A Cremophor-Free Self-Microemulsified Delivery System for Intravenous Injection of Teniposide: Evaluation In Vitro and In Vivo

Abstract

In order to tackle the problems on low water solubility of teniposide, involvement of toxic surfactant in its injection, and the poor stability during infusion, a Cremophor-free teniposide self-microemulsified drug delivery system (TEN-SMEDDS) was prepared for the first time, characterized, and evaluated in comparison with teniposide injection (VUMON) in vitro and in vivo. The optimized formulation contained N, N-dimethylacetamide, medium-chain triglyceride, lecithin, and dehydrated alcohol besides teniposide. The TEN-SMEDDS could form fine droplets with mean diameter of 282 ± 21 nm and zeta potential of -7.5 ± 1.7 mV after dilution with 5% glucose, which were stable within 4 h. The release of teniposide from TEN-SMEDDS and VUMON was similar. However, the pharmacokinetic behavior of TEN-SMEDDS in rats was different from that of VUMON, evidenced by the lower area under the concentration-time curve and larger volume of distribution in emulsion group. Finally, TEN-SMEDDS was found to distribute more teniposide in most tissues, especially in reticuloendothelial system, after intravenous administration to rats. Importantly, brain drug level in TEN-SMEDDS group was higher than or similar to that in control group, although the emulsion system had a lower plasma drug concentration. In conclusion, the novel SMEDDS prepared here, without toxic surfactant and as an oil solution before use, may be potential for clinical use due to its low toxicity and high store stability. It may be favorable for the treatment of some tumors like cerebroma, since it may achieve the relatively higher drug level in brain but lower blood concentration.

Cremophor-free intravenous self-microemulsions for teniposide: Safety, antitumor activity in vitro and in vivo

“…Previous pharmacokinetic and tissue distribution study indicated that the effective of TEN-SMEDDS for the treatment of brain tumors may have no significant difference compared to VUMON, or was better (He, Cui et al 2012). The pharmacodynamic study illustrated that TEN-SMEDDS had the potency of antitumor.…”

“…The total teniposide in the formed emulsion was detected through breaking the emulsion with 10 times of methanol and then analyzed by HPLC method (He, Cui et al 2012).…”

“…Hence in-line filters with i.v. sets were used (Vyas and Kadow 1995;He, Cui et al 2012). Extraction of diethylhexylphthalate plasticizers from conventional polyvinyl chloride i.v.…”

“…In order to avoid these disadvantages, a Cremophor-free self-microemulsified drug delivery system(TEN-SMEDDS) was developed and characterized (He, Cui et al 2012). Diluted with 5% glucose, the TEN-SMEDDS could form fine microemulsion with an average droplet size of 282 ± 21 nm and zeta potential of −7.5±1.7 mV, which were stable within 4 h. The release of teniposide from TEN-SMEDDS and VUMON was similar.…”

Nanocrystals for the parenteral delivery of poorly water-soluble drugs

“…In order to attain adequate bioavailability of poorly soluble drugs, special formulation strategies are employed to increase their dissolution in aqueous medium [2]. Traditionally, organic solvents are used as co-solvents [3] or a part of emulsion [4] to formulate the poorly soluble drugs as aqueous dosage forms. Alternatively, the drug is fitted in cyclodextrins, which have a hydrophobic interior and a hydrophilic exterior, and made soluble in water [5].…”