Abstract
Purpose:
Ilomastat is a matrix metalloproteinase inhibitor (MMPi) that has been shown to inhibit fibrosis after glaucoma filtration surgery (GFS) in a rabbit model of ocular fibrosis. To reduce scarring and fibrosis following glaucoma surgery, a sustained dosage form would be advantageous that allows a prolonged local concentration of ilomastat to be maintained within the subconjunctival space. Hyaluronic acid (HA) is used in ocular medicine. HA was examined as a matrix to fabricate a small tablet for subconjunctival implantation after GFS.
Methods:
Ilomastat (1.0 mg) was dissolved in butanol (40% w/v). An aqueous solution of hyaluronic acid (3.0 mg) was prepared. The ilomastat solutions was then added to the aqueous polymer solution and gently mixed overnight. The mixture was freeze dried. The lyophilised powder was pressed into a tablet using 3 mm punch and die. The release of ilomastat from the tablet in phosphate buffered saline (PH 7.4) was determined at flow rate of 2.0 µL at 35.0 °C in a flow rig. The concentration of the released ilomastat was measured using by HPLC at 280 nm.
Results:
A small tablet designed for ocular implantation was successfully fabricated with a dispersion of ilomastat in both linear and cross linked HA matrices. The weight of the tablet was in the range of 4.5-6.5 mg. Fabrication of the ilomastat tablet using linear HA (Healon® GV) resulted in a sustained release of ilomastat over 11 days with a total ilomastat release of 83.2±1.8% (maximum ilomastat concentration of 246.5±32.3 µM at tmax of 31.0±18.0 h). The release of ilomastat was more prolonged when cross linked HA (Healaflow®) was used. A total of 101.48±4.48% was released after 26 days with a maximum concentration of 212.01±23.31 µM (t max 4.3 h). The concentration of the released ilomastat was within the therapeutic range (10-100 µM). The total release of ilomastat from a mixture of linear and cross linked HA (1:1) was 63.3 % (maximum concentration of ilomastat was 199.5 µM at tmax of 33.1 h) after 14 days. The release of ilomastat was faster when more linear HA was incorporated in the dispersion mixture.
Conclusions:
Sustained release of ilomastat was achieved by its dispersion in cross linked HA matrix up to 28 days. The prolonged release of ilomastat from a dispersion of cross linked HA may be suitable for a successful sub-conjunctiva implant for improvement of the outcome of glaucoma filtration surgery.
Keywords: 765 wound healing •
474 conjunctiva