Complexation of the local anesthetic pramoxine with hydroxypropyl-beta-cyclodextrin can improve its bioavailability

Author(s)

Bezamat, Juliana M. ^[1] ; Yokaichiya, Fabiano ^{[2, 3]} ; Dias Franco, Margareth K. K. ^[3] ; Castro, Simone R. ^[1] ; de Paula, Eneida ^[1] ; Cabeca, Luis F. ^[4]

Affiliation

^[1] Univ Estadual Campinas, Biol Inst, Biochem & Tissue Biol Dept, Campinas, SP - Brazil

^[2] Helmholtz Zentrum, Dept Quantum Phenomena Novel Mat, Berlin - Germany

^[3] IPEN CNEN SP, Nucl & Energy Res Inst, Sao Paulo, SP - Brazil

^[4] Technol Fed Univ Parana, Londrina, Parana - Brazil

• Document type: Journal article
• Source: JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY; v. 55, FEB 2020.
• Web of Science Citations: 0

Abstract

Local anesthetics are widely used in clinical procedures, to eliminate pain during/after invasive procedures. A wide range of drug delivery systems has been developed to improve the effect of local anesthetics and/or to reduce their toxicity. Pramoxine (PMX) is a topical anesthetic agent with an unusual (morpholine ring) structure and low solubility (ca. 3 mM at pH 7.4). In this work, a novel formulation was devised for PMX in hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Host-guest inclusion complex was prepared by the co-solubilization method, with complexation kinetics of 10 h, and 1:1 PMX/HP-beta-CD stoichiometry. Complexation promoted 14-fold increase in the solubility of PMX. X-ray diffraction measurements revealed loss of the crystalline PMX pattern in the presence of HP-beta-CD, an indication of inclusion complexation. Using H-1 NMR (DOSY) experiments the association constant of PMX to HP-beta-CD (Ka = 923.1 mol/L) was determined, while nuclear Overhauser (ROESY) analysis confirmed the formation of PMX/HP-beta-CD inclusion complex, by detection of spatial proximities between hydrogens from PMX aromatic ring and cyclodextrin's cavity. In two in vitro toxicity models (mouse 3T3 fibroblasts in culture and red blood cells hemolysis) pramoxine toxicity was significantly reduced upon complexation into HP-beta-CD. These results point out PMX/HP-beta-CD as a promising pharmaceutical formulation to improve the bioavailability of pramoxine, allowing its application beyond topical anesthesia. (AU)

• FAPESP's process: 14/14457-5 - Lipid-based nanocarriers (SLN/NLC and remote-loading liposomes) used to improve the upload and potency of local anesthetics
• Grantee: Eneida de Paula
• Support Opportunities: Research Projects - Thematic Grants