Incomplete Desorption of Liquid Excipients Reduces the in Vitro and in Vivo Performance of Self-Emulsifying Drug Delivery Systems Solidified by Adsorption onto an Inorganic Mesoporous Carrier

Abstract

The purpose of the current study was to provide a mechanistic basis for in vitro and in vivo performance differences between lipid-based formulations solidified by adsorption onto a high surface area material and their respective liquid (i.e., nonadsorbed) counterparts. Two self-emulsifying formulations (based on either medium-chain or long-chain lipids) of the poorly water-soluble drug danazol were solidified by adsorption onto Neusilin US2. Liquid and adsorbed lipid-based formulations were subjected to in vitro dispersion-digestion tests, and additional in vitro experiments were performed to elucidate the cause of performance differences. The bioavailability of danazol after oral administration to rats was also assessed. The percentage of the dose solubilized in the aqueous phase during in vitro dispersion-digesting was ∼35% lower for the adsorbed formulations when compared to their liquid counterparts. This trend was also reflected in vivo, where the bioavailability of danazol after administration of the adsorbed formulations was ∼50% lower than that obtained after administration of the equivalent liquid formulation. Incomplete desorption of the microemulsion preconcentrate from the carrier on dispersion-digestion was identified as the main contributor to the reduced pharmaceutical performance of the adsorbed formulations. The results of the current study indicate that solidification of lipid-based formulations through adsorption onto a high surface area carrier may limit formulation (and drug) release in vivo and thereby reduce oral bioavailability.

Comparative evaluation of porous silica based carriers for lipids and liquid drug formulations

“…The obtained observations are comparable with Kang et al who reported slow and incomplete ibuprofen release from SMEDD formulation loaded with MAS [32]. In addition, Van Speybroeck et al observed incomplete desorption of danazol through MAS loaded SMEDD formulation [11]. Various researchers had attempted to determine the reason behind the poor release through adsorbent formulations.…”

“…Further understanding of the molecular determinants of the interaction with MAS was beyond the scope of the current study, but is the subject of ongoing investigations. Furthermore, it is reported Brought to you by | NDSU Library Periodicals Authenticated Download Date | 7/25/15 4:27 PM that Cremophor EL has affinity to MAS causing a reduction in danazol release from the solid SMEDDS [11]. To better understand the role of silanol/hydroxyl groups in the interaction with the liquids calcination was performed to reduce the possibility of H-bonding.…”

“…The extra peak of size (170 nm) in solid SMEDDS may be attributed to the adsorption of lipids or surfactants on the surface of MSG. If the adsorbents possess more affinity towards lipids or surfactants, the content of the surfactant in the dissolution media will be reduced and the emulsification will be poor with increased globule size [11]. However, a prominent peak is observed at 19nm size corresponding to the globules of SMEDDS and the observed dissolution capacity (Figure 8).…”

“…These delivery systems have been evaluated by various researchers with different success rates. Among them, lipid based drug delivery systems like simple oil solutions, self-emulsifying drug delivery systems (SEDDS) and self-micro emulsifying drug delivery systems (SMEDDS) are often used for delivery of poorly water-soluble drugs due to improved biocompatibility as opposed to alternate drug delivery systems where excipients may create compatibility issues in addition to higher solubility of the drug in the GIT and increased bioavailability of the poorly water-soluble drug [11]. Furthermore, lipid-based formulations can also be used to protect moisture sensitive drugs from hydrolysis and to improve enzymatic stability [12].…”

Triterpene-loaded microemulsion using Coix lacryma-jobi seed extract as oil phase for enhanced antitumor efficacy: preparation and in vivo evaluation

“…[15][16][17] In recent years, microemulsions have become an efficient approach to improving the solubility and poor oral bioavailability of insoluble drugs. [18][19][20] Given the relative low intestinal absorption of triterpene and adlay seed oil, introduction of microemulsion technology into the Ling-Yi formulation might be helpful in overcoming its intrinsic disadvantages, improving its bioavailability, and enhancing its therapeutic effect. However, a microemulsion containing a high concentration of a pharmaceutical adjuvant could potentially have a detrimental effect on normal body tissue.…”