Biodegradable ocular inserts for sustained delivery of brimonidine tartarate: preparation and in vitro/in vivo evaluation

Abstract

The bioavailability of therapeutic agents from eye drops is usually limited due to corneal barrier functions and effective eye protective mechanisms. Therefore, the current study aims to enhance ocular bioavailability of brimonidine, a potent antiglaucoma drug, through the preparation of ocular inserts. Solvent casting technique was employed to prepare the inserts using polyvinylpyrrolidone K-90 (PVP K-90) as film-forming polymer blended with different viscosity grades of bioadhesive polymers namely hydroxypropyl methycellulose, carbopol, sodium alginate, and chitosan. The prepared ocular inserts were evaluated for various physicochemical parameters, swelling behavior, and in vitro release patterns. Sodium alginate-based ocular inserts revealed the most sustainment in drug release (99% at 6 h), so it was selected for further modifications via coating it, on one side or dual sides, using hydrophobic film composed of either ethylcellulose or Eudragit RSPO. The obtained in vitro release results for the modified ocular inserts revealed that ethylcellulose is superior to Eudragit RSPO in terms of brimonidine release sustainment effect. Ocular inserts composed of 7% PVP K-90, 1.5% low molecular weight sodium alginate with or without ethylcellulose coat were able to sustain the in vitro release of brimonidine. Their therapeutic efficacy regarding intraocular pressure (IOP) lowering effect when inserted in albino rabbits eyes showed superior sustainment effect compared with that of brimonidine solution. Furthermore, due to both the mucoadhesive property and the drug sustainment effect, the one-side-coated ocular insert showed more IOP lowering effect compared with that of its non-coated or dual-side-coated counterpart.

Fig. 1

Insertion of the ocular insert in the cul-de-sac of the rabbit’s left eye

Fig. 2

a Swelling profiles of ocular inserts containing brimonidine. b Swelling profiles of ethylcellulose-coated ocular inserts (one side or dual sides) containing brimonidine. c Swelling profiles of Eudragit RLPO-coated ocular inserts (one side or dual sides) containing brimonidine. (LM low molecular weight, MM medium molecular weight, EC ethylcellulose, ED Eudragit RLPO)

Fig. 3

Brimonidine release pattern from ocular inserts prepared from different viscosity grades of sodium alginate, HPMC, and chitosan. (LM low molecular weight, MM medium molecular weight)

Fig. 4

Brimonidine release pattern from ocular inserts prepared from different viscosity grades of sodium alginate coated with Eudragit RSPO. (LM low molecular weight, MM medium molecular weight, ED Eudragit RSPO)

Fig. 5

Brimonidine release pattern from ocular inserts prepared from different viscosity grades of sodium alginate coated with ethylcellulose. (LM low molecular weight, MM medium molecular weight, EC ethylcellulose)

Fig. 6

DSC analysis of brimonidine, sodium alginate, PVP K-90, physical mixture of polymers, non-medicated F2a ocular insert and medicated ocular F2a insert

Fig. 7

XRD diffractometry of brimonidine (1), sodium alginate (2), PVP K-90 (3), physical mixture of polymers (4), non-medicated F2a ocular insert, (5) and medicated ocular F2a insert (6)

Fig. 8

FTIR spectra of brimonidine (1), sodium alginate (2), PVP K-90 (3), physical mixture of polymers, and (4) medicated ocular F2a insert (5)

Fig. 9

Percentage decrease in intraocular pressure (IOP) after administration of brimonidine solution and inserts