Design and Evaluation of Self-Microemulsifying Drug Delivery System (SMEDDS) of Tacrolimus

Abstract

Abstract. The objective of present investigation was to formulate self-microemulsifying drug delivery systems (SMEDDS) of tacrolimus (FK 506), a poorly water soluble immunosuppressant that exhibits low and erratic bioavailability. Solubility of FK 506 in various oils, surfactants cosurfactants and buffers was determined. Phase diagrams were constructed at different ratios of surfactant/cosurfactant (K m ) to determine microemulsion existence region. The effect of oil content, pH of aqueous phase, dilution, and incorporation of drug on mean globule size of resulting microemulsions was studied. The optimized SMEDDS formulation was evaluated for in vitro dissolution profile in comparison to pure drug and marketed formulation (Pangraf capsules). The in vivo immunosuppressant activity of FK 506 SMEDDS was evaluated in comparison to Pangraf capsules. Area of o/w microemulsion region in phase diagram was increased with increase in K m . The SMEDDS yielded microemulsion with globule size less than 25 nm which was not affected by the pH of dilution medium. The SMEDDS was robust to dilution and did not show any phase separation and drug precipitation even after 24 h. Optimized SMEDDS exhibited superior in vitro dissolution profile as compared to pure drug and Pangraf capsules. Furthermore, FK 506 SMEDDS exhibited significantly higher immunosuppressant activity in mice as compared to Pangraf capsules.

Poly(ethylene glycol)-Block-Poly(2-methyl-2-benzoxycarbonyl-propylene Carbonate) Micelles for Rapamycin Delivery: In Vitro Characterization and Biodistribution

“…The mean particle sizes, reported as the z-average based on mean intensity, were shown in Table 2. There was no significant difference in particle size among PEG 114 -b-PBC 8 , PEG 114 -b-PBC 17 , and PEG 114 -b-PBC 30 , the particle size range was from 65 to 75 nm. The morphology and particle size of micelles formed by PEG-b-PBC was determined by TEM ( Figure 5), which showed a uniform size distribution with average diameter below 50 nm, which is a little smaller than the z-average diameters obtained by DLS.…”

“…Using the peak areas of PEG CH 2 groups at * 3.6 and those of CH 2 in BC main chain at * 4.3, the degree of polymerization and molecular weight of the polymers was calculated and listed in Table 1. The M n s of PEG-b-PBC polymers with different hydrophobic core lengths determined by 1 H NMR were 7000 g/mol for PEG 114 -b-PBC 8 , 9250 g/mol for PEG 114 -b-PCD 17 , 12,500 g/mol for PEG 114 -b-PBC 30 , respectively. The other characteristics of PEG-b-PBC polymers are summarized in Table 1.…”

“…18,19 Briefly, 1 mg of rapamycin and 10 mg of PEG 114 -b-PBC 8 , PEG 114 -b-PBC 17 , or PEG 114 -b-PBC 30 were dissolved in 0.4 mL methylene chloride in a glass vial. The mixture was vortexed for 1 min to ensure homogeneity and the solvent was evaporated under N 2 flow to form the film.…”

“…All of the polymers showed narrow distribution in their molecular weights as revealed by the small value of PDI (1.03-1.15). A combined plot comparing the GPC chromatograms for PEG 114 -b-PBC 8 , PEG 114 -b-PBC 17 , and PEG 114 -b-PBC 30 was shown in Figure 2. The CMC of PEGb-PBC polymers were determined by fluorescence spectroscopy.…”

“…The CMC of PEGb-PBC polymers were determined by fluorescence spectroscopy. PEG 114 -b-PBC 8 , PEG 114 -b-PBC 17 , and PEG 114 -b-PBC 30 had low CMC values of 3.6 × 10 −3 , 7.9 × 10 −4 , and 4.0 × 10 −4 mg/mL, respectively ( Figure 4 and Table 1). The CMC of PEG 114 -b-PBC 30 was around 10-folds lower than those of PEG 114 -b-PBC 8 , indicating better stability of micelles prepared from PEG 114 -b-PBC 30 .…”