title: Formulation of sirolimus eye drops and corneal permeation studies.
abstract: The aim of this study was the development of eye drops with 1 mg/mL sirolimus and the evaluation of the drug's ability to permeate the freshly isolated pig cornea. Cyclodextrin solutions, liposomes, hydrotrope mixtures, poloxamer gels, and a microemulsion were tested for their suitability to dissolve the extremely hydrophobic drug sirolimus (solubility in water 2.6 microg/mL). The drug content in the formulations was determined by high-performance liquid chromatography, whereas this method is not sensitive enough for the quantification of therapeutic concentrations (7-12 ng/mL). Thus, the acceptor samples of the permeation tests were examined by microparticle enzyme immunoassay. A microemulsion is a suitable vehicle to prepare eye drops with sufficient sirolimus concentrations of 1 mg/mL in a formulation with acceptable tolerance and satisfactory stability over 12 months. However, the drug cannot permeate the intact cornea. After removal of the corneal epithelium, drug concentrations in the acceptor sample reach the lower limit of therapeutical levels. Conclusively, the present sirolimus eye drops might be promising therapeutic tools for the immunomodulatory treatment of ocular surface disorders, such as keratoconjunctivitis sicca, vernal conjunctivitis, or atopical blepharitis. They are not suitable to achieve therapeutic concentrations in the aqueous humour of patients with intact cornea.
authors.affiliation: Institute of Pharmacy, Free University of Berlin, Berlin, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Buech
authors.forename: Eckart
authors.initials: E
authors.lastname: Bertelmann
authors.forename: Uwe
authors.initials: U
authors.lastname: Pleyer
authors.forename: Ingo
authors.initials: I
authors.lastname: Siebenbrodt
authors.forename: Hans-Hubert
authors.initials: HH
authors.lastname: Borchert
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003315:Cornea / Q000187:drug effects* / Q000378:metabolism; D004355:Drug Stability; D004356:Drug Storage; D004655:Emulsions; D005079:Excipients / Q000737:chemistry*; D005782:Gels; D057927:Hydrophobic and Hydrophilic Interactions; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008081:Liposomes; D009883:Ophthalmic Solutions / Q000493:pharmacokinetics*; D010539:Permeability; D020442:Poloxamer / Q000737:chemistry; D020123:Sirolimus / Q000493:pharmacokinetics*; D012995:Solubility; D013552:Swine; D047392:beta-Cyclodextrins / Q000737:chemistry; D047408:gamma-Cyclodextrins / Q000737:chemistry
chemical_list: D004655:Emulsions; D005079:Excipients; D005782:Gels; D007166:Immunosuppressive Agents; D008081:Liposomes; D009883:Ophthalmic Solutions; D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins; C479659:hydroxypropyl-gamma-cyclodextrin; D020442:Poloxamer; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D020123:Sirolimus