Nanosuspension Formulations for Low-Soluble Drugs: Pharmacokinetic Evaluation Using Spironolactone as Model Compound

Abstract

Various particle sizes of spironolactone as a model low solubility drug were formulated to yield micro-and nanosuspensions of the type solid lipid nanoparticles and DissoCubes. Seven oral and one i.v. formulations were tested in an in vivo pharmacokinetic study in rats with the aim of characterizing the bioavailability of spironolactone on the basis of its metabolites canrenone and 7-alpha-thiomethylspirolactone. In addition, a dose escalation study was carried out using nonmicronized spironolactone suspension as well as a nanosuspension type DissoCubes. On the basis of AUC as well as Cmax ratios, three groups of formulations were distinguished. The biggest improvement was seen with a solid lipid nanoparticle formulation yielding a 5.7-fold increase in AUC for canrenone and a similar improvement based on the Cmax metric, followed by a group of three formulations containing nanosized, micronized, and coarse drug material and surfactant. The DissoCubes nanosuspension yielded highly significant improvements in bioavailability averaging 3.3-fold in AUC and 3.0-fold in terms of Cmax for canrenone. The third class encompasses all other formulations, which showed very little to no improvement in bioavailability. The results show that the particle size minimization was not the major determining factor in the bioavailability improvement. Rather, the type of surfactant used as stabilizer in the formulations was of greater importance. Improvement in drug solubility in the intestine as well as in dissolution rate of spironolactone are the most likely mechanisms responsible for the observed effect, although additional mechanisms such as permeability enhancement may also be involved.

Recent Advances in Lipid Nanoparticle Formulations with Solid Matrix for Oral Drug Delivery

“…Different formulations (SLNs and DissoCubes®) of spironolactone (poorly water soluble) with various particle sizes (micro and nano) were prepared and tested in rats (108). The bioavailability of spironolactone was determined on the basis of its metabolites canrenone and 7-α-thiomethylspirolactone.…”

Evaluation of Nanosuspensions for Absorption Enhancement of Poorly Soluble Drugs: In Vitro Transport Studies Across Intestinal Epithelial Monolayers

“…This factor may contribute to the higher bioavailability of nanosuspension formulations for poorly soluble compounds (15).…”

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“…[21] This method was found previously to be an efficient technique to prepare stable nanosuspensions of several drugs such as diclofenac, [22] paclitaxel, [23] budesonide, [24] clofazimine, [25] nifidepine, [26] bupravaquone, [27] amphotericin B, [28] and spironolactone. [29] Considering these general advantages of nanotechnology, the main objective of the present investigation was to prepare nanosuspensions of ibuprofen (IBU) which is a widely used non-steroidal anti-inflammatory drug. As its serum concentration and pharmacological effects are correlated, rapid drug absorption is a prerequisite for the quick onset of its analgesic action.…”