Synthesis and in vitro characterization of entirely S-protected thiolated pectin for drug delivery

Abstract

The study was aimed to synthesize a thiolated polymer (thiomer) that is resistant to oxidation in solutions above pH 5. In order to protect a pectin-cysteine conjugate against premature oxidation, the thiomer was S-protected by a disulfide connected leaving group. Therefore, 2-mercaptonicotinic acid was first coupled to L-cysteine by a disulfide exchange reaction and the purified product was subsequently attached to pectin by a carbodiimide mediated amid bond formation. The obtained fully S-protected thiolated pectin was in vitro characterized with respect to co- and mucoadhesive properties and stability toward oxidation. The results indicated a 1.8-fold and 2.3-fold enhanced disintegration time at pH 6.8 of the S-protected thiolated pectin (Pec-Cys-MNA) compared to thiolated pectin (Pec-Cys) and unmodified pectin (Pec). Moreover, rheological measurements of polymer/mucus mixtures showed a 1.6-fold (compared to Pec-Cys) and 6.7-fold (compared to Pec) increased dynamic viscosity of Pec-Cys-MNA. On the other hand, in the presence of a strong oxidizing agent such as H2O2 (0.3% v/v), no increase in viscosity of Pec-Cys-MNA could be observed. A 6-month experiment also demonstrated the long-term stability of a liquid formulation based on Pec-Cys-MNA. Further investigations proved that the first time all thiol groups on a thiolated polymer could be protected owing to the novel synthesis. Accordingly, these features may help to develop thiomer based liquid or gel formulations targeting mucosal surfaces such as nasal, ocular or vaginal drug delivery systems.

Totally S-protected hyaluronic acid: Evaluation of stability and mucoadhesive properties as liquid dosage form

“…The suspension was filtered and the solution loaded in a Dowex column and eluted as described previously (Hintzen, Hauptstein, Perera & Bernkop-Schnurch, 2013). The volume of the obtained product was reduced with a rotary-evaporator to 100 mL.…”

“…Totally protected hyaluronic acid was synthetized following a procedure previously described (Hintzen, Hauptstein, Perera & Bernkop-Schnurch, 2013). Briefly, the dimer was prepared by dispersing 2 g of MNA in 80 mL of deionized water.…”

“…To enlarge the field of application of thiolated polymers to liquid dosage forms an alternative synthesis yielding entirely S-protected polymers pectin has been previously reported showing prolonged stability of the synthesized polymer compared to the thiolated derivative polymer (Hintzen, Hauptstein, Perera & Bernkop-Schnurch, 2013). Accordingly, it was the aim of this study to synthesize an entirely S-protected HA derivative bearing prolonged stability and mucoadhesive properties as liquid dosage form.…”

Polysaccharide Based Formulations for Mucosal Drug Delivery: A Review

“…These include thiolated chitosan [35,36,37], carboxybutylchitosan [251], thiolated pectin, [258,259] and caboxymethyl xanthan [260,261,262]. The reader is referred to the references provided for more in depth evaluation of the unique characteristics of these chemically modified natural polysaccharides and their use as drug delivery systems for drug delivery across the various mucosal routes as discussed above.…”

Mucoadhesive polymers in ophthalmic therapy

“…In earlier studies, this type of protection was performed with pyridyl sulfhydryl (Dünnhaupt et al, 2012), 6-mercaptonicotinamide (Dünnhaupt et al, 2012, 2-mercaptonicotinamide (Wang et al, 2012;Hintzen et al, 2013) or 3-methyl-1-phenylpyrazole-5-thiol (Müller et al, 2013). Thanks to the addition of these protective agents, the thiolated polymers have improved stability and mucoadhesive, enzyme-inhibitory, permeation-enhancing and efflux-pump inhibiting properties (Dünnhaupt et al, 2012).…”