title: Influence of cyclodextrins on the in vitro corneal permeability and in vivo ocular distribution of thalidomide.
abstract: The aim of the present study has been to develop aqueous Thalidomide (THA) eye drops in order to minimize systemic side effects and to improve bioavailability following topical application. Cyclodextrins (CDs), suitable vehicles to improve aqueous solubility of THA, were evaluated with regard to their ability to influence in vitro corneal permeability of THA. Additionally, rabbit eyes received either THA-suspension (0.04%) (THA-SP) or THA (0.04%)/hydroxypropyl-beta-cyclodextrin (HP-beta-CD) (12.5%) solution (THA-CD). In vitro corneal permeation studies demonstrated that the absolute amount of THA permeated could not be increased by means of CDs. The percentile release of THA was extensively decreased using saturated THA/CD solutions. Following loading doses of either THA-CD or THA-SP onto the rabbit eye, significantly increased aqueous humor levels were obtained for THA-CD 30 min (THA-CD:THA-SP=4.6:1) and 60 min (THA-CD:THA-SP=3.1:1) post instillation (p<0.05). In the iris-ciliary body, significantly increased THA levels were obtained using THA suspension (THA-CD(60 min):THA-SP(60 min)=1:6.1) (p<0.05). In the cornea, conjunctiva, vitreous and sclera, differences between the THA tissue levels were not statistically significant. Cyclodextrins might be a useful tool to formulate aqueous THA eye drop solutions and modify intraocular drug bioavailability.
authors.affiliation: Klinge Pharma GmbH, Technological Development Laboratories, Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Siefert
authors.forename: U
authors.initials: U
authors.lastname: Pleyer
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: C
authors.initials: C
authors.lastname: Hartmann
authors.forename: S
authors.initials: S
authors.lastname: Keipert
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D001082:Aqueous Humor / Q000737:chemistry; D001682:Biological Availability; D002417:Cattle; D002924:Ciliary Body / Q000737:chemistry; D003228:Conjunctiva / Q000737:chemistry; D003315:Cornea / Q000502:physiology*; D003505:Cyclodextrins / Q000494:pharmacology*; D004347:Drug Interactions; D066298:In Vitro Techniques; D007498:Iris / Q000737:chemistry; D008297:Male; D009883:Ophthalmic Solutions / Q000493:pharmacokinetics; D010539:Permeability / Q000187:drug effects; D011817:Rabbits; D012590:Sclera / Q000737:chemistry; D013792:Thalidomide / Q000493:pharmacokinetics*; D013997:Time Factors; D014822:Vitreous Body / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D003505:Cyclodextrins; D009883:Ophthalmic Solutions; D013792:Thalidomide