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In vitro and in vivo quantification of chloroprocaine release from an implantable device in a piglet postoperative pain model

Authors De Gregori S, De Gregori M, Bloise N, Bugada D, Molinaro M, Filisetti C, Allegri M, Schatman ME, Cobianchi L

Received 13 July 2018

Accepted for publication 2 October 2018

Published 8 November 2018 Volume 2018:11 Pages 2837—2846

DOI https://doi.org/10.2147/JPR.S180163

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Katherine Hanlon


Simona De Gregori,1 Manuela De Gregori,1–4 Nora Bloise,5,6 Dario Bugada,3,4,7 Mariadelfina Molinaro,1 Claudia Filisetti,8 Massimo Allegri,3,9 Michael E Schatman,3,10,11 Lorenzo Cobianchi12,13

1Clinical and Experimental Pharmacokinetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 2Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 3Study in Multidisciplinary Pain Research Group, Parma, Italy; 4Young Against Pain Group, Parma, Italy; 5Department of Molecular Medicine, Centre for Health Technologies, INSTM UdR of Pavia, University of Pavia, Pavia, Italy; 6Department of Occupational Medicine, Toxicology and Environmental Risks, Istituti Clinici Scientifici Maugeri, IRCCS, Lab of Nanotechnology, Pavia, Italy; 7Emergency and Intensive Care Department – ASST Papa Giovanni XXIII, Bergamo, Italy; 8“V. Buzzi” Children Hospital, Pediatric Surgery, Milan, Italy; 9Anesthesia and Intensive Care Service, IRCCS MultiMedica Hospital, Sesto San Giovanni, Milano, Italy; 10Research and Network Development, Boston Pain Care, Waltham, MA, USA; 11Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA; 12General Surgery Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 13Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy

Background: The pharmacokinetic properties and clinical advantages of the local anesthetic chloroprocaine are well known. Here, we studied the pharmacokinetic profile of a new hydrogel device loaded with chloroprocaine to investigate the potential advantages of this new strategy for postoperative pain (POP) relief.
Materials and methods: We performed both in vitro and in vivo analyses by considering plasma samples of four piglets receiving slow-release chloroprocaine. To quantify chloroprocaine and its inactive metabolite 4-amino-2-chlorobenzoic acid (ACBA), a HPLC–tandem mass spectrometry (HPLC-MS/MS) analytical method was used. Serial blood samples were collected over 108 hours, according to the exposure time to the device.
Results: Chloroprocaine was consistently found to be below the lower limit of quantification, even though a well-defined peak was observed in every chromatogram at an unexpected retention time. Concerning ACBA, we found detectable plasma concentrations between T0 and T12h, with a maximum plasma concentration (Cmax) observed 3 hours after the device application. In the in vitro analyses, the nanogel remained in contact with plasma at 37°C for 90 minutes, 3 hours, 1 day, and 7 days. Chloroprocaine Cmax was identified 1 day following exposure and Cmin after 7 days, respectively. Additionally, ACBA reached the Cmax following 7 days of exposure.
Conclusion: A thorough review of the literature indicates that this is the first study analyzing both in vivo and in vitro pharmacokinetic profiles of a chloroprocaine hydrogel device and is considered as a pilot study on the feasibility of including this approach to the management of POP.

Keywords: postoperative outcome, hydrogel device, chloroprocaine, ACBA, pharmacokinetics

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