(647c) Electrospun Gelatin Nanofibers As Carrier for Controlled and Sustained Release of a Hydrophobic Drug

Controlled
drug release systems have gained a lot of attention in pharmaceutical industry,
due to its improved therapeutic efficacy by delivering drug molecules in a
predetermined rate at the targeted site for a prolong time. Designing polymer
based drug delivery system involves in-depth understanding of drug-device
interactions and good control over the parameters which can modulate transportation
of drug molecules as per the treatment. Recently, electrospun
nanofibers have attracted interest as a controlled drug delivery device due to
their unique structural features. Electrospinning has become the most common
nanofiber production method in the past decade due to its capability of
fabricating ultrafine fibers (nano to micron level)
from a variety of materials like synthetic and natural polymers, polymer
blends.  This is the most cost-effective
way to produce continuous fibers with very high surface-to-volume ratio,
interconnected porosity with tuneable pore dimensions.
The versatility in morphology in nanometer level accuracy of fibers can be
achieved by optimizing electrospinning process parameters, the polymer solution
properties. This kind of nanofibrous structure has
tremendous applications in different biomedical fields. 

The
purpose of the present study is to fabricate large surface area to volume
polymeric electrospun nanofibric
device for drug delivery application. The work includes main three steps i.e. (a)
fabrication of hydrophobic drug (piperine)
encapsulated hydrophilic natural polymer (gelatin) based nanofiber film, (b) modulating
the stability of hydrophilic film by crosslinking with saturated vapor of
glutaraldehyde (GTA) with minimal exposer time and (c) finally modifying the
vehicles with different crosslinking strategy and different layer by layer
deposition of polymer to achieve sustained and prolonged release of hydrophobic
drug piperine.

In
this work, first biodegradable polymer gelatin is electrospun
to produce continuous long nanofibers and then the possibility of using them as
a suitable carrier of hydrophobic drug (piperine) is
explored. Releasing hydrophobic drug is a challenge which significantly depends
upon the nature of drug and polymer and their interactions. Thus, drug-polymer
interactions are checked using Fourier Transform Infrared
spectroscopy (FTIR) and it is found that piperine
is intact in gelatin nanofiber mesh without reacting with polymer matrix. There
is no interference of polymer matrix is found from FTIR and the characteristic
peaks of piperine are present clearly. The morphology
of the fibers is also examined using Scanning
Electron Microscopy (SEM) imaging
instrument after gold coating fibers for 10 sec.  Long and continuous fibers with average
diameter of 150 nm and characteristic peaks of piperine
in gelatin nanofiber film are evidence which confirm the encapsulation of drug
in polymer matrix.

As
a next step, drug loaded gelatin nanofiber film is crosslinked using saturated
vapor of GTA only few minutes. In-vitro
degradation study of crosslinked samples (6 and 8 min) is performed to check
the stability of the vehicle in different physiological pHs for more than 24 h. The fusion of nanofibers at
the crossing points of fiber network is due to the water vapor in GTA solution
which is evident from SEM images. Interestingly, it is found that the presence
of hydrophobic drug can significantly reduce the fusion of gelatin fibers while
crosslinking with GTA vapor. Crosslinked samples shows significant amount of
improvement in terms of thermal stability after performing Thermogravimetric
analysis. Thus we have successfully fabricated piperine
encapsulated gelatin nanofiber based device which is chemically, thermally and
mechanically stable.

After
the fabrication of the device, in-vitro
release study is done to analyze the effect of release medium and
degree of crosslinking on the drug release from the nanofiber mat. While the
amount of drug release decreases with increase in crosslinking time, the same
increases with higher pHs.
Release profile shows bi-layered curves i.e. sudden release of drug followed by
sustained release which is far from zero-order kinetics. One very quick fit is
to increase the crosslinking timing which is not desirable because of the
toxicity of GTA and also it will reduce the overall total release. Thus new
strategies are incorporated to control the rapid release of drug during the initial
hours. Sandwiched structured nanofiber mesh with 6 min and 8 min crosslinking
with GTA is the next attempt in order to increase the diffusional barrier
between the drug molecules and release medium to tone down the initial rapid
release. Piperine loaded gelatin nanofiber layer is
basically put in-between two layers of only gelatin nanofiber layers. It is
evident that, increase in barrier layer decreases the initial release and also
decreases the drug loading.  As a
consequence different variation of barrier and core layer has been tried and
this greatly improves the release profile. In the present vehicle, with higher
drug loading the barrier is not able to release molecule in zero order manner.
Thus, the concept of sequential crosslinking comes into the scenario to give a
near zero order release profile. There is a hierarchy of crosslinking degree
within the layers in case of single time crosslinking for 6 min. To increase
the compactness of the fiber mesh uniformly within the layers, fiber mesh is
crosslinking each time for 2 min after depositing barrier layer, core layer and
finally at the end of opposite side barrier layer. This drastically improves
the release kinetics of higher drug encapsulated device.  These results suggest potential use of
biodegradable electrospun nanofibers as an oral drug
delivery system with promising controlled release features.