title: Characterisation of an inclusion complex between cladribine and 2-hydroxypropyl-beta-cyclodextrin.
abstract: Parenterally administered cladribine (2-chloro-2'-deoxyadenosine) has demonstrated promising efficacy and safety in clinical trials in patients with multiple sclerosis (MS). An oral formulation of this small molecule would be an attractive option for patients. Here, we describe the chemical characterisation of the inclusion complex between cladribine and the drug carrier molecule 2-hydroxypropyl-beta-cyclodextrin (2-HP-beta-CD). Several techniques were used to analyse the complex both in solution and in the solid state. These analyses provided evidence that the inclusion complex cannot be simply reduced to the sum of the two species, as it shows behaviour different from that of the physical mixture of the two components. Furthermore, solution nuclear magnetic resonance spectroscopy demonstrated the existence of an inclusion complex between cladribine and 2-HP-beta-CD. Importantly, analysis of a tablet formulation demonstrated that the chemical characteristics of the inclusion complex are not affected by the manufacturing process, and that the complex is stable during storage. This tablet formulation is currently under investigation for the treatment of patients with MS.
authors.affiliation: Merck Serono SpA, Tiburtina Site, via L Einaudi 11, 00012 Guidonia Montecelio, Roma, Italy. valeria.vanaxel@merckserono.net
authors.forename: Valeria
authors.initials: V
authors.lastname: Van Axel Castelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Trivieri
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zucchelli
authors.forename: Luigi
authors.initials: L
authors.lastname: Brambilla
authors.forename: Tony
authors.initials: T
authors.lastname: Barbuzzi
authors.forename: Chiara
authors.initials: C
authors.lastname: Castiglioni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Paci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zerbi
authors.forename: Margherita
authors.initials: M
authors.lastname: Zanol
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D002152:Calorimetry, Differential Scanning; D017338:Cladribine / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry*; D009103:Multiple Sclerosis / Q000188:drug therapy; D013057:Spectrum Analysis / Q000379:methods; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D007166:Immunosuppressive Agents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D017338:Cladribine