- Email: [email protected]
Morpho-functional changes on skin following in vitro iontophoresis
S148
Poster Session P2: Monday
16 September
A new pharmacokinetic model of stratum corneum with two parallel pathways: lipophilic and porous hydrophibc, is not well documented yet. The results of our previous studies supported this model - passive transport of zwitterionic species Iike amino acids and baclofen was described. Examination of pharmacokineticsof bsclofen penetratingthrough the sldn @omaqueousor ethanolicsolutionsin the presenceof somesorption promotersbrought &rther conclusionsabout the nature of the porous polar pathway of penetration. Still questionableis locatisation of the pores and the present experiments were designedto elucidate the contribution of exbacdlulsr lipids and intracdlular keratin to the structureof this pathway. Percutaneouspenetrationof bsclofen, a model zwitterion, was studied in vitro usins human cadaver skin and flowthrough diffusion cells.Aqueousor cthanolic saturatedsolutionsof the drug (C. 4.6 and 0.4 mgM, reape&veIy) were applied on the skin pretreated with: sodium lautyl sulphate 0.2?? (SLS), methanol-chloroform (Me-Ch) or acetone chloroform (Ac-Ch) (1:l) mixture, or Ac-Ch and subsa~uently SLS. Additionally flux corn aqueous solution was studied afler pretreatment with ethanol 95%. As controls baclofen penetration through the intact &II thickness skin was determinedand the tluxcs were: 0.14M.07 and 0.18M.05 crg/cm?h for aqueous and ethanolic solutions, respectively. When Mach was used for 1 h an increase of the pene.tration was observed, as could be expected. However fluxes were 3+g/cm*/h what gives only IO-fold enhancement, whik TI, was still about 20 h. Whm leas polar mixture Ac-Ch was used no enhancement we observed, and a decrease of penetration was even noted when ethanol was a vehicle for baclofbn. SLS is believed to change keratin confortnation thus it may change polar intracellular regions - pretmatment with SLS for 12h caused only 2-3 times larger penetration~dwysurprisinglynoe&et-notedwhenSLSwasusedforl h afler skin delipidization with Ac-Ch mixtute. Ethanol used for 5 h before application ofthe aqueous solution did not alT&t penetrationof baclofen. The results show that the polar pathway is connected with polar intacdhdar lipids and e&action of this 6action increasea penetration of the zwitte-rion. It is di5adt to explain a small eRect observed after skin pretreatmentwith SLS and intmccIluIarlocahzation of the polar pathway must be proved with lMhtr experiments.
In this study the bioavailability of different dilutions of three registered cwticosteroid preparations was evaluated using a chromameter. The ccrtiieroid preparations tested were: Betnelan p, Diprosone’ and Dermovate’. For each of the creams three dilutions were prepared: l/1,1/5 and 1110 (w/w). Each dilution was prepared wtth three diluent creams: cold cream, Beeler’s basis and cetomacrogol cream, respectively. As a reference formulation Diprosone. was diluted 113 (whir) with Beeler’s basis. For the skin blanching assay 500 mg of the formulation was applied on a forearm and protected with a nonoccluding tape guard during 15 hrs. Six formulations were tested simultaneously: the pure cortiiteroid preparation, the 3 dilutions, the pure diluent cream and the reference formulation. Each formulation was tested on 16 volunteers. The induced skin blanching was measured using a Minotta CR 200 chromameter 0.5 and 2 hrs after removal of the cream. All measurements were performed in triplicate and the average a-scale readings were used to differentiate between the tested formulations. The intervariabitii was determined using the a-scale readings alter application of the reference formulation. No significant (~0.05) difference between a-scale readings 0.5 and 2 hrs after removal of the cream could be observed, for all formulations tested. All formulations containing corticosteroids showed a significant (p
An alternative particular q&em to emulsions and lipaaomas for a topical adm;nistration are Sotkt Lipid Nanopartictes (SLN). The very small particle stze may assess a simtlar efficiency of good penetration between the stratum comeum ceils and active conpounds enrichment in the upper skin layers. SLN formulations are suitable for the incorporation of lipophilic, hydrophilic and poorly water soluble drugs [l]. Additionally SLN lead to a protecttve effect by enclosing chemically unstable drugs with a lipid cover. To develop SLN for the cosmetic application different lipid matrices typically used in cosmetic formulations WtKBstudii with regard to their feasibility to yield stable SLN dispersions. The lipids m selected considering physiological compatiblltty and i&resting properties for drug incorporation (i.e. protective effect against chemical degradation). A number of surfactants were selected (e.g. Tegin Normal, Mtranol and Plantaren) which are commercial products used in cosmetics and show no remarkable extend of skin irritations. SLN were produced by the hot homogenization technique with an high pressure homogenizer. The mean particle size and the polydisparsity index w~mt deternWed by Photon Correlation WY (PCS). the volume distrtbutlon_by Laser Dtffractomaby (LD). DtHWrenttalScanning Calorimetry (DSC) showed the degree of polymorphism and crtstallinity of the SLN formulations. The influence of the production parameters and the concentration of the surfactants ware investigated to assess a physically stable formulation during storage. [l] Miller and Lucks, European Patent Application PCT ! EP 92 I02132 (1992)
Poster Session P2: Monday
16 September
A new pharmacokinetic model of stratum corneum with two parallel pathways: lipophilic and porous hydrophibc, is not well documented yet. The results of our previous studies supported this model - passive transport of zwitterionic species Iike amino acids and baclofen was described. Examination of pharmacokineticsof bsclofen penetratingthrough the sldn @omaqueousor ethanolicsolutionsin the presenceof somesorption promotersbrought &rther conclusionsabout the nature of the porous polar pathway of penetration. Still questionableis locatisation of the pores and the present experiments were designedto elucidate the contribution of exbacdlulsr lipids and intracdlular keratin to the structureof this pathway. Percutaneouspenetrationof bsclofen, a model zwitterion, was studied in vitro usins human cadaver skin and flowthrough diffusion cells.Aqueousor cthanolic saturatedsolutionsof the drug (C. 4.6 and 0.4 mgM, reape&veIy) were applied on the skin pretreated with: sodium lautyl sulphate 0.2?? (SLS), methanol-chloroform (Me-Ch) or acetone chloroform (Ac-Ch) (1:l) mixture, or Ac-Ch and subsa~uently SLS. Additionally flux corn aqueous solution was studied afler pretreatment with ethanol 95%. As controls baclofen penetration through the intact &II thickness skin was determinedand the tluxcs were: 0.14M.07 and 0.18M.05 crg/cm?h for aqueous and ethanolic solutions, respectively. When Mach was used for 1 h an increase of the pene.tration was observed, as could be expected. However fluxes were 3+g/cm*/h what gives only IO-fold enhancement, whik TI, was still about 20 h. Whm leas polar mixture Ac-Ch was used no enhancement we observed, and a decrease of penetration was even noted when ethanol was a vehicle for baclofbn. SLS is believed to change keratin confortnation thus it may change polar intracellular regions - pretmatment with SLS for 12h caused only 2-3 times larger penetration~dwysurprisinglynoe&et-notedwhenSLSwasusedforl h afler skin delipidization with Ac-Ch mixtute. Ethanol used for 5 h before application ofthe aqueous solution did not alT&t penetrationof baclofen. The results show that the polar pathway is connected with polar intacdhdar lipids and e&action of this 6action increasea penetration of the zwitte-rion. It is di5adt to explain a small eRect observed after skin pretreatmentwith SLS and intmccIluIarlocahzation of the polar pathway must be proved with lMhtr experiments.
In this study the bioavailability of different dilutions of three registered cwticosteroid preparations was evaluated using a chromameter. The ccrtiieroid preparations tested were: Betnelan p, Diprosone’ and Dermovate’. For each of the creams three dilutions were prepared: l/1,1/5 and 1110 (w/w). Each dilution was prepared wtth three diluent creams: cold cream, Beeler’s basis and cetomacrogol cream, respectively. As a reference formulation Diprosone. was diluted 113 (whir) with Beeler’s basis. For the skin blanching assay 500 mg of the formulation was applied on a forearm and protected with a nonoccluding tape guard during 15 hrs. Six formulations were tested simultaneously: the pure cortiiteroid preparation, the 3 dilutions, the pure diluent cream and the reference formulation. Each formulation was tested on 16 volunteers. The induced skin blanching was measured using a Minotta CR 200 chromameter 0.5 and 2 hrs after removal of the cream. All measurements were performed in triplicate and the average a-scale readings were used to differentiate between the tested formulations. The intervariabitii was determined using the a-scale readings alter application of the reference formulation. No significant (~0.05) difference between a-scale readings 0.5 and 2 hrs after removal of the cream could be observed, for all formulations tested. All formulations containing corticosteroids showed a significant (p
An alternative particular q&em to emulsions and lipaaomas for a topical adm;nistration are Sotkt Lipid Nanopartictes (SLN). The very small particle stze may assess a simtlar efficiency of good penetration between the stratum comeum ceils and active conpounds enrichment in the upper skin layers. SLN formulations are suitable for the incorporation of lipophilic, hydrophilic and poorly water soluble drugs [l]. Additionally SLN lead to a protecttve effect by enclosing chemically unstable drugs with a lipid cover. To develop SLN for the cosmetic application different lipid matrices typically used in cosmetic formulations WtKBstudii with regard to their feasibility to yield stable SLN dispersions. The lipids m selected considering physiological compatiblltty and i&resting properties for drug incorporation (i.e. protective effect against chemical degradation). A number of surfactants were selected (e.g. Tegin Normal, Mtranol and Plantaren) which are commercial products used in cosmetics and show no remarkable extend of skin irritations. SLN were produced by the hot homogenization technique with an high pressure homogenizer. The mean particle size and the polydisparsity index w~mt deternWed by Photon Correlation WY (PCS). the volume distrtbutlon_by Laser Dtffractomaby (LD). DtHWrenttalScanning Calorimetry (DSC) showed the degree of polymorphism and crtstallinity of the SLN formulations. The influence of the production parameters and the concentration of the surfactants ware investigated to assess a physically stable formulation during storage. [l] Miller and Lucks, European Patent Application PCT ! EP 92 I02132 (1992)