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Sebastiano Mangiafico, Danilo Aleo, Maria G. Saita, Sergio Mangiafico, Melina G. Cro, Emanuala Esposito, Salvatore Cuzzocrea; A Mucoadhesive, Innovative, Topical Combination of Latanoprost and Dorzolamide. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5019.
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Topical 2% Dorzolamide (DZ) and 0.005% Latanoprost (LAT) are two of the most worldwide used drugs in the treatment of glaucoma and ocular hypertension. The combination of the two drugs in the same formulation could give several advantages in the management of glaucoma. However, the association of DZ and LAT in the same aqueous formulation is a very difficult problem in order to maintain their stability. The aim of the study was the preparation of a stable, well tolerated and bioavailable topical formulation of 2% DZ associated to a 0.005% LAT.
2% DZ•HCl was dissolved at pH 6.5 in Hydroxypropyl-β-cyclodextrin (HPβCD), 0.005% LAT and Hyaluronic acid were added in aqueous phosphate buffered and Polyhexanide preserved solution (COMBO 6.5). Stability was evaluated under ICH protocol. Intraocular bioavailability. COMBO 6.5 (Group I) was compared with TRUSOPT (Group II) and XALATAN (Group III). 36 pigmented rabbits (12 animals for each 3 group) were treated with 5 instillations (25µl) each within 15 minutes and aqueous humor concentrations of the actives evaluated after 1h, 2h, 4h and 8h of the last instillation. Irritation Test was performed by the reconstituted Human Corneal Epithelial (HCE) model from SkinEthic Laboratories. Local Acute Tolerability was performed by the classical Draize’s test.
Stability. COMBO 6.5 after 36 months of storage (25°C±2,RH40%), showed a 6% degradation of DZ. HPβCD exerted also a surprising effect on the LAT stability (-2%). No significant variation of osmolarity and pH were registered. Intraocular bioavailability. AUC0-8h of the aqueous humor concentrations of DZ and LAT of COMBO 6.5 were higher than those obtained after TRUSOPT or XALATAN instillations (AUC 0-8h TRUSOPT=20.5µg•h•ml-1,AUC 0-8h XALATAN=1020ng•h•ml-1, AUC 0-8h COMBO6.5 (DZ)=40.2 µg•h•ml-1 and AUC 0-8h COMBO 6.5 (LAT)=1143.5 ng•h•ml-1). Irritation Test. None of the tested formulations have demonstrated variations in the cell viability. Local Acute Tolerability. No edema or other significative alterations of ocular tissues have been noted in the rabbits treated with COMBO 6.5, TRUSOPT or XALATAN vs non treated controlateral eye.
COMBO 6.5 formulation is potentially very useful in the management of glaucoma and ocular hypertension.
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