POLYMERS USED IN THE PREPARATION OF NANOPARTICLES

IV. POLYMERS USED IN THE PREPARATION OF NANOPARTICLES

A successful nanoparticulate system may be one that has a high loading capacity, thus reducing the quantity of carrier required for administration.

Microparticles and Nanoparticles in Ocular Drug Delivery 445 The drug can be either adsorbed onto the surface of performed particles or

incorporated into the nanospheres during the polymerization process. Concerning the loading capacity of nanoparticles, it has been found that both the nature and quantities of the monomer used influences the absorp- tion capacity of the carrier. Generally, the longer the chain length, the higher is the affinity of the drug to the polymer, i.e., the capacity of adsorp- tion is related to the hydrophobicity of the polymer and to the specific area of the polymer (52).

Several types of polymeric nanoparticles are used in ophthalmic drug delivery

described earlier. Polymethylmethacrylate (PMMA) nanoparticles, which are excellent adju- vants for vaccines, can be produced by the emulsion polymerization techni- que. In this process, monomeric methylmethacrylate is dissolved in a concentration range of 0.1–1.5% in water or phosphate–buffered saline or

and prepared

a solution or suspension of drugs or antigens (33). The polymerization is polymerization using potassium peroxodisulfate and heating to high tem-

peratures. PMMA nanoparticles are generally produced without emulsifiers (12). The biologically active substance, such as drug or antigen, may be present during polymerization or can be added to previously produced nanoparticles. Polymerization in the presence of heat-sensitive materials

emulsion polymerization in continuous aqueous phase include acrylic copo- lymer nanoparticles (54–56), polystyrene (57–59), and polyvinyl pyridine (54,60). Nanoparticles made of polyacrylamide or PMMA do not degrade either biologically or enzymatically, which makes them less attractive for ophthalmic use.

Cellulose acetate phthalate has been used for in situ gelling of latex nanoparticles (61). The preparation of these latex particles involves emulsi- fication of polymer in organic solvent followed by solvent evaporation. This latex suspension, upon coming in contact with the lacrimal fluid at pH 7.2–

7.4, gels in situ, thus averting rapid washout of the instilled solution from the eye. The disadvantage of these preparations is vision blurring. PACA particles possess properties of biodegradation and bioadhesion, making them of considerable interest as possible drug carriers for controlled ocular drug delivery and drug targeting. Wood et al. (62) showed that PACA nanoparticles were able to adhere to the corneal and conjunctival surfaces, which represent their mucoadhesion property. This polymer has the ability to entangle in the mucin matrix and form a noncovalent or ionic bond with the mucin layer of the conjunctiva. PACA nanoparticles are prepared in the same manner as previously described for PMMA. The monomer at a concentration of 0.1–3% is added to an aqueous system or

446 Kothuri et al. to the drug solution (33). Polymerization starts at room temperature and is the most significant advantage over acrylic derivatives, as these particles

do not require high energy input for the polymerization process, and there is no effect on the stability of the absorbed drug. Alkyl cyanoacrylate particles polymerize according to an anionic mechanism in an aqueous medium using hydroxyl ions as the initiator. Starting with the polymeric reaction in an acidic medium and varying the pH of the medium during the polymerization process, the velocity of the polymerization and molecular weight of resultant polymer can be controlled, which in turn influences the particle size of the nanoparticles formed by this reaction (33,63). The main disadvantage of these carriers is that PACA nanoparticles penetrate into the outer layers of the corneal epithelium, causing a disruption of the cell membranes (64).

As an alternative to PACA nanoparticles, recent studies have shown mer systems for ocular drug delivery (65,66). Marchal-Heussler et al. (66)

compared nanoparticles prepared by using PACA, PECL, and polylactic- co-glycolic acid with betaxolol as model drug. It was shown that the PECL nanoparticles yielded the highest pharmacological effect. This was believed to be due to the agglomeration of these nanoparticles in the conjunctival sac.

In previous studies it has been shown that regarding ocular adminis- tration, the surface charge of the nanoparticles and binding type of the drug onto the nanoparticles were much more important parameters than the drug adsorption percentage onto the nanoparticles (67). It was assumed that coat- ing nanoparticles with positively charged bioadhesive polymers enhances the interaction between nanoparticles and the negatively charged corneal sur- face, but there are indications that this assumption may not always hold true (68). The bioavailability of nanoparticles coated with poly-l-lysine and chit- osan (both have positive charge) were compared to that of noncoated nano- particles. It was suggested that the specific nature of chitosan was responsible for bioavailability improvement rather than the charge. Using fluorescein- labeled chitosan, it was revealed that chitosan nanoparticles interact favor- ably with rabbit corneal and conjunctival epithelia and remain associated to these tissues for over 48 hours (68). By contrast, chitosan solutions were washed off the eye within a much shorter period of time.