Poly Alkyl Cyanoacrylate Nanoparticles

The first report on the synthesis of PACA nanoparticles appeared in 1979.16 PACA nanoparticles are biodegradable and hence are eliminated rapidly from the body.17 The cyanoacrylate monomers are polymerized in the aqueous medium by the anionic polymerization;16,18 the mechanism is

I Monomer

FIGURE 15.2 Mechanism of alkyl cyanoacrylate polymerization. (From Behan, N., Birkinshaw, C., and Clarke, N., Biomaterials, 22, 1335, 2001. With permission.)

depicted in Figure 15.2. The cyanoacrylate monomer is initiated by OHK ions, and the polymerization was performed at a low pH to control the reaction, which otherwise would have led to rapid polymerization resulting in the precipitation of large polymer aggregates. The stabilizers used were found to have a significant influence on the size of the formed polymer particles. High concentrations of poloxamer 188 (above 2%) reduced the particle size of polyisobutyl cyanoacrylate nanoparticles from around 200 nm without an emulsifier, to as low as 31-56 nm.19 Nanoparticles prepared without stabilizers or prepared using polysorbates were found to have monomodal molecular weight distribution, with mean molecular weights of 1000-4000 Da, whereas the stabilizers such as dextrans or poloxamers led to a distinctive bimodal distribution of the molecular weights, with peaks at 1000-4000 and 20,000-40,000 Da. This bimodal distribution is indicative of two separate polymerization reactions. The first reaction probably occurs in the aqueous phase where the termination of polymerization by H+ ions is rapid, leading to small molecular weights. The second reaction is possibly the polymerization of captured growing unter-minated polymer molecules within the primary particles. Due to the low concentration of H+ ions in this environment, the termination frequency is reduced and hence the molecular weights would be much higher. Due to the initiation of cyanoacrylate polymerization by bases, the basic drugs also can act as initiators. However, because of the complexity of cyanoacrylate polymerization, the resulting particle size in such multi-component systems is difficult to predict.

Poly(butyl cyanoacrylate) (PBCA) nanoparticles of n-butyl cyanoacrylate containing methotrexate were prepared by DP and EP.20 DP nanoparticles were prepared using dextran as a stabilizer; the EP nanoparticles were stabilized by poloxamer 188. A high zeta potential was observed for nanoparticles prepared by the DP method, whereas the incorporation of methotrexate resulted in a decrease in zeta potential. The DP nanoparticles exhibited a high release of metho-trexate, suggesting the channelizing effect of dextran chains incorporated into nanoparticles during polymerization. When tested in two different release media such as 0.1 molL-1 HCl and pH 7.4 phosphate buffer, a significant difference (p<0.01) in release rates was found for DP and EP nanoparticles. Drug release from both the nanoparticles followed Fickian diffusion in 0.1-molL-1 HCl, whereas the mechanism was found anomalous in pH 7.4 phosphate buffer. A similar study conducted on PBCA nanoparticles loaded with doxorubicin hydrochloride by incorporation and adsorption techniques21 showed rapid drug release in 0.001-N HCl from both DP and EP nanoparticles; the release kinetics followed the Higuchi equation.

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