Evaluation of mesoporous TCPSi, MCM-41, SBA-15, and TUD-1 materials as API carriers for oral drug delivery.

The feasibility of four mesoporous materials composed of biocompatible Si (TCPSi) or SiO(2) (MCM-41, SBA-15, and TUD-1) were evaluated for oral drug delivery applications. The main focus was to study the effect of the materials different pore systems (unidirectional/2D/3D) and their pore diameters, pore size distributions, pore volumes on the maximal drug load capacity, and release profiles of a loaded active pharmaceutical ingredient. Ibuprofen was used as the model drug. The total pore volume of the mesoporous solid was the main factor limiting the maximum drug load capacity, with SBA-15 reaching a very high drug load of 1:1 in weight due to its high pore volume. Dissolution experiments were performed in HBSS buffers of pH 5.5, 6.8, and 7.4 to mimic the conditions in the small intestine. At pH 5.5 the dissolution rate of ibuprofen released from the mesoporous carriers was significantly faster compared with the standard bulk ibuprofen (86-63% versus 25% released at 45 min), with the fastest release observed from the 3D pore network of TUD-1 carrier. The utilization of mesoporous carriers diminished the pH dependency of ibuprofen dissolution (pK(a) = 4.42), providing an interesting prospect for the formulation of poorly soluble drug compounds.

Surface chemistry and pore size affect carrier properties of mesoporous silicon microparticles.

Six different types of mesoporous silicon microparticles were prepared to evaluate the effect of surface treatment and pore sizes on their properties as drug carriers. The studied porous silicon particles were as-anodized, thermally carbonized (TCPSi) and thermally oxidized (TOPSi) in addition to three novel ones: annealed TCPSi, annealed TOPSi and thermally hydrocarbonized porous silicon (THCPSi). Drug dissolution at pH 5.5 and physical and chemical stabilities after 3 months of storage were used as experimental models to investigate the loaded particles. Loading degrees of ibuprofen in the particles were determined by several methods before and after storage, and the results were in good agreement with each other. Loading improved the dissolution rate of ibuprofen in all the studied cases, while the hydrophilic TCPSi material resulted in the fastest dissolution and the most stable mesoporous microparticles. The release profiles of ibuprofen did not change markedly during storage. The effect of storage on the loading degrees of the other PSi microparticles than the unstable (easily oxidized) as-anodized porous silicon was not notable.

Mesoporous silica material TUD-1 as a drug delivery system.

For the first time the feasibility of siliceous mesoporous material TUD-1 (Technische Universiteit Delft) for drug delivery was studied. Model drug, ibuprofen, was adsorbed into TUD-1 mesopores via a soaking procedure. Characterizations with nitrogen adsorption, XRD, TG, HPLC and DSC demonstrated the successful inclusion of ibuprofen into TUD-1 host. The amount of ibuprofen adsorbed into the nanoreservoir of TUD-1 material was higher than reported for other mesoporous silica drug carriers (drug/carrier 49.5 wt.%). Drug release studies in vitro (HBSS buffer pH 5.5) demonstrated a fast and unrestricted liberation of ibuprofen, with 96% released at 210 min of the dissolution assay. The drug dissolution profile of TUD-1 material with the random, foam-like three-dimensional mesopore network and high accessibility to the dissolution medium was found to be much faster (kinetic constant k = 10.7) and more diffusion based (release constant n = 0.64) compared to a mesoporous MCM-41 material with smaller, unidirectional mesopore channels (k = 4.7, n = 0.71). Also, the mesoporous carriers were found to significantly increase the dissolution rate of ibuprofen, when compared to the pure crystalline form of the drug (k = 0.6, n = 0.96). TUD-1 was constituted as a potential drug delivery device with fast release property, with prospective applications in the formulation of poorly soluble drug compounds.

Mesoporous silicon microparticles for oral drug delivery: loading and release of five model drugs.

Mesoporous silicon (PSi) microparticles were produced using thermal carbonization (TCPSi) or thermal oxidation (TOPSi) to obtain surfaces suitable for oral drug administration applications. The loading of five model drugs (antipyrine, ibuprofen, griseofulvin, ranitidine and furosemide) into the microparticles and their subsequent release behaviour were studied. Loading of drugs into TCPSi and TOPSi microparticles showed, that in addition to effects regarding the stability of the particles in the presence of aqueous or organic solvents, surface properties will affect compound affinity towards the particle. In addition to the surface properties, the chemical nature of the drug and the loading solution seems to be critical to the loading process. This was reflected in the obtained loading efficiencies, which varied between 9% and 45% with TCPSi particles. The release rate of a loaded drug from TCPSi microparticles was found to depend on the characteristic dissolution behaviour of the drug substance. When the dissolution rate of the free/unloaded drug was high, the microparticles caused a delayed release. However, with poorly dissolving drugs, the loading into the mesoporous microparticles clearly improved dissolution. In addition, pH dependency of the dissolution was reduced when the drug substance was loaded into the microparticles.

Water-soluble beta-cyclodextrins in paediatric oral solutions of spironolactone: preclinical evaluation of spironolactone bioavailability from solutions of beta-cyclodextrin derivatives in rats.

Water-soluble derivatives of beta-cyclodextrin have been considered for solubilization of spironolactone in the formulation of a safe liquid preparation for premature infants. The oral absorption of spironolactone was studied in rats to evaluate the need to adjust spironolactone dosage in prospective clinical studies. Spironolactone was administered in solutions of sulphobutyl ether beta-cyclodextrin (SBE7) or dimethyl-beta-cyclodextrin (DM-beta-CyD) and also as spironolactone-containing powder papers (reference preparation). Spironolactone in SBE7 solution was administered intravenously to assess the extent of intestinal absorption from the different formulations. Spironolactone and the metabolites 7alpha-thiospirolactone, 7alpha-thiomethylspirolactone and canrenone were determined in rat serum after intravenous administration of spironolactone. Half-lives for spironolactone, 7alpha-thiomethylspirolactone and canrenone were 0.72 +/- 0.17, 1.5 +/- 0.3 and 2.2 +/- 0.3 h, respectively. Although, according to Cmax values, 7alpha-thiomethylspirolactone was the major serum metabolite in rats, higher AUC (area under the serum concentration-time curve) values were obtained for canrenone. After oral administration of spironolactone the bioavailabilities evaluated from the AUC values of 7alpha-thiomethylspirolactone were 27.5 +/- 9.3%, 81.3 +/- 28.8% and 82.8 +/- 28.6% for powder papers, DM-beta-CyD and SBE7 solutions, respectively. The oral absorption of spironolactone by rats was better after administration of spironolactone in SBE7 and DM-beta-CyD solutions than after administration as powder papers. Both cyclodextrin formulations enhanced spironolactone bioavailability to a similar extent despite some deacetylation of spironolactone in the presence of SBE7. A reduction of spironolactone dosage would be recommended during clinical studies with premature infants. These results indicate that SBE7 could be a safe and suitable excipient for the solubilization of spironolactone in paediatric formulations.

High-performance liquid chromatography methods for the separation and quantitation of spironolactone and its degradation products in aqueous formulations and of its metabolites in rat serum.

HPLC assays have been developed for the determination of spironolactone and its degradation products 7 alpha-thiospirolactone and canrenone in aqueous solutions of beta-cyclodextrins and for the determination of spironolactone and its metabolites 7 alpha-thiospirolactone, 7 alpha-thiomethylspirolactone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone and canrenone in rat serum samples. Both methods were well suited for their respective applications, i.e., studying the stability of spironolactone in liquid formulations of beta-cyclodextrins and the oral absorption of spironolactone in rats. The HPLC method developed for spironolactone and its metabolites in rat serum requires very small volumes of serum making it possible to take several blood samples over a period of time.