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The effect of a low transition temperature mixture for enhanced bioavailability of celecoxib in combination with hyaluronic acid in a rat model with post-traumatic knee osteoarthritis
Publication . Roda, Ana; Rios, Jaqueline Lourdes; Dilek, Yeter; Warmink, Kelly; Escudero, Remei; Muenzebrock, Katrin A.; Du, Jie; Wu, Zhiming; Eijkelkamp, Niels; Paiva, Alexandre; Duarte, Ana Rita C.; Creemers, Laura B.; LAQV@REQUIMTE; Faculdade de Ciências e Tecnologia (FCT); DQ - Departamento de Química; Elsevier
Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability worldwide. Current therapies include pain relief with oral uptake of non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular injections of hyaluronic acid (HA), to restore the lubricant and protective properties of the joint (viscosupplementation). The administration of both therapies is limited, especially for NSAIDs, given the systemic side-effects. This work intended to explore the potential of a novel injectable gel for osteoarthritis treatment consisting of hyaluronic acid (HA) combined with celecoxib (CEX) incorporated in a glycerol:sorbitol (GS)-based Low Transition Temperature Mixture (LTTM) for enhanced bioavailability. The efficacy of HA+GS+CEX versus HA, HA+CEX and saline control was tested in a post-traumatic osteoarthritis rat model (female Sprague-Dawley rats, n = 6 per group), induced by unilateral anterior cruciate ligament transection and partial medial meniscectomy (ACLt+pMMx). Outcome measures included knee edema, pain-associated behaviour, systemic CEX levels, bone changes as detected by micro-computed tomography, joint degeneration by Mankin score and synovitis by Krenn score. No changes were observed in knee edema between treatments. All HA-containing formulations effectively reduced synovitis, and alleviated pain-associated behaviour. HA+GS+CEX injection limited the peak CEX systemic exposure, prevented the loss of integrity of the subchondral bone plate, and inhibited cartilage degeneration. Overall, although all HA-based formulations reduced pain and inflammation, only the combination of HA+GS+CEX inhibited joint degeneration, suggesting an added therapeutic benefit over HA or HA+CEX alone.
Engineering an LTTM-polymeric-drug formulation for osteoarthritis treatment
Publication . Roda, Ana Sofia Martins; Duarte, Ana; Paiva, Alexandre; Matias, Ana
Osteoarthritis (OA) is a common degenerative joint disease, a major cause of disability glob-
ally, whose economic burden is substantial, thus requiring effective treatments to reduce its
burden and improve patients’ quality of life. In this context, the main strategy here followed
was the use of Low Transition Temperature Mixtures (LTTMs) to incorporate drugs and biopol-
ymer(s) already prescribed in OA therapeutics (e.g.: non-steroidal anti-inflammatory drugs
(NSAIDs) and hyaluronic acid (HA), the main component of joints lubricant - synovial fluid), in
such a way that it can improve their efficiency, overcome their limitations, and reduce the ap-
proval-time needed to reach the market.
LTTMs are particularly promising to enhance drugs' bioavailability and to be used as con-
trolled delivery systems, especially upon combination with biomaterials, such as polymers.
Hence, the main scope of this thesis was to provide an innovative therapeutic approach com-
bining the following features:
i. LTTM constituents with beneficial properties for OA therapy. Different LTTM compositions
were designed, developed, and characterized envisioning added synergetic action in OA ther-
apy.
ii. Increased NSAIDs bioavailability. Selected LTTMs were studied to identify the most prom-
ising LTTM+NSAID combinations concerning this feature.
iii. Compatibility towards the inclusion of selected biopolymers. An injectable formulation
was designed and characterized envisioning the inclusion of selected biopolymers in the same
LTTM media used to enhance the bioavailability of NSAIDs.
iv. Viability for intra-articular administration. The designed formulation was studied aiming
to validate proper features for the intended application.
v.
In vivo therapeutic potential for OA. The developed injectable was evaluated in a post-
traumatic OA rat model.
Briefly, glycerol:sorbitol (GS) emerged as a promising lubricant LTTM, improved celecoxib’s
(CEX) solubility and was compatible with HA, rendering an alternative to conventional physio-
logic solutions. GS+HA combination yielded a stable, injectable gel mimicking synovial fluid
properties, further enhanced CEX bioavailability and modulated its release kinetics. In vivo, the
HA+GS+CEX formulation effectively reduced pain and inflammation while distinctively inhibit-
ing cartilage and bone degradation, contrarily to HA or HA+CEX alone.
Overall, this work allowed to develop a product prototype assembling two therapeutic
agents individually approved for OA therapy in a unique formulation with improved therapeu-
tic potential and convenience (2-in-1). An injectable formulation with the accomplished fea-
tures is not yet available in the market and such a product is of high social and economic
interest.
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SFRH/BD/144424/2019