A biodegradable injectable implant sustains systemic and ocular delivery of an aldose reductase inhibitor and ameliorates biochemical changes in a galactose-fed rat model for diabetic complications.
OBJECTIVE
To fabricate and characterize in vitro and in vivo performance of a sustained release biodegradable implant for N-4-(benzoylaminophenylsulfonyl glycine) (BAPSG), a novel aldose reductase inhibitor.


METHODS
The ability of BAPSG to inhibit aldose reductase activity and glucose-induced vascular endothelial growth factor (VEGF) expression was assessed in a retinal pigment epithelial cell line (ARPE-19). A poly (DL-lactic-co-glycolic acid) implant containing 50% w/w BAPSG was fabricated and characterized for drug loading, in vitro drug release, and the thermal behavior of the drug and the polymer. Implants were injected subcutaneously into a galactose-fed diabetic rat model and cataract scores, plasma and tissue drug levels, galactitol levels in the lens and the retina, glutathione levels in the plasma, lens, cornea and retina and VEGF expression in the retina were determined on or until 18 days.


RESULTS
BAPSG inhibited aldose reductase activity and reduced VEGF expression in ARPE-19 cells. Implants (1 x 4 mm), with a loading efficiency of 106 +/- 7% for BAPSG, were fabricated. Upon implant fabrication, while the glass transition temperature of the polymer decreased, the melting point of the drug was not affected. In vivo drug release correlated well with in vitro release, with approximately 44% drug release occurring in vivo by the end of 18 days. The implant reduced galactitol accumulation, glutathione depletion, cataract scores, and VEGF expression in galactose-fed rats.


CONCLUSIONS
An injectable biodegradable implant of BAPSG sustained drug release in vitro and in vivo, and reduced galactitol accumulation, glutathione depletion, cataract scores, and VEGF expression in galactose-fed rats.
Aukunuru
Jithan V
JV
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198-6025, USA.
Sunkara
Gangadhar
G
Ayalasomayajula
Surya P
SP
DeRuiter
Jack
J
Clark
Randall C
RC
Kompella
Uday B
UB
D020341:Absorbable Implants / Q000706:statistics & numerical data*; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods* / Q000706:statistics & numerical data; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D006801:Humans; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000097:blood; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C062604:N-(((4-benzoylamino)phenyl)sulfonyl)glycine; D000449:Aldehyde Reductase; D005998:Glycine