title: Spray-dried mucoadhesives for intravesical drug delivery using N-acetylcysteine- and glutathione-glycol chitosan conjugates.
abstract: This work describes N-acetylcysteine (NAC)- and glutathione (GSH)-glycol chitosan (GC) polymer conjugates engineered as potential platform useful to formulate micro-(MP) and nano-(NP) particles via spray-drying techniques. These conjugates are mucoadhesive over the range of urine pH, 5.0-7.0, which makes them advantageous for intravesical drug delivery and treatment of local bladder diseases. NAC- and GSH-GC conjugates were generated with a synthetic approach optimizing reaction times and purification in order to minimize the oxidation of thiol groups. In this way, the resulting amount of free thiol groups immobilized per gram of NAC- and GSH-GC conjugates was 6.3 and 3.6mmol, respectively. These polymers were completely characterized by molecular weight, surface sulfur content, solubility at different pH values, substitution and swelling degree. Mucoadhesion properties were evaluated in artificial urine by turbidimetric and zeta (ζ)-potential measurements demonstrating good mucoadhesion properties, in particular for NAC-GC at pH 5.0. Starting from the thiolated polymers, MP and NP were prepared using both the Büchi B-191 and Nano Büchi B-90 spray dryers, respectively. The resulting two formulations were evaluated for yield, size, oxidation of thiol groups and ex-vivo mucoadhesion. The new spray drying technique provided NP of suitable size (<1μm) for catheter administration, low degree of oxidation, and sufficient mucoadhesion property with 9% and 18% of GSH- and NAC-GC based NP retained on pig mucosa bladder after 3h of exposure, respectively.
  
  
  
  The aim of the present study was first to optimize the synthesis of NAC-GC and GSH-GC, and preserve the oxidation state of the thiol moieties by introducing several optimizations of the already reported synthetic procedures that increase the mucoadhesive properties and avoid pH-dependent aggregation. Second, starting from these optimized thiomers, we studied the feasibility of manufacturing MP and NP by spray-drying techniques. The aim of this second step was to produce mucoadhesive drug delivery systems of adequate size for vesical administration by catheter, and comparable mucoadhesive properties with respect to the processed polymers, avoiding thiolic oxidation during the formulation. MP with acceptable size produced by spray-dryer Büchi B-191 were compared with NP made with the apparatus Nano Büchi B-90.
authors.affiliation: Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Orabona, St. 4, 70125 Bari, Italy. Electronic address: nunzio.denora@uniba.it.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Denora
authors.affiliation: Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Orabona, St. 4, 70125 Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Lopedota
authors.affiliation: Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Orabona, St. 4, 70125 Bari, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Perrone
authors.affiliation: Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Orabona, St. 4, 70125 Bari, Italy.
authors.forename: Valentino
authors.initials: V
authors.lastname: Laquintana
authors.affiliation: Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Orabona, St. 4, 70125 Bari, Italy; Istituto Tumori IRCCS "Giovanni Paolo II", Flacco, St. 65, 70124 Bari, Italy.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Iacobazzi
authors.affiliation: Department of Chemistry, University of Bari "A. Moro", Orabona, St. 4, 70125 Bari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Milella
authors.affiliation: Department of Chemistry, University of Bari "A. Moro", Orabona, St. 4, 70125 Bari, Italy; CNR-Institute for Physical and Chemical Processes UOS, Bari, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Fanizza
authors.affiliation: CNR-Institute for Physical and Chemical Processes UOS, Bari, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Depalo
authors.affiliation: Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Orabona, St. 4, 70125 Bari, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Cutrignelli
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopalco
authors.affiliation: Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Orabona, St. 4, 70125 Bari, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Franco
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry / Q000494:pharmacology*; D000269:Adhesives / Q000494:pharmacology*; D000283:Administration, Intravesical; D000818:Animals; D048271:Chitosan / Q000494:pharmacology*; D002850:Chromatography, Gel; D003890:Desiccation; D016503:Drug Delivery Systems; D005978:Glutathione / Q000737:chemistry / Q000494:pharmacology*; D008863:Microspheres; D008970:Molecular Weight; D009077:Mucins / Q000494:pharmacology*; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D009391:Nephelometry and Turbidimetry; D056951:Photoelectron Spectroscopy; D012995:Solubility; D055672:Static Electricity; D013438:Sulfhydryl Compounds / Q000737:chemistry; D034421:Sus scrofa
chemical_list: D000269:Adhesives; D009077:Mucins; D013438:Sulfhydryl Compounds; C118638:glycol-chitosan; D048271:Chitosan; D005978:Glutathione; D000111:Acetylcysteine
keywords: Bladder drug delivery; Glycol chitosan; Mucoadhesion; Oxidation; Spray drying