Development and evaluation of a tacrolimus cream formulation using a binary solvent system.
We developed an oil/water-type tacrolimus (FK506) cream formulation as an alternative to Protopic ointment for atopic dermatitis treatment. We determined the effects of solvents used in topical preparations on FK506 solubility and stability, and evaluated FK506 transdermal absorption into rat skin from solutions, emulsions, and creams. Screening indicated that diethyl sebacate (DES), isopropyl myristate (IPM), propylene glycol (PG), and oleyl alcohol (OA) were adequate FK506 solvents. When FK506 solutions prepared using these solvents were transdermally administered, AUC0-24 values for DES and IPM were higher than or similar to that for 0.1% Protopic ointment. The AUC0-24 values for PG and OA were low, so these solvents did not enhance absorption. The residual ratios of FK506 in DES and IPM solutions after incubation at 70°C for 9d were 95.6% and 88.6%, respectively, so DES and IPM were chosen for emulsion preparation. When the emulsions were transdermally administered, the IPM emulsion AUC0-24 values increased 4.6-fold; DES emulsions did not show high transdermal absorption, but showed sustained characteristics. A cream formulation prepared by mixture of IPM and DES also showed high absorption and transdermal absorption increased with increasing IPM ratio. We developed an FK506 cream formulation with a controllable transdermal absorption rate by manipulating the IPM:DES ratio.
Astellas Pharma Inc., Project & Product Management, 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan; Department of Pharmaceutical Engineering, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Masayuki
M
Yamanaka
Astellas Pharma Inc., Project & Product Management, 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan.
Shoji
S
Yokota
Department of Pharmaceutical Engineering, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Yasunori
Y
Iwao
Department of Pharmaceutical Engineering, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Shuji
S
Noguchi
Department of Pharmaceutical Engineering, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: s-itai@u-shizuoka-ken.ac.jp.
Shigeru
S
Itai
D000818:Animals; D002626:Chemistry, Pharmaceutical; D055808:Drug Discovery / Q000379:methods*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012869:Skin Absorption / Q000187:drug effects* / Q000502:physiology; D063465:Skin Cream / Q000737:chemistry* / Q000493:pharmacokinetics; D012997:Solvents / Q000737:chemistry*; D016559:Tacrolimus / Q000737:chemistry* / Q000493:pharmacokinetics
D012997:Solvents; D016559:Tacrolimus
Binary solvent; Cream; Emulsion; Surfactant; Tacrolimus