title: Cyclooxygenase inhibition by diclofenac formulated in bioadhesive carriers.
abstract: Adverse effects and gastrointestinal toxicity limit the use of Diclofenac, a frequently-used NSAID for treatments of rheumatic disorders and other chronic inflammatory diseases. Diclofenac-carrier formulations may alleviate adverse effects, increase efficacy and allow local administration. We report here our first step, biophysical and biochemical investigations of Diclofenac formulated in our previously-developed bioadhesive liposomes carrying hyaluronan (HA-BAL) or collagen (COL-BAL) on their surface. Both liposome types encapsulated Diclofenac at high efficiency, encapsulated doses reaching 13 mg drug/ml, and performed as sustained-release Diclofenac depots, half-lives of drug release (under fastest conditions) ranging from 1 to 3 days. Therapeutic activity of liposomal Diclofenac was evaluated in CT-26 cells that possess the CD44 hyaluronan receptors and integrins, and are a bench-mark for intracellular COX enzymes. HA-BAL and COL-BAL showed high cellular-affinity that was 40 fold and 6 fold over that of regular liposomes. Free, and liposome-encapsulated, Diclofenac showed similar activities. For example: 2-3nM Diclofenac given to intact cells generated COX-inhibition levels in the range of 60-70% for free drug and for encapsulated drug in COL-BAL and in HA-BAL. We propose these novel Diclofenac formulations possess key physicochemical and biochemical attributes for task performance, meriting the next step into in vivo studies.
authors.affiliation: Department of Biochemistry, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Inbar
authors.initials: I
authors.lastname: Elron-Gross
authors.forename: Yifat
authors.initials: Y
authors.lastname: Glucksam
authors.forename: Dina
authors.initials: D
authors.lastname: Melikhov
authors.forename: Rimona
authors.initials: R
authors.lastname: Margalit
mesh_terms: D000268:Adhesiveness / Q000187:drug effects; D000818:Animals; D000906:Antibodies; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology*; D004337:Drug Carriers / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate; D006801:Humans; D007700:Kinetics; D008081:Liposomes; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
chemical_list: D000906:Antibodies; D016861:Cyclooxygenase Inhibitors; D004337:Drug Carriers; D008081:Liposomes; D004008:Diclofenac; D011451:Prostaglandin-Endoperoxide Synthases; D016650:Fluorescein-5-isothiocyanate