Drugs Used In Particulate Ocular Delivery

The first nanoparticulate system (average size, 0.3 ^m) for pilocarpine was introduced by Gurny and employed cellulose acetate hydrogen phthalate (CAP) pseudolatex as the polymer (82). The formulation increased the miosis time (up to 10 h) as well as AUC of the drug by 50% compared to the drug solution by decreasing the elimination rate of the drug. This was possible by the dissolution of the polymer at pH 7.2 (pH of tears) forming a viscous polymer solution when the formulation (pH 4.5) was administered in the eye (83). It has been shown that nanodispersions made of anionic lattices with low viscosity and containing large amount of polymeric material exhibit an important increase in viscosity when neutralized with a base (84). Wesslau (85) described this effect as an inner thickening that is due to the swelling of the nanoparticles from the neutralization of the acid groups contained on the polymer chain and the absorption of water.

A polybutylcyanoacrylate nanoparticle delivery system for pilocarpine nitrate has been evaluated in comparison to the solution of the drug for pharmacokinetic and pharmacodynamic aspects (86). Emulsion polymerization technique was employed in preparing nanoparticles, and in vivo experiments were performed by application of the formulations to the eyes of New Zealand white rabbits pretreated with betamethasone to create an elevated intraocular pressure mimicking glaucoma conditions. The results indicated an increase of 23% in pilocarpine levels in aqueous humor and prolonged t1/2 for the polybutylcyanoacrylate nanoparticle preparation compared to the aqueous control solution. It was possible to prolong the miosis with nanoparticles with lower drug content compared to the control solution. Betaxolol (80) and amikacin sulfate (87) loaded polyalkylcyanoacrylate nanoparticles have shown similar effects. The superficial charge and binding type of the drug onto the nanoparticles are important factors playing a role in the improvement of the therapeutic response. In another study, adsorption of pilocarpine onto polybutylcyanoacrylate nanoparticles enhanced the miotic response by about 22% compared to the control aqueous drug solution (35).

Diepold et al. (79) incorporated pilocarpine into polybutylcyanoacry-late nanoparticles and evaluated the aqueous humor drug levels and the intraocular pressure-lowering effects using three models (the water-loading model, the alpha-chymotrypsin model, and the betamethasone model) in rabbits. The miotic response was enhanced by about 33% while the miotic time increased from 180 to 240 minutes for nanoparticles compared to the control solution. Also, the intraocular pressure-lowering effects were prolonged to more than 9 hours in all three models mentioned. Vidmar et al. (88) showed that poly(lactic acid) microcapsules of pilocarpine hydrochlor-ide prepared by a solvent precipitation method prolonged miosis about 4 hours in comparison to control solution (< 2 hours) in rabbits (88). A significant improvement in the bioavailability of pilocarpine was attained by co-administering the pilocarpine-loaded albumin nanoparticles with the viscous bioadhesive polymer mucin (89).

In a clinical study with Piloplex® (latex emulsion of pilocarpine hydrochloride) a lower level of the drug with less fluctuation compared to the corresponding control solution was observed on the third day of treatment. This study involving nine subjects showed a reduction by 5.25 mmHg of the average diurnal intraocular pressure value compared to the control. Only one out of 30 patients complained of a local sensitivity reaction with Piloplex in the yearlong study (90). Similar results were obtained in yet another study involving 50 patients, where 67.6% of the eyes treated with the formulation were under control, while only 45.2% were under control with the pilocarpine solution (91).

Nanocapsules for topical ocular delivery of cyclosporin A (CyA) comprising an oily core (Miglyol 840) and a poly-e-caprolactone coating increased the corneal levels of the drug by 5 times compared to the oily solution of the drug when administered to the cul-de-sac of fully awake New Zealand white rabbits (92). Also, the drug levels remained higher for up to 3 days with the nanocapsule preparation. More than 90% of CyA could be encapsulated giving a maximum loading capacity of 50% (drug: polymer) (92). The enhancement in the drug levels occurred due to the increased uptake of nanocapsules by the corneal epithelial cells (93). Poly(acrylic acid) gel of nanocapsules containing 1% CyA showed a better percent absorption (7.92 ± 2.55%) compared to 1% CyA solution in olive oil (5.81 ± 2.04%) after 24-hour contact time on bovine cornea ex vivo owing to the bioadhesive behavior of poly(acrylic acid) polymer and the encapsulated form. The nanocapsules incorporated in the gel were prepared by interfacial polymer deposition method, with isobutyl-2-cyanoacrylate and Miglyol 812 forming the polymer coating and the oily core, respectively. The nanocapsule gel presents a potential ocular drug delivery system with higher absorption rate and lower risk of toxicity to the cornea (94). In a study by De Campos et al. (49), chitosan nanoparticles developed for intraocular delivery of CyA (73% association efficiency and 9% loading) by ionic gelation technique showed improved levels of the lipophilic drug in the cornea and conjunctiva on topical administration to rabbit eyes compared to an aqueous CyA suspension. The studies confirmed that CyA was preferentially accumulated on the external tissues from chitosan nanoparticles while sparing the intraocular structures (49).

Polyalkylcyanoacrylate nanoparticles could also be used for antiinflammatory drugs to target inflamed ocular tissue as they have four times more affinity towards inflamed tissue compared to healthy tissue (95). Both indomethacin-loaded nanoparticles and nanocapsules performed better in terms of bioavailability and drug levels in the cornea compared to the commercial solution of the drug Indocollyre® when administered to rabbit eye (96). The nanocapsules were prepared by interfacial polymerization using PECL, lecithin, Miglyol 840 as oil, acetone, and poloxamer 188, while the nanoparticles were prepared omitting the oil and lecithin using a nano-precipitation method, and nanoemulsions were prepared by using spontaneous emulsification technique. The authors suggest that the colloidal particles are taken up by the corneal epithelium through an endocytic mechanism, and additionally, the colloidal nature of these formulations (nanocapsules and nanoparticles) aids in increasing the bioavailability (Fig. 4). These formulations provide a potential for treating intraocular inflammatory diseases with reduced doses of indomethacin. In another study, chitosan and poly-L-lysine (PLL)-coated PECL nanocapsules increased indomethacin levels in the cornea and aqueous humor of rabbits four times and eight times, respectively, compared to Indocollyre, the commercial eye drops (67). The positively charged PLL and chitosan coatings were employed in an attempt to increase interaction of the particles with the negatively charged corneal epithelium. However, it was found that it was the specific nature of CS and not the positive charge that was responsible for the enhanced uptake. PLL coating failed to enhance the uptake of the drug compared to the corresponding uncoated PECL nanocapsules.

Poly-e-caprolactone nanocapsules also showed good performance in increasing the ocular availability of drugs such as metipranolol (65) and betaxolol (66) while suppressing their systemic absorption. The PECL nano-capsules of metipranolol were prepared by interfacial polymerization tech-

nique incorporating the drug in a Miglyol 840 oily core. When administered to rabbits, the nanocapsules decreased the intraocular pressure similar to the commercial ophthalmic solution of the drug, but the systemic side effects, studied by evaluation of the cardiovascular effects, were significantly suppressed with the nanocapsules. The heart rate reached normal values within an hour of administration of nanocapsules versus the commercial eye drops, which showed pronounced bradycardia for more than 2 hours (97).

Acyclovir-loaded PEG-coated polyethyl-2-cyanoacrylate (PECA) nanospheres prepared by emulsion polymerization technique showed increased drug levels in the aqueous humor compared to the free drug suspension in the rabbits (83). Polylactide and polylactide-co-glycolide biopolymers in the molecular weight range of 3000-109,000 have been employed in the preparation of microparticulate systems for intravitreal administration of acyclovir (98). Spray-drying technique was employed for the preparation and the in vivo evaluation was performed by intravitreal administration in rabbits. The poly-D, L-lactide microspheres of acyclovir were more efficient compared to the free drug in providing a sustained release of the drug in the vitreous humor in rabbits. Not only is the initial drug concentration in vitreous humor attained with microspheres higher

Fig. 4 Permeation of indomethacin through isolated rabbit cornea: (~) PECL nanoparticles; (O) PECL nanocapsules; (□) submicron emulsion; and (*) commercial eye drops (Indocollyre). (From Ref. 96.)

Fig. 4 Permeation of indomethacin through isolated rabbit cornea: (~) PECL nanoparticles; (O) PECL nanocapsules; (□) submicron emulsion; and (*) commercial eye drops (Indocollyre). (From Ref. 96.)

compared to the free drug, but the drug levels with the former remained constant for 14 days, unlike the free drug. The drug concentration diminished to undetectable levels with free drug after 3 days.

PECL nanoparticles and nanocapsules (with a TiO5 oily core) have been studied for the glaucoma drug carteolol (99). Both formulations demonstrated a pronounced decrease in the intraocular pressure compared to the commercial aqueous solution, Carteol®, in rabbits with induced intraocular hypertension. The PECL carriers increase the residence time of the drug, enhance the corneal uptake of the drug in unionized form, and decrease the systemic side effects. Moreover, the studies show that PECL nanocapsules demonstrate a better effect compared to the PECL nanoparticles for carteolol. It was concluded that the drug entrapped in the oily core is more available for corneal absorption.

H-Labeled hydrocortisone- 17-butyrate-21-propionate (3H-HBP) loaded lipid microspheres have been shown to produce a significant increase in the drug levels in the cornea of rabbits compared to the control 3H-HBP suspension after 1 and 3 hours of administration (100). Kimura et al. (101) prepared 75:25 lactide/glycolide microspheres for an antifungal agent, fluconazole, used for the treatment of endophthalmitis. Microspheres of 1-10 ^m in diameter have been prepared with hyaluronate esters incorporating methylprednisolone as a model drug and by using the spray-drying technique (102,103). The carboxyl group of methylprednisolone was esterified for 50% of the drug content, while the remaining half was present as the sodium salt. From in vivo studies it was found that the drug could be delivered for long time with a lower drug peak concentration, diminished side effects, and enhanced bioavailability compared to the control suspension.

Pilocarpine-loaded albumin or gelatin microspheres (104) and acyclo-vir-loaded chitosan microspheres (105) have also been studied. Both micro-particulate systems were found to be superior to conventional dosage forms in terms of in vivo performance. Pilocarpine-loaded albumin or gelatin microspheres with an average particle size of 30 ^m were prepared by emul-sification of the aqueous solution of pilocarpine nitrate together with the macromolecule in sunflower oil and subsequent crosslinking with formaldehyde (for gelatin microspheres) or heating to 150° C (for albumin microspheres). Further, the oil was removed by washing with ether. The AUC of the miosis versus time curve was increased by 2.3 and 3.3 times for the gelatin and albumin microspheres, respectively, compared to the aqueous solution of the drug (104).

Binding betaxolol to ion-resin exchange resin microparticles (Betoptic® S) increases the drug bioavailability by reducing the drug release in the tear. Betoptic S 0.25% and Betoptic solution 0.5% are considered bioequivalent. Since introduction in the market, Betoptic S

has increased patient compliance by reducing the dose and frequency of dosing (106). Marchal-Heussler et al. (66) studied betaxolol-loaded nano-spheres or nanocapsules using three different polymers: polyisobutylcya-noacrylate, a copolymer of lactic and glycolic acid, and PECL. The intraocular pressure-lowering effect was most pronounced for the PECL nanocapsules or nanospheres compared to other two polymers as well as the commercial eye drops, owing to the higher hydrophobicity exhibited by PECL. The hydrophobic character of the polymer allows agglomeration of the nanoparticles in the eye and subsequent prolongation of the drug residence time in the precorneal area. Further, PECL nanocapsules performed better compared to the corresponding nanospheres in that the drug entrapped in the unionized form in the oily core could penetrate better into the cornea (66).

5-Fluorouracil and adriamycin loaded microspheres or poly(lactic acid) and copolymer of lactic/glycolic acid have been prepared using the solvent evaporation method (107,108). The formulations for both the antiproliferative drugs excelled in their in vivo intravitreal kinetics in rabbits compared to their corresponding controls. A 10 ^g injection of adriamycin solution led to severe toxic reaction in the retina, while the same amount of drug incorporated in the microspheres substantially decreased the rate of retinal detachment after 4 weeks with no detectable toxic effects. The drug release from 5-FU loaded microspheres extended up to 7 days with no subsequent adverse effects to the ocular tissue.

As shown in Fig. 5, piroxicam loaded in the pectin microspheres (M1, M2) showed faster in vitro dissolution rates compared to the solid micro-nized drug (109). The precorneal retention of fluorescein-loaded piroxicam microspheres was evaluated in vivo in albino rabbits, and it was observed that an aqueous dispersion of microspheres showed a significantly increased residence time in the eye (2.5 vs. 0.5 h) when compared to a control fluorescein solution. This study also showed significantly improved bioavailability of piroxicam from microspheres in aqueous humor when compared to the commercial piroxicam eyedrops.

In a study involving pilocarpine (110), polyisobutylcyanoacrylate nanocapsules containing 1 % pilocarpine were dispersed in an aqueous medium (I) and compared to the same nanocapsule formulation incorporated into a Pluronic® F127 gel delivery system (II) and 1% pilocarpine incorporated into a Pluronic F127 gel containing 5% methyl cellulose (III), by measuring the miotic response in the albino rabbit eye. As shown in Figure 6, polyisobutylcyanoacrylate nanocapsules of pilocarpine dispersed in the Pluronic F127 gel (II) showed extended release of pilocarpine compared to formulations (I) and (III) with respect to the length of miotic response time. As shown in Table 2, statistical analysis indicated a rank

Fig. 5 In vitro release profiles of piroxicam microspheres M1 and M2 compared to the dissolution profile of micronized piroxicam powder. (From Ref. 109.)
Fig. 6 Miotic response to various formulations of 1% pilocarpine in the albino rabbit eye. (From Ref. 110.)

Table 2 Mitotic Response to Various Pilocarpine Formulations in Albino Rabbit Eyea

Ol 8

Time to peak response (Tp, min)

Duration of mitotic response (min)

Intensity of response (AUC,b mm. min)

Peak change in the pupil diameter (Imax, mm)


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