New mucoadhesive chitosan film for ophthalmic drug delivery of timolol maleate: in vivo evaluation.
OBJECTIVE
Chitosan, a cationic polysaccharide biopolymer with mucoadhesive properties, presents a promising future in the prolonged ocular delivery of drugs. The present study compared the efficacy and safety of chitosan-coated timolol maleate (TM) mucoadhesive film, using a 0.5% TM commercial ophthalmic solution in a rabbit model. In addition, this study investigates the maximum release time of these implants in vivo.


METHODS
The mucoadhesive films were prepared by means of a casting and solvent evaporation technique performed in a 2 wt% acetic acid solution and distilled water. Physical properties were characterized by release and swelling studies, differential scanning calorimetry, and attenuated total reflectance fourier transformed infrared spectroscopy (ATR-FTIR). The developed formulations were evaluated for their pharmacodynamics in ocular normotensive albino rabbits, in which the intraocular pressure (IOP) was measured by means of applanation tonometer on alternative days (13 h) for 11 weeks. For 15 days, 0.5% TM commercial ophthalmic solution was administered twice a day (n=5) and compared to chitosan-coated TM (n=5). In the control group (n=5), saline was used twice a day. The maximum TM release time from chitosan films were also recorded. After euthanasia, the right eyes were removed from the 3 groups for histological analyses.


RESULTS
In an in vitro study, TM was released over a 4-week period, in which 85% of the drug was released over the first 2 weeks. However, the film's release of TM lowered the in vivo IOP levels over a 10-week period. No significant difference in the lowering of IOP in rabbits treated with 0.5% TM commercial ophthalmic solution, as compared to those that received the films (P<0.05), could be observed. No signs of ocular discomfort or irritations could be identified upon ophthalmic examination by slit-lamp biomicroscopy. Ophthalmic structures that came in direct contact with the films revealed no alterations within the histopathological studies. Moreover, the animals showed no signs of ocular discomfort during the experimental assays.


CONCLUSIONS
These findings suggest that the TM-loaded chitosan film is safe and efficient and presents a promising future as an ocular drug delivery system in the treatment and prevention of glaucoma.
Department of Ophthalmology, School of Veterinary Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil. fulgenciobr@yahoo.com.br
Gustavo de Oliveira
Gde O
Fulgêncio
Fernando Antônio Bretas
FA
Viana
Raul Rio
RR
Ribeiro
Maria Irene
MI
Yoshida
André Gomes
AG
Faraco
Armando da Silva
Ada S
Cunha-Júnior
D000287:Administration, Topical; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage* / Q000032:analysis; D000818:Animals; D002152:Calorimetry, Differential Scanning; D048271:Chitosan; D016503:Drug Delivery Systems; D005123:Eye / Q000187:drug effects / Q000473:pathology; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D009883:Ophthalmic Solutions; D011817:Rabbits; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared; D013999:Timolol / Q000008:administration & dosage* / Q000032:analysis; D014014:Tissue Adhesives; D014867:Water / Q000032:analysis
D000319:Adrenergic beta-Antagonists; D009883:Ophthalmic Solutions; D014014:Tissue Adhesives; D014867:Water; D013999:Timolol; D048271:Chitosan