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Physicochemical interaction of local anesthetics with lipid model systems: Correlation with in vitro permeation and in vivo efficacy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2002 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 81, no 1-2, 33-43 p.Article in journal (Refereed) Published
Abstract [en]

In dermal/transdermal drug administration stratum corneum (SC) is often the rate-limiting step. Furthermore, the intercellular lipid domain of SC is nowadays widely accepted as the major contributor to the skin barrier. The current work investigates whether the difference in the level of topical efficacy of local anesthetic compounds correlates with the type of interaction between the drug and the intercellular lipids of SC. Therefore, local anesthetics of varying topical efficacy were evaluated with respect to their effect on the morphology of various model lipid systems using small and wide angle X-ray diffraction (SWAXD) and differential scanning calorimetry (DSC). The model lipids used were glyceryl monooleate, sphingomyelin and lipids isolated from human SC. Furthermore, partitioning into isolated human SC as well as permeation through isolated human SC and human tape-stripped skin were investigated in vitro. The results indicate that local anesthetics may act as their own permeation enhancers by increasing the degree of hydrocarbon chain fluidity of the intercellular lipids. Eventually these interactions may induce non-lamellar reversed types of liquid crystalline structures locally in SC, which further facilitate the drug mobility. The large difference in topical efficacy of the investigated local anesthetics could not be explained simply by looking at their effect on the phase behavior of lipid model systems. Despite the similarities in physicochemical properties of these substances, the in vitro skin permeability differed markedly (AD>EMLA>lidocaine>prilocaine>sameridine). Thus, it was concluded that sufficient drug permeability over SC is essential to obtain local anesthesia by blocking the superficial nociceptors.

Place, publisher, year, edition, pages
2002. Vol. 81, no 1-2, 33-43 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-89454DOI: 10.1016/S0168-3659(02)00035-4PubMedID: 11992676OAI: oai:DiVA.org:uu-89454DiVA: diva2:160899
Available from: 2001-10-03 Created: 2001-10-03 Last updated: 2013-05-17Bibliographically approved
In thesis
1. Formulations, Release and Skin Penetration of Topical Anesthetics
Open this publication in new window or tab >>Formulations, Release and Skin Penetration of Topical Anesthetics
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes certain critical aspects of the development of semisolid topical anesthetic formulations requiring a fast onset of action. Furthermore, local anesthetics were investigated regarding their phase interaction with membrane lipids.

A new long acting and topically effective local anesthetic/analgesic agent, isopropyl-methyl-[2-(3-propoxyphenoxy)-ethyl]-amine (amino diether, AD), was used as the model compound. The nonionized form of AD is liquid oil at room temperature with low water solubility. A submicron o/w emulsion with Newtonian flow property was prepared with AD as the disperse phase. The kinetic stability of this emulsion was increased to prevent Ostwald ripening by addition of small amounts of a hydrophobic excipient to the disperse phase. The emulsion allowed a high in vitro release and permeation rate of AD as well as a sufficient in vivo efficacy.

To achieve a plastic property, hydrophilic polymers were added to the o/w emulsion resulting in a significant reduction of the release and permeation rate of AD. In order to avoid the addition of these polymers, a semisolid w/o emulsion was evaluated with AD as the continuous phase. The inherent plastic property of this formulation allows sufficient skin adhesion. Furthermore, the release and permeation rate of AD from this formulation is comparable to that of the Newtonian submicron o/w emulsion. A close correlation between the in vitro permeation studies and the in vivo human plasma profiles was observed using the convolution/deconvolution


Furthermore, x-ray and calorimetric data indicated that local anesthetics are able to interact with skin lipids both by increasing the chain fluidity of the crystalline lipids and by probably producing phase inversions in the grain borders of the stratum corneum lipid multilayers. It was also shown that this lipid interaction was not directly correlated with the different levels of skin permeation and/or topical efficacy of the investigated compounds.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2001. 53 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 258
Pharmacy, FARMACI
National Category
Pharmaceutical Sciences
Research subject
urn:nbn:se:uu:diva-1395 (URN)91-554-5115-2 (ISBN)
Public defence
2001-10-05, BMC, B22, Uppsala, 13:15
Available from: 2001-10-03 Created: 2001-10-03Bibliographically approved

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