Development and Characterization of Self-Microemulsifying Drug Delivery System of Tacrolimus for Intravenous Administration

Abstract

Tacrolimus (FK 506), a poorly soluble immunosuppressant is currently formulated in nonaqueous vehicle containing hydrogenated castor oil derivative for intravenous administration. Hydrogenated castor oil derivatives are associated with acute anaphylactic reactions. This proposes to overcome the problems of poor aqueous solubility of the drug and the toxicity associated with currently used excipients by the development of a new parenterally acceptable formulation using self-microemulsifying drug delivery system (SMEDDS). Solubility of FK 506 in various oils, surfactants, and cosurfactants was determined to identify SMEDDS components. Phase diagrams were constructed at different ratios of surfactants:cosurfactant (K(m)) to determine microemulsion existence area. Influence of oily phase content, K(m), aqueous phase composition, dilution, and incorporation of drug on mean globule size of microemulsions was studied. SMEDDSs were developed using ethyl oleate as oily phase and Solutol HS 15 as surfactant. Glycofurol was used successfully as a cosurfactant. Developed SMEDDS could solubilize 0.8% (wt/wt) FK 506 and on addition to aqueous phase could form spontaneous microemulsion with mean globule size < 30 nm. The resulting microemulsion was iso-osmotic, did not show any phase separation or drug precipitation even after 24 h, and exhibited negligible hemolytic potential to red blood cells.

Physicochemical characterization of tacrolimus-loaded solid dispersion with sodium carboxylmethyl cellulose and sodium lauryl sulfate

“…It is a poorly water-soluble compound which gave the low aqueous solubility of about 1-2 µg/mL (Hane et al, 1992;Honbo et al, 1987;Tamura et al, 2002). Various oral formulations of tacrolimus such as inclusion complex (Arima et al, 2001), nanoparticle (Nassar et al, 2008;Sinswat et al, 2008), Prodrug with poly (ethylene glycol) esters (Chung and Cho, 2004), liposome (Lee et al, 1995), microemulsion (Borhade et al, 2008a;2008b) and solid dispersion (Yamashita et al, 2003) were developed to improve the solubility of tacrolimus.…”

Nanoencapsulation of Tacrolimus in Lipid-Core Nanocapsules Showed Similar Immunosuppressive Activity After Oral and Intraperitoneal Administrations

“…2 9 Furthermore, considering the poor water solubility of tacrolimus (about 1-2 g mL −1 , the marketed intravenous product contains polyoxyl 60 hydrogenated castor oil (HCO-60), which may cause allergic symptoms such as leukocytosis, hyperpyrexia and eruption. 11 Various pharmaceutical strategies such as the development of water soluble tacrolimus derivates, 12 microemulsions, [13][14][15] solid dispersions, 16 17 liposomes, [18][19][20][21] nanosomes, 22 cyclodextrin complexes, 23 24 micelles, 25 microparticles 26 27 and nanoparticulate systems 6 7 28-32 have been described in an effort to overcome the biopharmaceutical limitations of this drug. Some studies have reported the potential use of tacrolimus entrapped into polymeric nanoparticles aiming at a selective drug deposition in inflamed tissues 6 7 as well as to improve the lymphatic targeting efficiency and reduce the drug toxicity.…”

Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view

“…It also facilitates the dispersion process in the medium. Commonly used co-surfactants include ethanol, propylene glycol and other newer co-surfactants such as transcutol P and glycofurol, etc (Kale & Patravale, 2008, Borhade et al, 2009). …”