Abstract
The aim of the present work was the development of a novel glycosaminoglycan (GAG)-based injectable formulation intended for intra-articular administration that should best mimic the healthy synovial fluid. Hyaluronic acid (HA) was chosen among GAG polymers, since it is the most abundant component of the synovial fluid. A DoE (Design of Experiment) approach was used for the development of a formulation containing two HA (very high (VHMW) and low (LMW) molecular weight) grades. The rationale for this choice is that so far, no commercial product based on a single HA grade or even on binary HA mixture possesses optimal viscoelastic properties in comparison with healthy synovial fluid. A full factorial design was chosen to investigate the influence of concentration and relative fraction of the two polymer grades (retained as factors of the model) on formulation functional (viscosity and viscoelastic) properties, which are considered response variables. Thanks to the DoE approach, the composition of the optimized HA formulation was found. The addition to such formulation of an injectable grade fat-free soy phospholipid, which was rich in phosphatidylcholine (PC), resulted in improved lubrication properties. The final HA + PC formulation, packaged in pre-filled sterile syringes, was stable in long-term and accelerated ICH (International Council for Harmonisation) storage conditions. The overall results pointed out the formulation suitability for further steps of pharmaceutical developments, namely for the passage to pilot scale.
Highlights
All human joints are lined with a tissue called synovium, which is surrounded by synovial fluid [1]
The aim of the present work was the development of a novel glycosaminoglycan (GAG)-based injectable formulation intended for intra-articular administration that should best mimic the healthy synovial fluid
A DoE (Design of Experiment) approach was used for the development of a formulation containing two Hyaluronic acid (HA) (very high (VHMW) and low (LMW) molecular weight) grades
Summary
All human joints are lined with a tissue called synovium, which is surrounded by synovial fluid [1]. HA is a high-molecular-weight linear (MW) natural glycosaminoglycan, consisting of D-glucuronic acid and D-N-acetylglucosamine disaccharides bound with β-glycosidic linkages [4]. It is an essential component of the extracellular matrix (ECM) that is present at high concentration in human umbilical cord, synovial fluids, connective tissue, skin, and vitreous body [5]. An increase in MW and/or concentration corresponds to high values of viscoelastic moduli and a marked shear-thinning behaviour [6] These properties are relevant for the structural function of HA in connective tissue as well as for the lubricating and cushioning activities in the ophthalmic aqueous humour and synovial fluid [4]
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