Pharmaceutical Characterization and In Vivo Evaluation of Orlistat Formulations Prepared by the Supercritical Melt-Adsorption Method Using Carbon Dioxide: Effects of Mesoporous Silica Type

Abstract

Orlistat, an anti-obesity drug, has two critical issues-the first is its low efficacy due to low water solubility and the second is side effects such as oily spotting due to its lipase inhibition. The present study was designed to propose a solution using a formulation with mesoporous silica to simultaneously overcome two issues. Orlistat was loaded onto mesoporous silica by the supercritical melt-adsorption (SCMA) method, using carbon dioxide (CO₂). Various types of mesoporous silica were used as adsorbents, and the effects of the pore volume, diameter and particle size of mesoporous silica on the pharmaceutical characteristics were evaluated by various solid-state characterization methods and in vitro and in vivo studies in relation to pharmacological efficacy and the improvement of side effects. The results showed that the pore volume and diameter determine loadable drug amount inside pores and crystallinity. The dissolution was significantly influenced by crystallinity, pore diameter and particle size, and the inhibition of lipase activity was in proportion to the dissolution rate. In vivo studies revealed that the serum triglyceride (TG) concentration was significantly decreased in the group administered amorphous orlistat-loaded Neuisilin^®UFL2 with the highest in vitro dissolution rate and lipase activity inhibition in comparison to the commercial product. Furthermore, oily spotting tests in rats revealed that undigested oil was adsorbed onto mesoporous silica after orlistat was released in the gastro-intestinal tract, and it correlated with in vitro result that oil adsorption capacity was dependent on the surface area of empty mesoporous silica. Therefore, it was concluded that mesoporous silica type plays a major role in determining the pharmaceutical characteristics of orlistat formulation prepared using SCMA with CO₂ for improving the low solubility and overcoming the side effects.

Keywords: crystallinity; in vivo evaluation; mesoporous silica; orlistat; supercritical melt-adsorption.

Figure 1

Chemical structure of orlistat.

Figure 2

SEM images of particles with various raw mesoporous silica and orlistat adsorbed on them at three different drug loading ratio by SCMA process: (a) raw orlistat, (b) Neusilin^® UFL2; (c) Neusilin^® US2; (d) MCM-41; (e) SBA-15; and (f) SBA-15_LP.

Figure 3

Nitrogen adsorption/desorption isotherms for raw Neusilin^®UFL2 and orlistat-loaded Neusilin^®UFL2 at three different drug loading ratio.

Figure 4

DSC thermograms (a) and PXRD patterns (b) of raw orlistat and orlistat-loaded mesoporous silica at 20%, 40%, and 60% drug loading ratio. D:A is the mass ratio of drug to adsorbent.

Figure 5

Influence of orlistat concentration on lipase activity.

Figure 6

The relationship between DE₆₀ and lipase inhibition % at 60 min.

Figure 7

(a) Oil adsorption capacity of mesoporous silica and (b) relationship with specific surface area.

Figure 8

(a) Oil adsorption capacity of orlistat-loaded Neusilin^®UFL2 (UFL_3, 60% drug loading ratio) after dissolution test (b) and nitrogen adsorption isotherms both before and after dissolution test.

Figure 9

(a) ΔTG vs. time profiles and (b) AUC_0→12 of ΔTG in SD-rats, after oral administration 1 mL olive oil, followed by administration of raw orlistat, the commercial product, and SCMA processed orlistat formulations (n = 6). *: p < 0.05, vs. control; ⁺: p < 0.05, vs. raw orlistat; ^#: p < 0.05, vs. commercial product.

Figure 10

Effects of raw orlistat, the commercial product, and UFL_1 on fat excretion in feces of mice fed a high-fat diet for 5 days. *: p < 0.05, vs. control.

Figure 11

Number of rats showing oily spotting after administration of raw orlistat, the commercial product (Xenical^®), and orlistat-loaded mesoporous silica (n = 26).