Lipid Digestion as a Trigger for Supersaturation: Evaluation of the Impact of Supersaturation Stabilization on the in Vitro and in Vivo Performance of Self-Emulsifying Drug Delivery Systems

Abstract

The generation of supersaturation in the gastrointestinal (GI) tract is an increasingly popular means of promoting oral absorption for poorly water-soluble drugs. The current study examined the impact of changes to the quantities of medium-chain (MC) lipid (Captex 300:Capmul MCM), surfactant (Cremophor EL) and cosolvent (EtOH), and the addition of polymeric precipitation inhibitors (PPI), on supersaturation during the dispersion and digestion of MC self-emulsifying drug delivery systems (SEDDS) containing danazol. The data suggest that digestion acts as a "trigger" for enhanced supersaturation and that solubilization/precipitation behavior is correlated with the degree of supersaturation on dispersion (S(M)DISP) or digestion (S(M)DIGEST). The ability of the formulation to maintain solubilization in vitro decreased as the S(M) of the formulation increased. PPI significantly increased supersaturation stabilization and precipitation was inhibited where S(M)DISP < 3.5 and S(M)DIGEST < 4. In the presence of polymer, some degree of supersaturation was maintained up to S(M)DIGEST ∼ 8. Differentiation in the ability of SEDDS to maintain drug solubilization stems from the ability to stabilize supersaturation and for MC SEDDS, utilization of lower drug loads, higher surfactant levels (balanced against increases in S(M)DISP), lower cosolvent and the addition of PPI enhanced formulation performance. In vivo studies confirmed the ability of PPI to promote drug exposure at moderate drug loads (40% of saturated solubility in the formulation). At higher drug loads (80% saturation) and in lipid-free SEDDS, this effect was lost, suggesting that the ability of PPIs to stabilize supersaturation in vitro may, under some circumstances, overestimate utility in vivo.

An in Vitro Digestion Test That Reflects Rat Intestinal Conditions To Probe the Importance of Formulation Digestion vs First Pass Metabolism in Danazol Bioavailability from Lipid Based Formulations

“…While the rat data presented here indicate a very large first pass effect; under conditions where first pass metabolism was inhibited, absolute bioavailability was high, suggesting that the fraction absorbed was also high. This was not expected based on previous in vitro digestion data showing considerable drug precipitation under simulated dog GI environments, 9,22 which was seemingly reflected in previous bioavailability data in the dog 22,60 showing significant formulation effects on bioavailability. However, much improved absorption in the rat is consistent with the lower extent of precipitation obtained in the in vitro tests conducted in the current studies under the lower dilution conditions and lower digestive enzyme levels expected in the rat.…”

“…Danazol solubilization during digestion of SEDDS L -III under three conditions: (A) in vitro digestion utilizing the previous dog digestion model (high dilution/high enzyme activity) using 4 mL of porcine pancreatin extract (data from Anby et al9 ), (B) a rat digestion model (high dilution/low enzyme activity) using 1 mL of rat pancreatic/biliary fluid, and (C) a rat digestion model (high dilution/low enzyme activity) using 17 μL of porcine pancreatin extract to match the activity of ex vivo rat pancreatic/biliary fluid. Bars represent danazol in aqueous colloidal (light blue), oil phase below colloidal phase (light yellow), and precipitate (dark gray) [mean ± SD (n = 3)].…”

Biopharmaceutic Profiling of Salts to Improve Absorption of Poorly Soluble Basic Drugs

“…Supersaturation may be achieved using a number of different formulation approaches such as an amorphous form of the compound, 12-16 a less stable crystalline form, 17,18 crystalline salts, 11,19,20 formulating with cosolvents, 21 adsorption-based formulations, 22 cocrystals, 23,24 and lipid-based formulations. [25][26][27][28] However, in generating supersaturation, the drug in solution is thermodynamically unstable, generating a driving force for precipitation in the GI tract. There are some reports available regarding formulation strategies that can be applied to inhibit in vivo precipitation.…”

The Biopharmaceutics Classification System: Subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC

“…The drug solubility and dissolution rate would be significantly affected by their particle size and size distribution, and especially formulations factors (Anby et al, 2012; Williams et al, 2012b), as well as the in vivo luminal environment (Jinno et al, 2008; Sheng et al, 2008; Willmann et al, 2010). The BCS Class IIc drugs that have biopharmaceutical properties similar to those of fenofibrate will have longer residence times throughout small and large intestines i.e.…”