IJPI's Journal of Pharmaceutics and Cosmetology: Hydrogel As A Controlled Drug Delivery System
IJPI's Journal of Pharmaceutics and Cosmetology: Hydrogel As A Controlled Drug Delivery System
IJPI's Journal of Pharmaceutics and Cosmetology: Hydrogel As A Controlled Drug Delivery System
www.ijpijournals.com
Department of Pharmaceutics,
B.S. Patel Pharmacy College,
Linch, Mehsana, Gujarat
ABSTRACT:
Hydrogels are polymeric networks that absorb large quantities of water while remaining insoluble in
aqueous solutions due to chemical or physical cross linking of individual polymer chains. Hydrogels have
played a very important role in biomedical applications. Proper network design and accurate mathematical
modelling are keys to tuning the drug release rates as well as to modulating tissue regeneration. Although
many fundamental studies have revealed the basic molecule release mechanisms from hydrogel-based
controlled release devices, many parameters in the current models are unknown and/or change with time or
position and need to be identified in order to accurately predict drug release profiles. Novel engineering of
hydrogels for drug delivery can done by Biodegradable hydrogels, Smart hydrogels, Molecule release
mechanisms for hydrogel formulations and Bio mimetic hydrogels.
1. INTRODUCTION
An ordered polymer network composed of macromers with well understood chemistries yields hydrogels with
well-defined physicochemical properties and reproducible drug-release profiles. In a complimentary fashion, a
quantitative mathematical understanding of material properties, interaction parameters, kinetic events, and transport
phenomena within complex hydrogel a assists network design by identifying the key parameters and mechanisms that
govern the rate and extent of drug release. Hydrogels are polymeric networks that absorb large quantities of water
while remaining insoluble in aqueous solutions due to chemical or physical cross linking of individual polymer chains.
Hydrogels can be prepared from natural or synthetic polymers. Although hydrogels made from natural polymers may
not provide sufficient mechanical properties and may contain pathogens or evoke immune/inflammatory responses,
they do offer several advantageous properties such as inherent biocompatibility, biodegradability, and biologically
recognizable moieties that support cellular activities. Synthetic hydrogels, on the other hand, do not possess these
inherent bio-active properties. Fortunately, synthetic polymers usually have well-defined structures that can be
modified to yield tailorable degradability and functionality. Even if a hydrogel delivery formulation is designed with
the appropriate physical and transport properties, it may still fail to perform its therapeutic role when implanted in vivo
due to a localized inflammatory response. The formation of a fibrous capsule surrounding the delivery device creates
additional diffusion barriers that may limit drug release rates while increased proteolytic activity may increase rates of
matrix and drug degradation. Proper material selection, fabrication process, and surface texture of the device are
therefore always critical in designing biocompatible hydrogel formulations for controlled release.
1.1 Polymers Used In Hydrogel: [1,2]
Natural polymer Synthetic monomer
been previously developed to predict the release of an active agent from a hydrogel device as a function of time. These
models are based on the rate-limiting step for controlled release and are therefore categorized as follows:
1. Diffusion-controlled
2. Swelling- controlled
3. Chemically-controlled
1.2.1 Diffusion-controlled[3]
Diffusion-controlled is the most widely applicable mechanism for describing drug release from hydrogels. Fick‟s law
of diffusion with either constant or variable diffusion coefficients is commonly used in modelling diffusion-controlled
release [3]. Drug diffusivities are generally determined empirically or estimated a priori using free volume,
hydrodynamic, or obstruction-based theories.
1.2.2 Swelling- controlled[4, 5]
Swelling-controlled release occurs when diffusion of drug is faster than hydrogel swelling. The modelling of this
mechanism usually involves moving boundary conditions where molecules are released at the interface of rubbery and
glassy phases of swollen hydrogels [4]. The release of many small molecule drugs from hydroxyl propyl methylcellulose
(HPMC) hydrogel tablets is commonly modelled using this mechanism. For example, MethocelR matrices, a
combination of methylcellulose and HPMC, from Dow Chemical Company are commercially available for preparing
swelling-controlled drug delivery formulations exhibiting a broad range of delivery timescales.
1.2.3 Chemically-controlled[3,6,7]
Chemically-controlled release is used to describe molecule release determined by reactions occurring within a delivery
matrix. The most common reactions that occur within hydrogel delivery systems are cleavage of polymer chains via
hydrolytic or enzymatic degradation or reversible or irreversible reactions occurring between the polymer network and
releasable drug. Under certain conditions the surface or bulk erosion of hydrogels will control the rate of drug release.
Alternatively, if drug-binding moieties are incorporated in the hydrogels, the binding equilibrium may determine the
drug release rate. Chemically controlled release can be further categorized according to the type of chemical reaction
occurring during drug release. Generally, the liberation of encapsulated or tethered drugs can occur through the
degradation of pendant chains or during surface-erosion or bulk degradation of the polymer backbone. A more
thorough discussion of these mechanisms can be seen in a later section of this review as well as in several other
excellent reviews.
Even if a hydrogel delivery formulation is designed with the appropriate physical and transport properties, it may still
fail to perform its therapeutic role when implanted in vivo due to a localized inflammatory response. The formation of
a fibrous capsule surrounding the delivery device creates additional diffusion barriers that may limit drug release rates
while increased proteolytic activity may increase rates of matrix and drug degradation. Proper material selection,
fabrication process, and surface texture of the device are therefore always critical in designing biocompatible hydrogel
formulations for controlled release.
Table 1: Design criteria for hydrogels in drug delivery formulations.[10,11]
Design criteria Design variables
Transport properties Molecular weight and size of protein
Molecular diffusion Molecular weight of polymer
Cross linking density
Polymer protein interaction
Additional functionalities
Hydrogel degradation rate
hydrogel networks and the advantages of in situ fabrication, most research efforts are focused on understanding
diffusion-controlled release of encapsulated drugs from three-dimensional hydrogel matrices.
Drug diffusion within highly swollen hydrogels is best described by Fick‟s law of diffusion or Stefan-Maxwell
equations. Diffusion-controlled hydrogel delivery systems can be either reservoir or matrix systems. For a reservoir
system where the drug depot is surrounded by a polymeric hydrogel membrane, Fick‟s first law of diffusion can be
used to describe drug release through the membrane:
JA=-DdCA/dx (1)
Here, JA is the flux of the drug, D is the drug diffusion coefficient, and C A is drug concentration. In many cases, the
drug diffusion coefficient is assumed constant to simplify the modelling. However, in the general case it is a function
of drug concentration and a special correlation incorporating the concentration-dependent drug diffusivity must be
utilized to accurately predict drug flux. Another assumption of this expression is that J A is the drug flux corresponding
to the mass average velocity of the system.
For a matrix system where the drug is uniformly dispersed throughout the matrix, unsteady-state drug diffusion
in a one-dimensional slap-shaped matrix can be described using Fick‟s second law of diffusion:
dCA/dt=Dd2CA/dx2 (2)
Here, the drug diffusion coefficient is again assumed as a constant. Other assumptions include sink condition
and a thin planar geometry where the release through slab edges is neglected. When diffusivity is concentration-
dependent the following equation is used:
∂CA/∂t=∂/∂x(D{CA}∂CA/∂x}) (3)
Many previous attempts to model diffusion-controlled drug delivery from hydrogels rely largely on empirically
determined diffusion coefficients. Once the diffusion coefficient is determined, equation (1) to (3) can be solved,
together with proper initial and boundary conditions, to yield drug concentration profiles that dictate the release
kinetics. For example, an exact analytical solution to equation (2) can be obtained using separation of variable
technique. Although this simple solution applies to many diffusion-controlled drug release systems, model complexity
will increase as other mechanisms, polymer-drug interactions, and when non-spherical drugs are used [19].
Another empirical equation developed by Peppas et al. assumes a time-dependent power law function [6, 4]:
Here, k is a structural/geometric constant for a particular system and n is designated as release exponent representing
the release mechanism.
transition temperature (Tg) is reached, causing the systematic release of loaded drugs. The drug release rates are
modulated by the rate of water transport and the thickness of the gel layer.
Figure2: Schematic of HPMC Hydrogel tablet in the glassy (left) and Rubbery (right)state
Drug diffusion time and polymer chain relaxation time are two key parameters determining drug delivery from
polymeric matrices. In diffusion-controlled delivery systems, the time-scale of drug diffusion, t, (where t=δ(t)2/D and
δ(t) is the time-dependent thickness of the swollen phase) is the rate-limiting step while in swelling-controlled delivery
systems the time-scale for polymer relaxation (λ) is the rate-limiting step. The Deborah number (De) is used to
compare these two time-scales:
In diffusion-controlled delivery systems (De << 1), Fickian diffusion dominates the molecule release process and
diffusion equations described in the previous section can be used to predict molecule release. In swelling-controlled
delivery systems (De >> 1), the rate of molecule release depends on the swelling rate of polymer networks.
2. CONCLUSION
Hydrogels have played a very important role in biomedical applications. With increasing efforts devoted to
controlled molecule release, the applications of hydrogels will continue to grow in the future. Proper network design
and accurate mathematical modeling are keys to tuning the drug release rates as well as to modulating tissue
regeneration. Although many fundamental studies have revealed the basic molecule release mechanisms from
hydrogel-based controlled release devices, many parameters in the current models are unknown and/or change with
time or position and need to be identified in order to accurately predict drug release profiles. Reduced release
efficiency, burst effects, complex geometries, and unknown correlations between in vitro and in vivo release further
complicate our understanding of these materials as delivery devices and present difficult challenges to developing
mathematical models that accurately describe the transport and release of molecules from these systems. Furthermore,
as more advanced release devices are developed such as affinity hydrogels, microparticle systems, and in-situ forming
gels, more rigorous mathematical modeling approaches are needed to describe the coupled mechanisms governing
molecule release from these systems.
3. REFERENCES
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growth factors. Journal of Controlled Release 2000;65:389-402.
22. Soppimath KS, Aminabhavi TM, Dave AM, Kumbar SG, Rudzinski WE. Stimulusresponsive "smart"
hydrogels as novel drug delivery systems. Drug Development And Industrial Pharmacy 2002;28:957-974.
23. Taylor SJ, McDonald JW, Sakiyama-Elbert SE. Controlled release of neurotrophin-3 from fibrin gels for
spinal cord injury. Journal of Controlled Release 2004;98:281 294.
24. Yoshida R, Sakai K, Okano T, Sakurai Y. Pulsatile drug-delivery systems using hydrogels. Advanced Drug
Delivery Reviews 1993;11:85-108.
25. Brazel CS, Peppas NA. Dimensionless analysis of swelling of hydrophilic glassy polymers with subsequent
drug release from relaxing structures. Biomaterials 1999;20:721-732