Transdermal delivery of levosimendan.
The aim of this study was to determine if transdermal penetration of levosimendan, a novel positive inotropic drug, could be enhanced and controlled by formulation modifications. Penetration of levosimendan across human epidermis in vitro was determined using abdominal excised skin and diffusion cells. Predicted steady-state plasma concentrations of levosimendan were estimated using permeabilities and pharmacokinetic parameters of levosimendan. For penetration enhancement we used different pH values, co-solvents, cyclodextrins, surfactants, penetration enhancers, liposomes, and iontophoresis. Sodium lauryl sulfate, ethanol, oleic acid, and soya phosphatidylcholine or their combinations clearly increased levosimendan permeation across the skin in vitro. Iontophoresis was also an efficient method to increase transdermal permeation of levosimendan. A hydrophilic co-solvent/penetration enhancer is needed to achieve better permeability of levosimendan across the skin. In conclusion, transdermal delivery of levosimendan can be significantly increased by formulation modification. Based on kinetic calculations, therapeutic plasma concentrations may be achievable transdermally.
Valjakka-Koskela
R
R
Pharmaceutical Development Department, Orion Corporation Orion Pharma, P.O. Box 1780, 70701, Kuopio, Finland. riitta.valjakka-koskela@orion.fi
Hirvonen
J
J
Mönkkönen
J
J
Kiesvaara
J
J
Antila
S
S
Lehtonen
L
L
Urtti
A
A
D000279:Administration, Cutaneous; D002316:Cardiotonic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration; D011724:Pyridazines / Q000737:chemistry / Q000493:pharmacokinetics*; D000077464:Simendan; D012869:Skin Absorption / Q000187:drug effects* / Q000502:physiology; D013501:Surface-Active Agents / Q000493:pharmacokinetics
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D013501:Surface-Active Agents; D000077464:Simendan