In situ intestinal permeability and in vivo oral bioavailability of celecoxib in supersaturating self-emulsifying drug delivery system

Abstract

In order to characterize the in situ intestinal permeability and in vivo oral bioavailability of celecoxib (CXB), a poorly water-soluble cyclooxygenase (COX)-2 inhibitor, various formulations including the self-emulsifying drug delivery system (SEDDS) and supersaturating SEDDS (S-SEDDS) were compared. The S-SEDDS formulation was obtained by adding Soluplus as a precipitation inhibitor to SEDDS, composed of Capryol 90 as oil, Tween 20 as surfactant, and Tetraglycol as cosurfactant (1:4.5:4.5 in volume ratio). An in situ single pass intestinal perfusion study in rats was performed with CXB-dissolved solutions at a concentration of 40 μg/mL. The effective permeability (Peff) of CXB in the control solution (2.5 v/v% Tween 20-containing PBS) was 6.39 × 10(-5) cm/s. The Peff value was significantly increased (P < 0.05) by the lipid-based formulation, yielding 1.5- and 2.9-fold increases for the SEDDS and S-SEDDS solutions, respectively, compared to the control solution. After oral administration of various formulations to rats at the equivalent dose of 100 mg/kg of CXB, the plasma drug level was measured by LC-MS/MS. The relative bioavailabilities of SEDDS and S-SEDDS were 263 and 355 %, respectively, compared to the CXB suspension as a reference. In particular, S-SEDDS revealed the highest Cmax and the smallest Tmax, indicating rapid and enhanced absorption with this formulation. This study illustrates the potential use of the S-SEDDS formulation in the oral delivery of poorly water-soluble compounds.

Enhanced oral bioavailability of valsartan using a polymer-based supersaturable self-microemulsifying drug delivery system

“…With a greater quantity of SMEDDS (500-600 mg), VST dissolution was increased, showing a mild oversaturation effect: increase to over 65% (500 mg) or 80% (600 mg) at 15 min, but gradually decreasing to below 60% (500 mg) or 70% (600 mg) at 2 h. For further comparison, the dissolution enhancing capacity per unit quantity y is the percentage of dissolved product. 20,21 As shown in Figure 3B, DEC proportionally increased up to 400 mg SMEDDS, but reached a plateau afterward. Therefore, we decided the maximum quantity of SMEDDS to be 400 mg for further studies.…”

“…Biorelevant dissolution can be used successfully to predict in vivo behavior of poorly water-soluble drugs in SMEDDS formulations. 21,42 Among poorly water-soluble drugs, BCS class II drugs could be applied to IVIVC, since dissolution is the rate-limiting step for drug absorption in the gut. 43 However, since the present study was aimed at developing a novel S-SMEDDS with minimal quantity, while improving dissolution and oral absorption of VST, unit , where the AUC difference between the specific SMEDDS formulation and VST suspension was divided by the quantity of the relevant SMEDDS formulation.…”

“…There are numerous reports that BA enhancement generally correlates with the increase in dissolution rate of a drug. 21,38 Meanwhile, when compared with SMEDDS (320 mg), the RBAs of S-SMEDDS_LQ and S-SMEDDS_RQ were 127% and 106%, respectively. Addition of supersaturating agents further increased the oral BA, which is consistent with an earlier report that incorporation of 10% polymer to a SMEDDS formulation resulted in a supersaturated solution of a poorly soluble drug that presented higher amounts for absorption throughout the experimental timeframe.…”

“…Poloxamers, Vitamin E TPGS, and Soluplus ® have been incorporated into aqueous formulations to increase solubility and improve dissolution and BA of poorly water-soluble drugs. 21,27,28 They are usually used above the critical micelle concentration (CMC) to solubilize drugs by micelle formation or below the CMC to inhibit drug precipitation. 12,29 The supersaturating agents were added at 5% (w/w) to the VST (80 mg)-containing SMEDDS (400 mg) to prepare S-SMEDDS, and the dissolution profiles were compared to select a good supersaturating agent, which could increase the high-energy form of the drug molecule in the solution.…”

Development and optimization of a self-microemulsifying drug delivery system for atorvastatin calcium by using D-optimal mixture&nbsp;design

“…14 Spontaneous formation of a microemulsion delivers the drug in a solubilized form; further, small droplet size allows rapid dissolution of the drug and provides a large surface area for its absorption, enhancing its permeation across the intestinal membrane. 15 In addition, the drug solubilized in oil droplets is carried by lymphatic transport through the intestine to avoid first-pass metabolism in the liver. 16 Development of a SMEDDS formulation is timeconsuming, labor-intensive, and expensive, and involves an empirical design based on trial and error.…”