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In vitro permeation profile of a local anaesthetic compound from topical formulations with different rheological behaviour - verified by in vivo efficacy data
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2001 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 14, no 3, 229-236 p.Article in journal (Refereed) Published
Abstract [en]

The object of this study was to develop a topical cream of suitable consistency, i.e. with a high apparent yield stress, without affecting the in vitro permeation profile and the subsequent in vivo efficacy of the formulation. Different formulations of a model compound were manufactured, an oil-in-water (o/w) emulsion, a cream consisting of the o/w emulsion thickened with various concentrations of neutralised Carbopol934P gel, and a semisolid water-in-oil (w/o) emulsion. Rheological measurements were performed giving the apparent yield stress of the formulations. The in vitro permeation rate of the compound was measured, using static diffusion cells with both guinea pig and human skin as membrane. The o/w emulsion without polymer was used as reference. The in vivo efficacy of the formulations was investigated on guinea pigs by the pinprick method. The apparent yield stress of the w/o emulsion was in the same range as that of the most viscous o/w cream while the o/w emulsion behaved as a Newtonian liquid. Furthermore, the yielding property of the w/o emulsion was not as temperature-sensitive as that of the o/w cream. The permeation rate of the compound from the two emulsions, o/w and w/o, was similar at 6% (w/w), while the o/w cream resulted in a significantly lower permeation rate at the same concentration. The two emulsions produced sufficient and comparable in vivo efficacy, while the o/w cream was less efficient. In conclusion, a reversed-phase emulsion may be used to produce the appropriate apparent yield stress, without affecting the in vivo efficacy of the formulation. The viscosity of a w/o emulsion depends on the amount of the aqueous phase and the degree of dispersity. Thus, the transport of the active compound is not prevented by the excipients present in the formulation, as is the case for the o/w cream.

Place, publisher, year, edition, pages
2001. Vol. 14, no 3, 229-236 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-89452DOI: 10.1016/S0928-0987(01)00181-6PubMedID: 11576828OAI: oai:DiVA.org:uu-89452DiVA: diva2:160897
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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