L-Carnosine: multifunctional dipeptide buffer for sustained-duration topical ophthalmic formulations.
OBJECTIVE
The use of l-carnosine as an excipient in topical ophthalmic formulations containing gellan gum, a carbohydrate polymer with in-situ gelling properties upon mixing with mammalian tear fluid, was developed as a novel platform to extend precorneal duration. Specific utilisation of l-carnosine as a buffer in gellan gum carrying vehicles was characterised.


METHODS
Buffer capacity was evaluated using 7.5, 13.3, and 44.2 mm l-carnosine in a pH range of 5.5-7.5. Accelerated chemical stability was determined by HPLC at l-carnosine concentrations of 5-100 mm. Combinations of 7.5 mm l-carnosine with 0.06-0.6% (w/v) gellan gum were characterised rheologically. l-Carnosine-buffered solutions of gellan gum were tested for acute topical ocular tolerance in vivo in pigmented rabbits. A unique formulation combining timolol (which lowers intraocular pressure) in l-carnosine-buffered gellan gum was compared with Timoptic-XE in normotensive dogs.


RESULTS
l-Carnosine exhibited optimal pharmaceutical characteristics for use as a buffer in chronically administered topical ocular formulations. Enhancement trends were observed in solution-to-gel transition of l-carnosine-buffered vehicles containing gellan gum vs comparators. Topical tolerability of l-carnosine-buffered gellan gum formulations and lowering of intraocular pressure were equivalent with timolol and Timoptic-XE.


CONCLUSIONS
Functional synergy between excipients in gellan gum formulations buffered with l-carnosine has potential for topical ocular dosage forms with sustained precorneal residence.
Singh
Swita R
SR
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Carreiro
Samantha T
ST
Chu
Jessie
J
Prasanna
Ganesh
G
Niesman
Michael R
MR
Collette Iii
Walter W
WW
Younis
Husam S
HS
Sartnurak
Soisurin
S
Gukasyan
Hovhannes J
HJ
D000287:Administration, Topical; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology; D002021:Buffers; D002336:Carnosine / Q000008:administration & dosage* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004151:Dipeptides / Q000008:administration & dosage* / Q000494:pharmacology; D004285:Dogs; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D005079:Excipients / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D005782:Gels; D006863:Hydrogen-Ion Concentration; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D009883:Ophthalmic Solutions; D011135:Polysaccharides, Bacterial / Q000737:chemistry; D011817:Rabbits; D012212:Rheology; D013999:Timolol / Q000008:administration & dosage / Q000494:pharmacology
D000959:Antihypertensive Agents; D002021:Buffers; D003692:Delayed-Action Preparations; D004151:Dipeptides; D004337:Drug Carriers; D005079:Excipients; D005782:Gels; D009883:Ophthalmic Solutions; D011135:Polysaccharides, Bacterial; C048288:gellan gum; D013999:Timolol; D002336:Carnosine