title: Formation of drug-arylsulfonate complexes inside liposomes: a novel approach to improve drug retention.
abstract: The development of procedures to enhance drug retention in liposomes is important in order to achieve therapeutically optimized rates of drug release from liposomal carriers. In this study, the ability of lipophilic weak base drugs to complex with arylsulfonates resulting in formation of intravesicular precipitates is investigated as a means to enhance drug retention. It is shown that the arylsulfonates benzenesulfonate and hydroxybenzenesulfonate (HBS) induce precipitation of ciprofloxacin and vinorelbine, two representative weak base drugs that are difficult to retain in liposomal systems. The most complete precipitation was observed at pH values corresponding to charge neutralization of the drug-arylsulfonate complex. HBS is shown to be a much more effective precipitating agent than benzenesulfonate. It is also shown that vinorelbine and ciprofloxacin can be loaded into large unilamellar vesicles (LUV) containing the calcium salt of HBS using an ionophore-based loading method. Following drug loading, the formation of intravesicular drug-arylsulfonate precipitates of vinorelbine and ciprofloxacin was observed by cryo-electron microscopy. In vitro release experiments showed substantial improvements in drug retention for both vinorelbine and ciprofloxacin when HBS was present as compared to standard loading procedures employing MgSO4 as the entrapped solute. In vivo release experiments for vinorelbine in NuNu mice indicated a half-time for release for HBS-containing LUV of approximately 30 h, compared to 6.4 h for LUV loaded employing MgSO4. It is suggested that encapsulation procedures employing HBS in the internal medium can improve the retention of drugs that are difficult to retain in liposomes, possibly leading to enhanced therapeutic properties.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Electronic address: ig0rz@yahoo.com.
authors.forename: Igor V
authors.initials: IV
authors.lastname: Zhigaltsev
authors.affiliation: Inex Pharmaceuticals Corporation, 100-8900 Glenlyon Parkway, Burnaby, British Columbia, Canada V5J 5J8.
authors.forename: Norbert
authors.initials: N
authors.lastname: Maurer
authors.affiliation: Department of Physical Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Edwards
authors.affiliation: Department of Physical Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Karlsson
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3; Inex Pharmaceuticals Corporation, 100-8900 Glenlyon Parkway, Burnaby, British Columbia, Canada V5J 5J8.
authors.forename: Pieter R
authors.initials: PR
authors.lastname: Cullis
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001190:Arylsulfonates / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D020285:Cryoelectron Microscopy; D005079:Excipients; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008081:Liposomes; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009368:Neoplasm Transplantation; D012996:Solutions; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D000077235:Vinorelbine
chemical_list: D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D001190:Arylsulfonates; D005079:Excipients; D008081:Liposomes; D012996:Solutions; D002939:Ciprofloxacin; D014747:Vinblastine; D000077235:Vinorelbine