Ex vivo propofol permeation across nasal mucosa: A proof-of-concept study for outpatient light sedation via nasal route

Michele Domenico Spampinato; Anna Costanzini; Roberto De Giorgio; Angelina Passaro; Nicola Realdon; Fabrizio Bortolotti; Sabrina Banella; Gaia Colombo

doi:10.5599/admet.2403

Authors

Michele Domenico Spampinato Department of Translational Medicine, St. Anna University Hospital of Ferrara, University of Ferrara, 44124 Ferrara, Italy https://orcid.org/0000-0002-2285-327X
Anna Costanzini Department of Translational Medicine, St. Anna University Hospital of Ferrara, University of Ferrara, 44124 Ferrara, Italy https://orcid.org/0000-0002-8644-1135
Roberto De Giorgio Department of Translational Medicine, St. Anna University Hospital of Ferrara, University of Ferrara, 44124 Ferrara, Italy https://orcid.org/0000-0003-0867-5873
Angelina Passaro Department of Translational Medicine, St. Anna University Hospital of Ferrara, University of Ferrara, 44124 Ferrara, Italy https://orcid.org/0000-0001-8462-7000
Nicola Realdon Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy https://orcid.org/0000-0001-5624-6876
Fabrizio Bortolotti Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 19, 44121 Ferrara, Italy https://orcid.org/0009-0007-5053-2127
Sabrina Banella Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 19, 44121 Ferrara, Italy https://orcid.org/0000-0003-2676-1951
Gaia Colombo Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 19, 44121 Ferrara, Italy https://orcid.org/0000-0001-9033-2305

DOI:

https://doi.org/10.5599/admet.2403

Keywords:

Sedative drug, nasal administration, aqueous solubility, betha-cyclodextrin, transmucosal permeation

Abstract

Background and Purpose: Aiming to achieve light sedation via intranasal administration, this study showed that propofol (PPF) did not permeate across the rabbit nasal mucosa ex vivo from its marketed emulsion for injection. Experimental approach: Dilution of the emulsion with methyl-b-cyclodextrin in saline solution increased propofol solubility in water and diffusion across the nasal epithelium. Key results and conclusion: Despite these positive effects of the cyclodextrin, the amount of PPF permeated was minimal in 3 h, exceeding the formulation residence time in the nose. These results highlight the key role of formulation and the need for innovation in solubility and transmucosal transport enhancement techniques to optimize drug delivery and therapeutic efficacy.

Downloads

Download data is not yet available.

References

A.Y. Feng, A.D. Kaye, R.J. Kaye, K. Belani, R.D. Urman. Novel propofol derivatives and implications for anesthesia practice. Journal of Anaesthesiology Clinical Pharmacology 33 (2017) 9-15. http://dx.doi.org/10.4103/0970-9185.202205

B. Wilhelms, J. Broscheit, S. Shityakov. Chemical Analysis and Molecular Modelling of Cyclodextrin-Formulated Propofol and Its Sodium Salt to Improve Drug Solubility, Stability and Pharmacokinetics (Cytogenotoxicity). Pharmaceuticals (Basel) 16 (2023) 667. https://doi.org/10.3390/ph16050667

I. Cappellini, G. Bavestrello Piccini, L. Campagnola, C. Bochicchio, R. Carente, F. Lai, S. Magazzini, G. Consales. Procedural Sedation in Emergency Department: A Narrative Review. Emergency Care and Medicine 1 (2024) 103-136. https://doi.org/10.3390/ecm1020014

W.H. Cordell, K.K. Keene, B.K. Giles, J.B. Jones, J.H. Jones, E.J. Brizendine. The high prevalence of pain in emergency medical care. The American Journal of Emergency Medicine 20 (2002) 165-169. https://doi.org/10.1053/ajem.2002.32643

EUSEM - European Curriculum of Emergency Medicine, https://eusem.org/education/curriculum/european-curriculum-of-emergency-medicine (last accessed July 30th, 2024)

S. Serra, M.D. Spampinato, A. Riccardi, M. Guarino, A. Fabbri, L. Orsi, F. De Iaco. Pain Management at the End of Life in the Emergency Department: A Narrative Review of the Literature and a Practical Clinical Approach. Journal Of Clinical Medicine 12 (2023) 4357. https://doi.org/10.3390/jcm12134357

Y. Kanno, T. Ohira, Y. Harada, S. Koshita, T. Ogawa, H. Kusunose, Y. Koike, T. Yamagata, T. Sakai, K. Masu, K. Yonamine, K. Miyamoto, M. Tanaka, T. Shimada, F. Kozakai, K. Endo, H. Okano, D. Komabayashi, T. Shimizu, S. Suzuki, K. Ito. Safety and Recipient Satisfaction of Propofol Sedation in Outpatient Endoscopy: A 24-Hour Prospective Investigation Using a Questionnaire Survey. Clinical Endoscopy 54 (2021) 340-347. https://doi.org/10.5946/ce.2020.138

G.F. Ferrazzano, T. Cantile, M. Quaraniello, M. Iannuzzi, D. Palumbo, G. Servillo, S. Caruso, F. Fiasca, A. Ingenito. Effectiveness and Safety of Intravenous Sedation with Propofol in Non-Operating Room Anesthesia (NORA) for Dental Treatment in Uncooperative Paediatric Patients. Children (Basel) 8 (2021) 648. https://doi.org/10.3390/children8080648

M. Kazi, A. Alqahtani, M. Alharbi, A. Ahmad, M.D. Hussain, H. Alothaid, M.S. Aldughaim. The Development and Optimization of Lipid-Based Self-Nanoemulsifying Drug Delivery Systems for the Intravenous Delivery of Propofol. Molecules 28 (2023) 1492. https://doi.org/10.3390/molecules28031492

A.A. Date, M.S. Nagarsenker. Design and evaluation of microemulsions for improved parenteral delivery of propofol. AAPS PharmSciTech 9 (2008) 138-145. https://doi.org/10.1208/s12249-007-9023-7

T.D. Egan. Exploring the frontiers of propofol formulation strategy: is there life beyond the milky way. British Journal of Anaesthesia 104 (2010) 533-535. https://doi.org/10.1093/bja/aeq059

W. Zhang, J. Yang, J. Fan, B. Wang, Y. Kang, J. Liu, W. Zhang, T. Zhu. An improved water-soluble prodrug of propofol with high molecular utilization and rapid onset of action. European Journal of Pharmaceutical Sciences 127 (2019) 9-13. https://doi.org/10.1016/j.ejps.2018.09.024

L.A. Keller, O. Merkel, A. Popp. Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Delivery and Translational Research 12 (2022) 735-757. https://doi.org/10.1007/s13346-020-00891-5

L. Tiozzo Fasiolo, M.D. Manniello, E. Tratta, F. Buttini, A. Rossi, F. Sonvico, F. Bortolotti, P. Russo, G. Colombo. Opportunity and challenges of nasal powders: Drug formulation and delivery. European Journal of Pharmaceutical Sciences 113 (2018) 2-17. https://doi.org/10.1016/j.ejps.2017.09.027

S. Serra, M.D. Spampinato, A. Riccardi, M. Guarino, R. Pavasini, A. Fabbri, F. De Iaco. Intranasal Fentanyl for Acute Pain Management in Children, Adults and Elderly Patients in the Prehospital Emergency Service and in the Emergency Department: A Systematic Review. Journal of Clinical Medicine 12 (2023) 2609. https://doi.org/10.3390/jcm12072609

V. Pansini, A. Curatola, A. Gatto, I. Lazzareschi, A. Ruggiero, A. Chiaretti. Intranasal drugs for analgesia and sedation in children admitted to pediatric emergency department: a narrative review. Annals of Translational Medicine 9 (2021) 189. https://doi.org/10.21037/atm-20-5177

A. Riccardi, M. Guarino, S. Serra, M.D. Spampinato, S. Vanni, D. Shiffer, A. Voza, A. Fabbri, F. De Iaco. Narrative Review: Low-Dose Ketamine for Pain Management. Journal of Clinical Medicine 12 (2023) 3256. https://doi.org/10.3390/jcm12093256

F. Cossovel, A. Trombetta, A. Ramondo, G. Riccio, L. Ronfani, A. Saccari, G. Cozzi, E. Barbi. Intranasal dexmedetomidine and intranasal ketamine association allows shorter induction time for pediatric sedation compared to intranasal dexmedetomidine and oral midazolam. Italian Journal of Pediatrics 48 (2022) 5. https://doi.org/10.1186/s13052-021-01196-0

S.B. Shrewsbury. The Upper Nasal Space: Option for Systemic Drug Delivery, Mucosal Vaccines and "Nose-to-Brain". Pharmaceutics 15 (2023) 1720. https://doi.org/10.3390/pharmaceutics15061720

I.F. Uchegbu, M.C. Jones, F. Corrente, L. Godfrey, D. Laghezza, M. Carafa, P. Holm, A.G. Schätzlein. The Oral and Intranasal Delivery of Propofol Using Chitosan Amphiphile Nanoparticles. Pharmaceutical Nanotechnology 2 (2014). https://doi.org/10.2174/2211738502666140616184703

A. Haasbroek-Pheiffer, S. Van Niekerk, F. Van der Kooy, T. Cloete, J. Steenekamp, J. Hamman. In vitro and ex vivo experimental models for evaluation of intranasal systemic drug delivery as well as direct nose-to-brain drug delivery. Biopharmaceutics and Drug Disposition 44 (2023) 94-112. https://doi.org/10.1002/bdd.2348

F. Bortolotti, A.G. Balducci, F. Sonvico, P. Russo, G. Colombo. In vitro permeation of desmopressin across rabbit nasal mucosa from liquid nasal sprays: the enhancing effect of potassium sorbate. European Journal of Pharmaceutical Sciences 37 (2009) 36-42. https://doi.org/10.1016/j.ejps.2008.12.015

A.G. Balducci, L. Ferraro, F. Bortolotti, C. Nastruzzi, P. Colombo, F. Sonvico, P. Russo, G. Colombo. Antidiuretic effect of desmopressin chimera agglomerates by nasal administration in rats. International Journal of Pharmaceutics 440 (2013) 154-160. https://doi.org/10.1016/j.ijpharm.2012.09.049

G. Colombo, F. Bortolotti, V. Chiapponi, F. Buttini, F. Sonvico, R. Invernizzi, F. Quaglia, C. Danesino, F. Pagella, P. Russo, R. Bettini, P. Colombo, A. Rossi. Nasal powders of thalidomide for local treatment of nose bleeding in persons affected by hereditary hemorrhagic telangiectasia. International Journal of Pharmaceutics 514 (2016) 229-237. https://doi.org/10.1016/j.ijpharm.2016.07.002

L. Tiozzo Fasiolo, M.D. Manniello, S. Banella, L. Napoli, F. Bortolotti, E. Quarta, P. Colombo, E. Balafas, N. Kostomitsopoulos, D.M. Rekkas, G. Valsami, P. Papakyriakopoulou, G. Colombo, P. Russo. Flurbiprofen sodium microparticles and soft pellets for nose-to-brain delivery: Serum and brain levels in rats after nasal insufflation. International Journal of Pharmaceutics 605 (2021) 120827. https://doi.org/10.1016/j.ijpharm.2021.120827

G. Trapani, A. Latrofa, M. Franco, A. Lopedota, E. Maciocco, G. Liso. Effect of 2-hydroxypropyl-β-cyclodextrin on the aqueous solubility of the anaesthetic agent propofol (2,6-diisopropylphenol). International Journal of Pharmaceutics 139 (1996) 218. https://doi.org/10.1021/js970178s

M.K. Babu, T.N. Godiwala. Toward the development of an injectable dosage form of propofol: preparation and evaluation of propofol-sulfobutyl ether 7-beta-cyclodextrin complex. Pharmaceutical Development and Technology 9 (2004) 265-275. https://doi.org/10.1081/pdt-200031428

G. Kali, S. Haddadzadegan, A. Bernkop-Schnürch. Cyclodextrins and derivatives in drug delivery: New developments, relevant clinical trials, and advanced products. Carbohydrate Polymers 324 (2024) 121500. https://doi.org/10.1016/j.carbpol.2023.121500

P. Yang, Y. Li, W. Li, H. Zhang, J. Gao, J. Sun, X. Yin, A. Zheng. Preparation and evaluation of carfentanil nasal spray employing cyclodextrin inclusion technology. Drug Development and Industrial Pharmacy 44 (2018) 953-960. https://doi.org/10.1080/03639045.2018.1425426

C. Muankaew, T. Loftsson. Cyclodextrin-Based Formulations: A Non-Invasive Platform for Targeted Drug Delivery. Basic & Clinical Pharmacology & Toxicology 122 (2018) 46-55. https://doi.org/10.1111/bcpt.12917

G. Rassu, M. Sorrenti, L. Catenacci, B. Pavan, L. Ferraro, E. Gavini, M.C. Bonferoni, P. Giunchedi, A. Dalpiaz. Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives. Pharmaceutics 13 (2021) 1180. https://doi.org/10.3390/pharmaceutics13081180

J.Y. Sim, S.H. Lee, D.Y. Park, J.A. Jung, K.H. Ki, D.H. Lee, G.J. Noh. Pain on injection with microemulsion propofol. British Journal of Clinical Pharmacology 67 (2009) 316-325. https://doi.org/10.1111/j.1365-2125.2008.03358.x

M. Yamakage, S. Iwasaki, J.I. Satoh, A. Namiki. Changes in concentrations of free propofol by modification of the solution. Anesthesia & Analgesia 101 (2005) 385-388. https://doi.org/10.1213/01.ANE.0000154191.86608.AC

R. Damitz, A. Chauhan, N. Gravenstein. Propofol emulsion-free drug concentration is similar between batches and stable over time. Romanian Journal of Anaesthesia and Intensive Care 23 (2016) 7-11. https://doi.org/10.21454/rjaic.7518.231.emf

R. Mitra, I. Pezron, W.A. Chu, A.K. Mitra. Lipid emulsions as vehicles for enhanced nasal delivery of insulin. International Journal of Pharmaceutics 205 (2000) 127-134. https://doi.org/10.1016/s0378-5173(00)00506-8

T. Loftsson, H.H. Sigurdsson, P. Jansook. Anomalous Properties of Cyclodextrins and Their Complexes in Aqueous Solutions. Materials 16 (2023) 2223. https://doi.org/10.3390/ma16062223

P. Papakyriakopoulou, K. Manta, C. Kostantini, S. Kikionis, S. Banella, E. Ioannou, E. Christodoulou, D.M. Rekkas, P. Dallas, M. Vertzoni, G. Valsami, G. Colombo. Nasal powders of quercetin-β-cyclodextrin derivatives complexes with mannitol/lecithin microparticles for Nose-to-Brain delivery: In vitro and ex vivo evaluation. International Journal of Pharmaceutics 607 (2021) 121016. https://doi.org/10.1016/j.ijpharm.2021.121016

V. Raje, S. Palekar, S. Banella, K. Patel. Tunable Drug Release from Fused Deposition Modelling (FDM) 3D-Printed Tablets Fabricated Using a Novel Extrudable Polymer. Pharmaceutics 14 (2022) 2192. https://doi.org/10.3390/pharmaceutics14102192

M. Pozzoli, D. Traini, P.M. Young, M.B. Sukkar, F. Sonvico. Development of a Soluplus budesonide freeze-dried powder for nasal drug delivery. Drug Development and Industrial Pharmacy 43 (2017) 1510-1518. https://doi.org/10.1080/03639045.2017.1321659