Abstract:
Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation of the
joints, which in turn cause swelling, pain, stiffness and redness in the joints. Methotrexate
is immunosuppressant and inhibiting proliferation of the lymphocytes through to be
responsible for synovial inflammation in rheumatoid arthritis. Local delivery of drugs
offers the potential for high local drug concentration while minimizing systemic toxicity,
which often observed with oral dosing. However, local depots are typically administered
less frequently and include an initial burst followed by a continuous release. To maximize
efficiency of therapy, it is critical to ensure that drug is only released when needed. An
optimal system would be nontoxic and only release drugs during the period of
exacerbation, self-titrating in response to the level of inflammation. The aim of present
investigation was to develop and characterize on demand drug delivery from selfassembled
hydrogel of methotrexate for rheumatoid arthritis. Development of an
injectable self-assembled fibrous hydrogel, from a generally recognized as safe material,
which is capable of encapsulation and release of agents in response to specific enzyme
lipase that are significantly upregulated in a diseased state. Drug excipients compatibility
was determined using FTIR. Self-assembled hydrogel was prepared using amphiphilic
polymer ascorbyl palmitate. Batches were prepared by taking various concentrations of
amphiphilic polymer. Optimized batch of self-assembled hydrogel containing
methotrexate (2 mg), ascorbyl palmitate (1%w/v) and phosphate buffer saline pH 7.4 (2
ml) was characterized for sol to gel time, drug content, clarity, pH, viscosity and rheology. Optimized self-assembled hydrogel was also evaluated Scanning electron
microscopy, X-ray diffraction, syringeability, texture analysis and sterility test. In-vitro
drug release study was performed in presence and absence of lipase enzyme to evaluate
on demand drug release. Stability study was performed at room temperature and
accelerated condition. FTIR study confirms absence of incompatibility between drug and
excipients.
Sol to gel time and drug content of optimized batch was found to be 4.5±0.41 min,
95.83±0.59 % respectively. Rheological characterization showed thixotropic behavior of
prepared self-assemble fibrous hydrogel suitable for injection in intra articular space.
Scanning electron microscopy and X-ray diffraction confirms the fibrous structure of
self-assembled-fibrous hydrogel. Syringeability was found to be optimum to pass
solution from 22-25 gauge needles. Higher value of adhesiveness measured by texture
analysis confirms intimate contact with surface like tissues. Absence of microbial growth
was confirmed by sterility testing. In vitro drug release study reveals that self-assembled
fibrous hydrogel showed drug release in presence of lipase up to 7 days. Stability study
results indicated that self-assembled hydrogel stored at room temperature remains stable
with almost no change in evaluated parameter. This novel approach represents a nextgeneration
therapeutic strategy for localized treatment of rheumatoid arthritis with
reduced systemic toxicity associated with certain drug like methotrexate.