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In vitro-in vivo correlation in man of a topically applied local anesthetic agent using numerical convolution and deconvolution
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2003 (English)In: Internation Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 92, no 2, 398-406 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to evaluate the relevance of the in vitro permeation method used at our laboratory in predicting in vivo dermal and transdermal absorption. Two different emulsions, a submicron oil-in-water (o/w) emulsion and a semisolid water-in-oil (w/o) emulsion, containing a model compound were investigated. The in vitro permeation rate of the compound from these emulsions was measured using static diffusion cells with human skin as membrane. The emulsions were allowed to remain in contact with the skin in the donor chamber for 15, 60, and 240 min. The study was monitored for 240 min and the steady state flux was calculated. The systemic concentration of the compound was measured in vivo as a function of time after dermal application to healthy volunteers with 15 and 60 min of application. A short-lasting i.v. infusion study in healthy volunteers was used to simulate the i.v. bolus dose. Numerical convolution was used to predict the in vivo plasma concentration of the compound while the in vivo absorption rate of the compound was estimated using numerical deconvolution. To establish correlation, the predicted in vivo flux was compared with the corresponding observed in vitro parameter after adjusting for the lag time. No major differences were seen in the systemic plasma levels between the two emulsions, which is in close agreement with the steady state flux measured in vitro. A linear correlation representing a point-to-point relationship was established for each of the investigated formulations and application times. The longer application time was predicted more accurately for both emulsions.

Place, publisher, year, edition, pages
2003. Vol. 92, no 2, 398-406 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-89453DOI: 10.1002/jps.10203PubMedID: 12532389OAI: oai:DiVA.org:uu-89453DiVA: diva2:160898
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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