occasionally observed higher degradation
rates in vivo are repeatedly assigned to enzymatic
catalysis, but may also be based on other factors,
e.g. inflammatory cell/tissue responses or
plasticization of the polymer by molecules present in
Drug Effects on Polymer Degradation
• The incorporation of any substances including drugs
into a polymer matrix may change the polymers
• This is very obvious in the case of embedded highly
soluble drugs or additives of similar properties, which
may change the osmotic pressure in the matrix and
increase water uptake.
• E.g., an increased catalytic degradation of PLGA
implants was observed depending on the loading with
a water-soluble N-acetyl cysteine, which enhanced
• For basic drugs, e.g., thioridazine, an
amine catalyzed hydrolysis of the polymer
matrix during the particle preparation and
a faster release were observed,
• This could be reduced by performing the
o/w emulsification at lower temperatures
or erasing the drug’s basicity by the
formation of salts.
Drug Release Characteristics of Degradable
• Polymers in Commercial Parenteral Drug
• The employed carrier strategies include
microparticles, preformed implants, and in situ
• Importantly, in all but one of the so far
commercialized products, PLA/PLGA is used
as matrix polymer.
• The largest number of degradable parenteral
controlled release products are based on
microparticles as drug carriers.
• Beneficial aspects of microparticles as drug depots
compared to preformed implants include their
injectability through needles of smaller diameters as
well as the advantages of all multiple unit dosage
forms, i.e., a possibly better average reproducibility
of their properties.
• Preformed implants in the classical rod-like
shape with the single functionality to act as drug
depot, processing of drug loaded degradable
polymers into advanced shapes has opened
new fields of application that combine drug
release and a supporting function.
• Particularly the stent technology for the
treatment of coronary artery diseases is
demanding such degradable material concepts
In Situ Forming Drug Depots
• In situ implants are formed in the tissue after
injection, mostly due to polymer precipitation
from organic solutions.
• In situ forming gels, i.e., solvent rich matrices
consisting of hydrophilic or amphiphilic
molecules, may employ various mechanisms of
• (1) thermosensitive materials gelling upon
decrease in temperature include materials like
• (2) thermosensitive materials, which gel upon
increase in temperature, gelation occurs, e.g.
due to the formation of block copolymer micelles
• (3) covalent crosslinking of network precursors,
e.g. by enzymatic reactions
• (4) ionic crosslinking, e.g. of charged polymers
• (5) pH changes, e.g. for charged polymers such
Strategies to Control Drug Release Rates
from Degradable Polymers Toward Zero
• Relevance of In Vitro Zero Order Release and
• Research on controlled release formulations aims to
provide delivery systems that show zero order drug
release i.e., constant release rates over time.
• for degradable matrix polymers, e.g. plasticization,
potential catalytic activities of enzymes, or possible
alterations in local environment due to cellular
immune response, may have to be included for in
vitro zero order release.
• Approaches to overcome undesired high initial
• improve miscibility of the drug and the polymer,
• to reduce diffusion to interfaces by advanced
carrier processing techniques.
• In addition to the drug/polymer properties on the
molecular level, processing-derived properties of
the carrier such as the surface area and the
porosity will impact the release kinetics.
• Degradable, polymer-based drug carriers remain a
scientiﬁcally and commercially important strategy to
control the release of bioactive molecules over time
periods ranging from several days to several
• Drug release from these carriers is governed by a
complex interplay of parameters including drug
properties, polymer degradation/erosion
characteristics, and osmotically driven mechanisms,
as well as environmental conditions and processing-
derived device properties