BIODEGRADATION AND DRUG RELEASE FROM PARTICULATE SYSTEMS

V. BIODEGRADATION AND DRUG RELEASE FROM PARTICULATE SYSTEMS

In order to prolong the entrance of drugs into the intraocular structures, a long residence time of the particles in the cul-de-sac and a total desorption

Microparticles and Nanoparticles in Ocular Drug Delivery 447 of the drug from the particles during that time have to be attained. Alkyl

cyanoacrylate polymers degrade relatively rapidly in vivo when compared to other polymers used in particulate ocular drug delivery such as poly(lactic acid) and its copolymers with glycolic acid (69). The degradation time is dependent on the alkyl chain length and ranges from a few hours (when methyl cyanoacrylate is used) to approximately 3 days (when 80% of iso- butyl cyanoacrylate is used) (70). The degradation of cyanoacrylates leads to the formation of alcohol together with formaldehyde and poly(cyanoacrylic acid) compounds, which could be toxic in high concentrations (71). Too rapid a degradation can lead to a burst release of degradation products, possibly causing cytotoxic effects (70). In order to assess the relevance of the degradation products regarding possible toxic effects in humans, their rate of release during particle degradation and the maximum local concentra- tions must be considered (69).

The rate of degradation of cyanoacrylate particles is dependent on the alkyl chain length, and the dominating mechanism of particle degradation was found to be a surface erosion process (72,73). By this mechanism, the polymeric chain remains intact, but it gradually becomes more and more hydrophilic until it is water-soluble. Since the biodegradability of polyalk- ylcyanoacrylate particles depends on the length of the alkyl chain, it is theoretically possible to choose a monomer whose polymerized form has the desirable release characteristics (74). However, the release of a drug cannot always be attributed to polymer degradation alone. Drug desorption from the polymer surface and diffusion of the drug through the polymer matrix are other mechanisms by which a drug can be released from the

nanoparticles. By using a radiolabeling technique ( 14 C-labeled nanoparticles loaded with 3 H-labeled actinomycin), drug release from polyisobutylcya- noacrylate nanoparticles was found to be a direct consequence of polymer bioerosion (71). The main mechanism of the interaction of PACA particles with cells in culture was found to be endocytosis, leading to intralysosomal localization of the carrier (75). As shown in Figure 2, the particles with a low drug payload and a lower negative surface charge (suspension A, suspension

C) trigger a better response compared to the particles containing a greater amount of drug adsorbed onto their surface along with a more negatively charged surface (suspension B) (values are shown in Table 1).

VI. TRANSPORT PATHWAY OF NANOPARTICLES Ocular transport of polybutylcyanoacrylate nanoparticles has been studied

by Zimmer et al. (54) using fluoroscence microscopy. Nanoparticles were labeled with rhodamine 6G or propidium iodide as fluorescent dyes and

448 Kothuri et al.

Fig. 2 Adsorption isotherms of betaxolol chlorhydrate. ~, Betaxolol solution; &, suspension A; ~, suspension B; &, suspension C. (From Ref. 80.)

Microparticles and Nanoparticles in Ocular Drug Delivery 449 Table 1 Physicochemical Characteristics a of Polyalkylcyanoacrylate

Nanoparticles Adsorption

Size (nm)

Zeta-potential

percentage

(S.D.) Suspension A

(S.D.)

(mV) (S.D.)

without betaxolol chl.

30 (3) Suspension B without betaxolol chl.

with betaxolol chl.

65 (2) Suspension C without betaxolol chl.

with betaxolol chl.

with betaxolol chl.

22 (3) a Physicochemical characteristics of particles at 25 C and pH 7.4

S.D. = standard deviation; n ¼ 9; Suspension A = Isobutylcyanoacrylate nanoparticles in acidic aqueous solution

M HCl) with a stabilizer dextran 70000 (1%).

Suspension B = Isobutylcyanoacrylate nanoparticles in acidic aqueous solution (10

M HCl) with a mixture of dextran 70000 (0.8%) and dextran sulfate (0.3%) Suspension C = Isobutylcyanoacrylate nanoparticles in acidic aqueous solution (10

M HCl) with a mixture of dextran 70000 (0.5%) and N- acetylglucosamine (0.5%). Source: Ref. 80.

incubated with freshly excised rabbit cornea and conjunctiva for about 30 minutes in standard perfusion cells. After incubation, it was found that there is a fluorescence signal inside the cells, which indicates uptake of nanopar- ticles by the cornea and conjunctiva. Fluorescent particles were visually observed inside the cells in what appeared to be vesicles or granules. Thus, either endocytosis of the nanoparticles by conjunctival tissue or lysis of the cell membrane by the nanoparticle metabolic degradation pro- ducts explained the results of their experiments. The authors also found that the penetration was limited to the first two cell layers of the cornea, and further penetration did not occur.

VII. OCULAR DISTRIBUTION OF NANOPARTICLES The fate of nanoparticles in the body depends on the physicochemical prop-

erties of the nanoparticles (76). Properties such as pH, surfactant, and sta- bilizers influence the mucoadhesion properties to the ocular membrane and

450 Kothuri et al. thereby modify the precorneal retention of the nanoparticles. It has been

shown that the molecular weight of the polymer influences the residence time of nanoparticles in the precorneal area (Fig. 3) (77). As the molecular weight increases, the polymer becomes poorly retained, whereas low mole- cular weight polymers are retained for a longer time. Experimental data on the disposition of polyhexylcyanoacrylate nanoparticles in tears, the aqu- eous humor, cornea, and conjunctiva of albino rabbits clearly showed adhe- sion of nanoparticles to absorbing tissue (74). Polyalkylcyanoacrylate colloidal carriers were eliminated from the tears with a half-life of about 15–20 minutes (78). This is significantly slower than the elimination rate of aqueous drops, which show a half-life of 1–3 minutes. With pilocarpine, it was found that PACA nanoparticles were able to prolong the intraocular pressure-reducing effect of pilocarpine in rabbits for more than 9 hours (79). Similar results were obtained with betaxolol as a model drug (80). Thus, either prolonged drug release or increased contact time between the corneal tissue and drug could improve the bioavailability and the therapeutic effi- ciency.

Wood et al. (62) studied the disposition of 14 C-labeled polyhexylcya- noacrylate nanoparticles using radiotracer techniques. The concentration of nanoparticles in the cornea, conjunctiva, and aqueous humor was found to

be three to five times higher in rabbit eyes in which chronic inflammation had been induced. This is an important observation that suggests that cya-

Fig. 3. Precorneal drainage profile of poly(isobutylcyanoacrylate) nanoparticles: M.W. (*) 4,275; (&) 13,178; (~) 72,030; (þ) 128,865; (&) 607,439 in g/mol. (From Ref. 77.)

Microparticles and Nanoparticles in Ocular Drug Delivery 451 noacrylates may have an enhanced bioadhesiveness to inflamed tissues. In

addition, the ratio of nanoparticles between inflated and normal tissue was higher in the conjunctiva than in the cornea. This is especially favorable since various anti-inflammatory drugs are used in conjunctival inflamma- tion, but these have some side effects after diffusion through the cornea into the aqueous humor. Marchal-Heussler et al. (80) showed that the surface charge and hydrophobicity of the drug play an important role in drug adsorption onto the particles. It has been observed that polyethylene gly- col–coated (PEG) nanospheres made of polyethyl-2-cyanoacrylate (PECA) particles loaded with acyclovir showed significant improvement in bioavail- ability (81). The improved bioavailability is due to better interaction of the PEG-coated PECA nanospheres with the corneal epithelium, thereby increasing ocular mucoadhesion.