Cultured skin loaded with tetracycline HCl and chloramphenicol as dermal delivery system: mathematical evaluation of the cultured skin containing antibiotics.
Dermal patches consisting of cultured human skin with antibiotics, which have a protective effect on wound skin as well as a preventative effect on second infection of the skin, were prepared and mathematically analyzed as a new drug delivery system (DDS) that can be applied to serious skin defects such as severe burns. In the present study, a three-dimensional cultured human skin model (living skin equivalent-high, LSE-high) was used as a cultured skin membrane and tetracycline HCl (TC-HCl) and chloramphenicol (CP) were used as antibiotics. At first, antibiotics were entrapped in the LSE-high from the dermal side through culture medium in order to obtain a drug-loaded LSE-high. The antibiotic release from the drug-loaded LSE-high was then examined and the resulting release data were used to calculate the effective diffusion coefficient of the antibiotics (D(LSE)) and initial loading concentration of the antibiotics (C0) in the LSE-high. The release profile of TC-HCl was represented by general diffusion-limited kinetics, whereas an initial burst effect was found in the release profile of CP. Therefore, the burst effect was taken into account for analyzing the release profile of CP. Stripped skin excised from hairless rats was used as a wound model, and the antibiotic permeation through the skin from aqueous solution was examined and evaluated using differential equations for Fick's second law of diffusion to obtain the effective diffusion coefficient of the antibiotics in the wound skin (D(skin)). Furthermore, the antibiotic permeation profile through the excised stripped skin from the drug-loaded LSE-high was measured and theoretically evaluated by Fick's second law of diffusion with previously obtained parameters (C0, D(LSE), D(skin)) using a newly constructed two- or three-layered diffusion model. The calculated concentrations of TC-HCl and CP in the upper epidermis of the model wound skin were over their minimum inhibitory concentration (MIC) for several hours against various bacteria, suggesting that this dosage system is useful for the treatment of severe burns. In addition, the present analytical method and diffusion model, with the drug-loaded LSE-high and stripped rat skin, are useful tools for evaluating this new DDS.
Hada
Nobuko
N
Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan.
Hasegawa
Tetsuya
T
Takahashi
Hidekazu
H
Ishibashi
Takuya
T
Sugibayashi
Kenji
K
D000279:Administration, Cutaneous; D000465:Algorithms; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D002701:Chloramphenicol / Q000008:administration & dosage*; D002851:Chromatography, High Pressure Liquid; D004058:Diffusion; D016503:Drug Delivery Systems; D015233:Models, Statistical; D009924:Organ Culture Techniques; D051381:Rats; D012867:Skin / Q000293:injuries / Q000378:metabolism*; D012869:Skin Absorption; D012879:Skin Physiological Phenomena; D013056:Spectrophotometry, Ultraviolet; D013752:Tetracycline / Q000008:administration & dosage*; D014945:Wound Healing
D000900:Anti-Bacterial Agents; D002701:Chloramphenicol; D013752:Tetracycline