Alginates as tablet disintegrants: Understanding disintegration mechanisms and defining ranges of applications.

Alginates are biopolymers that have been investigated for their use in food and medical fields. Minimal information is available regarding their potential application as tablet superdisintegrants. Here we studied the disintegration action of sodium alginate (SA), calcium alginate (CA) and alginic acid (AA). Initially, we characterised the swelling and wicking abilities and the disintegration mechanism of pure disintegrants. We found that the liquid uptake of both CA and AA is more swelling-driven in phosphate buffer and more wicking-driven in hydrochloric acid and water. CA acts by shape-recovery, AA by a combination of swelling and shape-recovery mechanisms. SA cannot be used as disintegrant due to gelling. In the second part of the paper, the disintegration time of formulations with different physico-chemical properties and different alginate concentrations (i.e. 4% and 10%) was measured, thus delivering a direct readout for the ranges of application of alginates as tablets disintegrants. The main observations are: i) CA and AA often provide very rapid disintegration, similarly to the superdisintegrants used as controls; ii) the action of CA is more susceptible to the medium conditions than AA; iii) CA underperforms in hard tablets containing a binder; iv) both CA and AA have slightly slower disintegration than other superdisintegrants in tablets containing a hydrophobic component. While the suitability of CA as a disintegrant is formulation- and medium- dependent, AA appears as a promising tablet superdisintegrant, particularly for the development of uncomplicated hydrophilic formulations for the nutraceutical and supplement industry, where natural ingredients are favoured.

Disintegrant Selection in Hydrophobic Tablet Formulations.

The hydrophobicity of poorly soluble drugs can delay tablets disintegration. We probed here the influence of different disintegrants on the disintegration of challenging hydrophobic formulations. Tablets containing diluents, hydrogenated vegetable oil and either sodium starch glycolate (SSG), croscarmellose sodium (CCS) or crospovidone (XPVP) were prepared. The disintegration time of tablets was tested immediately and after storage at 40 °C and 75% RH in sealed bags. Results show that storage and compression force had a negative effect on disintegration, particularly with 1% disintegrant. The performance of the three disintegrants was in the following order: CCS (best) > SSG > XPVP. For example, tablets containing 1% CCS, SSG and XPVP, compressed at 20 kN, disintegrated in ≈3, ≈12 and ≈69 min, respectively, after two months storage. Settling volume, liquid uptake and effect of storage on physical properties of the pure disintegrants were also studied and revealed that the reduced performance of XPVP is related to: 1) its rapid, yet short-range expansion upon liquid exposure and 2) its change of behaviour on storage. In conclusion, CCS ensured rapid disintegration at low concentration across various compression forces and storage times. Thus, the use of CCS in hydrophobic tablet formulations is recommended.

A library of strictly linear poly(ethylene glycol)-poly(ethylene imine) diblock copolymers to perform structure-function relationship of non-viral gene carriers.

A library of 39 strictly linear poly(ethylene glycol)-poly(ethylene imine) (PEG-PEI) diblock copolymers was synthesized for the delivery of plasmid DNA using PEG of 2, 5, or 10 kDa in combination with linear PEI with a molecular weight (MW) ranging from 1.5 to 10.8 kDa. In contrast to other approaches, the copolymers demonstrated a clear separation between the hydrophilic PEG and the nucleic acid condensing PEI moieties. Hence, the hypothesis was that PEG may not sterically counteract the interaction between the nucleic acid and PEI and that consequently, the copolymers are perfectly suited to build small and stable polyplexes. Analysis of the polyplexes revealed structure-function relationships and the general guideline was that the PEG domain had a greater influence on the physicochemical properties of the polyplexes than PEI. A PEG content higher than 50% led to small (<150 nm), nearly neutral polyplexes with favorable stability. The transfection efficacy of these polyplexes was significantly reduced compared to the PEI homopolymer, but was restored by the application of the corresponding degradable copolymer, which involved a redox triggerable PEG domain. In conclusion, valuable design criteria for the optimization of gene delivery carriers, which is only possible through the screening of such a large library, were gained.

Delivery of nucleic acids via disulfide-based carrier systems.

Nucleic acids are not only expected to assume a pivotal position as "drugs" in the treatment of genetic and acquired diseases, but could also act as molecular cues to control the microenvironment during tissue regeneration. Despite this promise, the efficient delivery of nucleic acids to their side of action is still the major hurdle. One among many prerequisites for a successful carrier system for nucleic acids is high stability in the extracellular environment, accompanied by an efficient release of the cargo in the intracellular compartment. A promising strategy to create such an interactive delivery system is to exploit the redox gradient between the extra- and intracellular compartments. In this review, emphasis is placed on the biological rationale for the synthesis of redox sensitive, disulfide-based carrier systems, as well as the extra- and intracellular processing of macromolecules containing disulfide bonds. Moreover, the basic synthetic approaches for introducing disulfide bonds into carrier molecules, together with examples that demonstrate the benefit of disulfides at the individual stages of nucleic acid delivery, will be presented.