Design, Characterization, and In Vivo Pharmacokinetics of Tacrolimus Proliposomes

AAPS PharmSciTech Design, Characterization, and In Vivo Pharmacokinetics of Tacrolimus Proliposomes Vijaykumar Nekkanti ) 1 Javier Rueda 0 Zhijun Wang 0 Guru V Betageri 0 1 0 College of Pharmacy, Western University of Health Sciences , Pomo- na, California , USA 1 Graduate College of Biomedical Sciences, Western University of Health Sciences , 309 E. Second Street, Pomona, California 91766 , USA The objective of this study was to develop proliposomal formulation for a poorly bioavailable drug, tacrolimus. Proliposomes were prepared by thin film hydration method using different lipids such as hydrogenated soy phosphatidylcholine (HEPC), soy phosphatidylcholine (SPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoylphosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. Proliposomes were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague-Dawley (SD) rats. Among the different formulations, proliposomes with drug/DSPC/cholesterol in the ratio of 1:2:0.5 demonstrated the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes compared to pure tacrolimus in purified water after 1 h. Tacrolimus permeability across PAMPA and everted rat intestinal perfusion models was significantly higher with proliposomes. The optimized formulation of proliposomes indicated a significant improvement in the rate and absorption of tacrolimus. Following a single oral administration, a relative bioavailability of 193.33% was achieved compared to pure tacrolimus suspension. everted rat; oral bioavailability; PAMPA; pharmacokinetics; proliposomes; tacrolimus - The oral route is the most commonly preferred route of administration because of its convenience in dosing and patient compliance. However, drugs administered by oral route may often result in suboptimal therapeutic response because of the drug’s poor solubility, inadequate permeation, and extensive first-pass effect. Proliposomes are reported as drug delivery carriers for enhancing the oral bioavailability of drugs with poor bioavailability (1–7). Proliposomes are dry, free flowing powders that can form multilamellar vesicles upon hydration. Liposomes can either be formed in vivo upon contact with physiological fluids or preformed by hydration with water before administration (8). Due to structural similarity between phospholipid bilayers and biological membranes, liposomes play an imperative role in facilitating the oral absorption of the poorly soluble drugs (9). The lipidbased systems following oral administration, especially the formulations with long chain fatty acids, promote the absorption of lipophilic drugs by simulating the formation of low-density lipoproteins and chylomicrons which are transported via the intestinal lymphatic system, circumventing the first-pass effect resulting in improved oral bioavailability (10). Proliposomes is an emerging platform technology for improving the oral delivery of drugs with poor bioavailability (11). In this study, we made an effort to improve the oral bioavailability of tacrolimus by formulating into proliposomes. Tacrolimus is a potent immunosuppressive drug used in transplanted patients to minimize the risk of organ rejection. Tacrolimus is also a drug of choice for atopic dermatitis in reducing the side effects related with topical corticosteroids. Tacrolimus is classified as a class II drug according to the biopharmaceutical classification system (12). Tacrolimus exhibits poor aqueous solubility, P-gp efflux, and extensive presystemic metabolism resulting in low bioavailability following oral administration (13–16). The reported mean bioavailability is approximately 21% with large intersubject variability. The therapeutic application of tacrolimus is complex because of its narrow therapeutic index (5–15 ng/mL) and large inter/intrasubject variability in pharmacokinetic profile. The half-life of tacrolimus is 8.7 to 11.3 h and the mean time to achieve the peak plasma concentrations was reported as 1.5 to 2.0 h (17–19). Tacrolimus is a known P-gp and P450 3A4 (CYP3A4) substrate; therefore, any P-gp or CYP3A4 modulator can alter the pharmacokinetic properties of tacrolimus (20). Several formulation approaches have been reported to improve the oral bioavailability of tacrolimus. Most of these techniques have been focused on improving the solubility and absorption of tacrolimus from the GI tract or reducing P-gp efflux and CYP-450-mediated metabolism, with limited success. The reported approaches include prodrug (21), cyclodextrin complexes (22), solid disper (...truncated)