Poly(allylamine)/tripolyphosphate coacervates enable high loading and multiple-month release of weakly amphiphilic anionic drugs: an in vitro study with ibuprofen

Abstract

When synthetic polyamines, such poly(allylamine hydrochloride) (PAH), are mixed with crosslink-forming multivalent anions, they can undergo complex coacervation. This phenomenon has recently been exploited in various applications, ranging from inorganic material synthesis, to underwater adhesion, to multiple-month release of small, water-soluble molecules. Here, using ibuprofen as a model drug molecule, we show that these coacervates may be especially effective in the long-term release of weakly amphiphilic anionic drugs. Colloidal amphiphile/polyelectrolyte complex dispersions are first prepared by mixing the amphiphilic drug (ibuprofen) with PAH. Pentavalent tripolyphosphate (TPP) ions are then added to these dispersions to form ibuprofen-loaded PAH/TPP coacervates (where the strongly-binding TPP displaces the weaker-bound ibuprofen from the PAH amine groups). The initial ibuprofen/PAH binding leads to extremely high drug loading capacities (LC-values), where the ibuprofen comprises up to roughly 30% of the coacervate mass. Conversely, the dense ionic crosslinking of PAH by TPP results in very slow release rates, where the release of ibuprofen (a small, water-soluble drug) is extended over timescales that exceed 6 months. When ibuprofen is replaced with strong anionic amphiphiles, however (i.e., sodium dodecyl sulfate and sodium dodecylbenzenesulfonate), the stronger amphiphile/polyelectrolyte binding disrupts PAH/TPP association and sharply increases the coacervate solute permeability. These findings suggest that: (1) as sustained release vehicles, PAH/TPP coacervates might be very attractive for the encapsulation and multiple-month release of weakly amphiphilic anionic payloads; and (2) strong amphiphile incorporation could be useful for tailoring PAH/TPP coacervate properties.

Scheme 1. Chemical structures of (a) PAH and sodium salts of (b) TPP and (c) ibuprofen.

Fig. 1. Titrations of 15 mM ibuprofen (a and c) into (■) 5 mM, () 10 mM and () 30 mM PAH at pH 7.0 (all without TPP) and (b and d) into 30 mM PAH mixed with TPP at () 0.00 : 1, (■) 0.20 : 1 and () 0.40 : 1 TPP : PAH molar ratios analyzed by (a and b) ITC and (c and d) light scattering. The error bars are standard deviations and the lines are guides to the eye.

Fig. 2. Schematic drawings and digital photographs of the formation of ibuprofen-loaded PAH/TPP coacervates.

Fig. 3. Drug concentration effects on the (a) LE and (b) LC of ibuprofen uptake into PAH/TPP coacervates achieved at PAH () 0.3 and (■) 1.0 wt% PAH concentrations. The error bars are standard deviations while the lines are guides to the eye.

Fig. 4. Dynamic rheology of PAH/TPP coacervates comparing () G′ and () G′′ for (a) ibuprofen-free coacervates and (b) coacervates formed in the presence of 24.3 mM ibuprofen. Both coacervate types were analyzed after 72 h of equilibration in the mixtures from which they formed.

Fig. 5. Ibuprofen release profiles from PAH/TPP coacervates loaded using (■) 4.9 and () 24.3 mM initial ibuprofen concentrations, 0.3 wt% PAH, and (a and b) 1× PBS and (c and d) DI water as the release media. The release profiles are plotted in terms of the (a and c) percent or (b and d) total mass of the ibuprofen released. The error bars are standard deviations and the lines are a guide to the eye.

Fig. 6. Gravimetric analysis of the stability of PAH/TPP coacervates loaded with 24.3 mM ibuprofen and 0.3 wt% PAH during drug release into (■) DI water and () 1× PBS. The error bars are standard deviations while the dashed line indicates the initial coacervate weight.

Fig. 7. Digital photographs of (a) PAH/TPP coacervates prepared in the presence of: (i) no payload, (ii) ibuprofen, (iii) SDBS and (iv) SDS (with each amphiphilic payload present at a concentration of 24.3 mM) and (b) the same PAH/TPP coacervates after 7 d of equilibration in the presence of 1.0 ml of 2.1 mM RhB dye.