Improvement of the ocular bioavailability of timolol by sorbic acid.
The ocular bioavailability of timolol increased in sorbic acid solution due to ion pair formation. Its octanol/water partition coefficient also increased, suggesting the formation of a more lipophilic complex. The concentration of timolol in rabbit aqueous humor was determined after instillation of timolol ophthalmic solution containing sorbic acid. When the molar ratio of sorbic acid to timolol was two or higher, the concentration of timolol in the aqueous humor was higher than with timolol alone. In the presence of sorbic acid the maximal aqueous humor concentration and the area under the curve were more than two-fold higher than those of Timoptol, a timolol maleate ophthalmic solution, and similar in value to TIMOPTIC-XE, a gel-forming ophthalmic solution. To investigate the transcorneal absorption mechanism, in vitro permeation profiles across the intact and de-epithelialyzed cornea were analyzed on the basis of the bilayer diffusion model. The partition coefficient in the epithelium was about twice as high in the presence of sorbic acid than with timolol alone, although the diffusion coefficient in the epithelium did not change. We conclude that the improved ocular bioavailability in the presence of sorbic acid is due to increased partitioning of timolol in the corneal epithelium.
Higashiyama
Masayo
M
Research Laboratories, Senju Pharmaceutical Co., Ltd., 1-5-4 Murotani, Nishi-ku, Kobe 651-2241, Japan. m-higashiyama@senju.co.jp
Inada
Katsuhiro
K
Ohtori
Akira
A
Tojo
Kakuji
K
D000287:Administration, Topical; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003315:Cornea / Q000187:drug effects / Q000378:metabolism; D005079:Excipients / Q000737:chemistry / Q000494:pharmacology*; D005782:Gels; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D000442:Octanols / Q000737:chemistry; D009883:Ophthalmic Solutions; D010539:Permeability; D011817:Rabbits; D013011:Sorbic Acid / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D013999:Timolol / Q000737:chemistry / Q000493:pharmacokinetics*; D014867:Water / Q000737:chemistry
D000319:Adrenergic beta-Antagonists; D005079:Excipients; D005782:Gels; D000442:Octanols; D009883:Ophthalmic Solutions; D014867:Water; D013999:Timolol; D013011:Sorbic Acid