Comparison across Three Hybrid Lipid-Based Drug Delivery Systems for Improving the Oral Absorption of the Poorly Water-Soluble Weak Base Cinnarizine.

Three state-of-the-art drug delivery vehicles engineered by nanostructuring lipid colloids within solid particle matrices were fabricated for the oral delivery of the poorly water-soluble, weak base, cinnarizine (CIN). The lipid and solid phase of each formulation was varied to systematically analyze the impact of key material characteristics, such as nanostructure and surface chemistry, on the in vitro and in vivo fate of CIN. The three systems formulated were: silica-stabilized lipid cubosomes (SSLC), silica-solid lipid hybrid (SSLH), and polymer-lipid hybrid (PLH) particles. Significant biopharmaceutical advantages were presented for CIN when solubilized in the polymer (poly(lactic-co-glycolic) acid; PLGA) and lipid phase of PLH particles compared to the lipid phases of SSLC and SSLH particles. In vitro dissolution in simulated intestinal conditions highlighted reduced precipitation of CIN when administered within PLH particles, given by a 4-5-fold improvement in the extent of CIN dissolution compared to the other delivery vehicles. Furthermore, CIN solubilization was enhanced 1.5-fold and 6-fold under simulated fasted state lipid digestion conditions when formulated with PLH particles compared to SSLH and SSLC particles, respectively. In vivo pharmacokinetics correlated well with in vitro solubilization data, whereby oral CIN bioavailability in rats, when encapsulated in the corresponding formulations, increased from SSLC < SSLH < PLH. The pharmacokinetic data obtained throughout this study indicated a synergistic effect between PLGA nanoparticles and lipid droplets in preventing CIN precipitation and thus, enhancing oral absorption. This synergy can be harnessed to efficiently deliver challenging poorly water-soluble, weak bases through oral administration.

Synergistic role of solid lipid and porous silica in improving the oral delivery of weakly basic poorly water soluble drugs.

Oral absorption of weakly basic drugs (e.g. cinnarizine (CIN)) is limited by their pH dependent precipitation in intestinal conditions. To overcome this challenge, a novel drug delivery system composed of solid lipid and porous silica, namely silica encapsulated solid lipid (SESL) particles, was developed via hot homogenization of melted lipid dispersion, followed by ultra-sonication of the silica stabilized homogenized melted lipid dispersion. Scanning electron microscope (SEM) images of the SESL formulation revealed non-spherical and aggregated hybrid particles, with rough exterior and structured nanoparticles visible on the surface. A 1.5, 2.2 and 7-fold improvement in the dissolution of CIN was observed for the SESL particles, under simulated intestinal non-digesting conditions, in comparison to the drug loaded in solid lipid (CIN-SL) matrix, drug loaded in porous silica (CIN-PS) and pure drug powder. Under simulated intestinal digestive condition, significant improvement in the drug solubilization was reported for the SESL formulation in compared to the individual drug loaded systems i.e. CIN-PS and CIN-SL. Thereby, silica encapsulated solid lipid system provides a promising oral delivery approach for poorly water soluble weakly basic drugs.

Porous Silica-Supported Solid Lipid Particles for Enhanced Solubilization of Poorly Soluble Drugs.

Low dissolution of drugs in the intestinal fluid can limit their effectiveness in oral therapies. Here, a novel porous silica-supported solid lipid system was developed to optimize the oral delivery of drugs with limited aqueous solubility. Using lovastatin (LOV) as the model poorly water-soluble drug, two porous silica-supported solid lipid systems (SSL-A and SSL-S) were fabricated from solid lipid (glyceryl monostearate, GMS) and nanoporous silica particles Aerosil 380 (silica-A) and Syloid 244FP (silica-S) via immersion/solvent evaporation. SSL particles demonstrated significantly higher rate and extent of lipolysis in comparison with the pure solid lipid, depending on the lipid loading levels and the morphology. The highest lipid digestion was observed when silica-S was loaded with 34% (w/w) solid lipid, and differential scanning calorimeter (DSC) analysis confirmed the encapsulation of up to 2% (w/w) non-crystalline LOV in this optimal SSL-S formulation. Drug dissolution under non-digesting intestinal conditions revealed a three- to sixfold increase in dissolution efficiencies when compared to the unformulated drug and a LOV-lipid suspension. Furthermore, the SSL-S provided superior drug solubilization under simulated intestinal digesting condition in comparison with the drug-lipid suspension and drug-loaded silica. Therefore, solid lipid and nanoporous silica provides a synergistic effect on optimizing the solubilization of poorly water-soluble compound and the solid lipid-based porous carrier system provides a promising delivery approach to overcome the oral delivery challenges of poorly water-soluble drugs.

Lyophilized silica lipid hybrid (SLH) carriers for poorly water-soluble drugs: physicochemical and in vitro pharmaceutical investigations.

Lyophilization was investigated to produce a powdery silica-lipid hybrid (SLH) carrier for oral delivery of poorly water-soluble drugs. The silica to lipid ratio, incorporation of cryoprotectant, and lipid loading level were investigated as performance indicators for lyophilized SLH carriers. Celecoxib, a nonsteroidal anti-inflammatory drug, was used as the model poorly soluble moiety to attain desirable physicochemical and in vitro drug solubilization properties. Scanning electron microscopy and confocal fluorescence imaging verified a nanoporous, homogenous internal matrix structures of the lyophilized SLH particles, prepared from submicron triglyceride emulsions and stabilized by porous silica nanoparticles (Aerosil 380), similar to spray-dried SLH. 20-50 wt % of silica in the formulation have shown to produce nonoily SLH agglomerates with complete lipid encapsulation. The incorporation of a cryoprotectant prevented irreversible aggregation of the silica-stabilized droplets during lyophilization, thereby readily redispersing in water to form micrometre-sized particles (<5 µm). The lyophilized SLH produced approximately 1.5-fold and fivefold increased drug solubilization than the pure drug under nondigesting and digesting conditions, respectively. The feasibility of lyophilization for producing nanostructured SLH formulations with desirable lipid loading and drug solubilization properties for enhanced oral delivery of poorly water-soluble therapeutics is confirmed.