title: Preparation and solid-state characterization of bupivacaine hydrochloride cyclodextrin complexes aimed for buccal delivery.
abstract: Binary products of bupivacaine hydrochloride (BVP HCl), an amide type local anesthetic, with parent beta-cyclodextrin (beta-CD) and its soluble beta-cyclodextrin-epichlorohydrin polymer (EPI-beta-CD) were prepared and evaluated as a first phase in the development of a novel mucoadhesive formulation aimed for buccal delivery of this drug. The solid products were obtained by physical mixing, ball milling in high-energy mills, co-evaporation and lyophilisation, in order to rationally select the most effective preparation technique. The solid products obtained were carefully characterised by differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared spectroscopy (FTIR) and environmental scanning electron microscopy (ESEM). The impact of the preparation techniques on the physicochemical properties of plain drug was also studied. Results of solid-state analysis revealed more intense interactions of BVP HCl with EPI-beta-CD than with native beta-CD, accompanied by stronger reduction of drug crystallinity in the samples, probably favoured by the amorphous nature of the polymeric carrier. While summarising the results of DSC and XRPD analyses, it seems that ball milling of drug/cyclodextrin binary mixtures was particularly efficient in inducing solid-state interaction between the components and it can be considered as the method of choice for preparation of complexes of BVP HCl with beta-CD and EPI-beta-CD. In vitro dissolution properties in artificial saliva of ball-milled BVP HCl and corresponding CD complexes were investigated by simulating the conditions present at the surface of the buccal mucosa. The obtained results confirmed that complexation of BVP HCl with beta-CD and EPI-beta-CD is a suitable tool for properly tailoring the dissolution properties of the drug and it can be favourably exploited for the development of an effective buccal drug delivery system.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovacića 1, HR-10000 Zagreb, Croatia. mjug@pharma.hr
authors.forename: Mario
authors.initials: M
authors.lastname: Jug
authors.forename: Francesca
authors.initials: F
authors.lastname: Maestrelli
authors.forename: Marco
authors.initials: M
authors.lastname: Bragagni
authors.forename: Paola
authors.initials: P
authors.lastname: Mura
mesh_terms: D000278:Administration, Buccal; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000737:chemistry*; D002045:Bupivacaine / Q000008:administration & dosage / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D004304:Dosage Forms; D004337:Drug Carriers; D004339:Drug Compounding; D004811:Epichlorohydrin / Q000737:chemistry*; D005612:Freeze Drying; D007700:Kinetics; D008855:Microscopy, Electron, Scanning; D011108:Polymers / Q000737:chemistry*; D033362:Powder Diffraction; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013678:Technology, Pharmaceutical / Q000379:methods; D014835:Volatilization; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000779:Anesthetics, Local; D004304:Dosage Forms; D004337:Drug Carriers; D011108:Polymers; D047392:beta-Cyclodextrins; C102558:cyclodextrin-epichlorohydrin polymer; D004811:Epichlorohydrin; D002045:Bupivacaine