Thao Do Thi

Ordered mesoporous silica material SBA-15: a broad-spectrum formulation platform for poorly soluble drugs.

Encapsulating poorly soluble drugs in mesoporous silicates is an emerging strategy to improve drug dissolution. This study evaluates the applicability of the ordered mesoporous silicate SBA-15 as an excipient to enhance dissolution, for a test series of 10 poorly soluble compounds with a high degree of physicochemical diversity (carbamazepine, cinnarizine, danazol, diazepam, fenofibrate, griseofulvin, indomethacin, ketoconazole, nifedipine, and phenylbutazone). A generic solvent impregnation method was used to load all model compounds. The target drug content was 20%. The physical nature of the formulations was investigated using differential scanning calorimetry (DSC) and the pharmaceutical performance evaluated by means of in vitro dissolution. Aliquots of each formulation were stored at 25 degrees C/52% RH for 6 months, and again subjected to DSC and in vitro dissolution. The target drug content of 20% was attained in all cases. DSC data evidenced the noncrystalline state of the confined drugs. All SBA-15 formulations exhibited an enhanced dissolution as compared to their corresponding crystalline materials, and the high pharmaceutical performance of all formulations was retained during the 6 months storage period. The results of this study suggest that encapsulation in SBA-15 can be applied as a dissolution-enhancing formulation approach for a very wide variety of poorly soluble drugs.

Enhanced absorption of the poorly soluble drug fenofibrate by tuning its release rate from ordered mesoporous silica

The aim of the present study was to evaluate the effect of release rate from ordered mesoporous silica materials on the rate and extent of absorption of the poorly soluble drug fenofibrate. Three ordered mesoporous silica materials with different pore diameter (7.3 nm, 4.4 nm and 2.7 nm) were synthesized and loaded with fenofibrate via impregnation. Release experiments were conducted under sink conditions and under supersaturating conditions in biorelevant media, simulating the fasted and the fed state. Subsequently, all silica-based formulations were evaluated in vivo (rat model). The release experiments under sink conditions indicated a clear increase in release rate with increasing pore size. However, under supersaturating conditions (FaSSIF), the, pharmaceutical performance (in terms of both the degree and duration of supersaturation), increased with decreasing pore size. The same trend was observed in vivo (fasted state): the area under the plasma concentration-time profile amounted to 102 ± 34 μMh, 86 ± 19 μMh and 20 ± 13 μMh for the materials with pore diameter of 2.7 nm, 4.4 nm and 7.3 nm, respectively. The results of this, study demonstrate that a decrease in drug release rate - and thus, a decrease of the rate at which supersaturation is created - is beneficial to the absorption of fenofibrate.

Combined use of ordered mesoporous silica and precipitation inhibitors for improved oral absorption of the poorly soluble weak base itraconazole

The release of poorly soluble drugs from mesoporous silicates is often associated with the generation of supersaturation, which implies the risk of drug precipitation and reduced availability for absorption. The aim of this study was to enhance the in vivo performance of an ordered mesoporous silicate (SBA-15) by combining it with the precipitation inhibitors hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS). The poorly soluble weak base itraconazole was used as a model compound. Formulations were prepared by physically blending itraconazole-loaded SBA-15 with the precipitation inhibitors. In vitro release experiments implementing a transfer from simulated gastric fluid to simulated intestinal fluid were used to evaluate the pharmaceutical performance. Subsequently, the formulations were evaluated in vivo in rats. When high enough amounts of HPMC were co-administered with itraconazole-loaded SBA-15 (itraconazole:SBA-15:HPMC 1:4:6), the extent of absorption was increased by more than 60% when compared to SBA-15 without precipitation inhibitors (AUC 14,937+/-1617 versus 8987+/-2726nMh). HPMCAS was found ineffective in enhancing the in vivo performance of SBA-15 due to its insolubility in the stomach. The results of this study demonstrate that the pharmaceutical performance of SBA-15 is enhanced through addition of an appropriate precipitation inhibitor.

Formulate-ability of ten compounds with different physicochemical profiles in SMEDDS

In order to gain a better understanding of the reasons of successful self-microemulsifying drug delivery systems (SMEDDS) formulation, ten poorly water-soluble drugs, exhibiting different physicochemical properties, were selected. The solubility of the compounds was determined in various oils (long and medium chain) and surfactants (HLB>12 and HLB<10). The best performing excipients were selected for SMEDDS formulation. The droplet size and zeta potential of SMEDDS were measured in the absence and the presence of drug. Media, time and the presence of drug showed little or no influence on droplet size of most systems. Some systems displayed a different zeta potential in the presence of drugs. In vitro pharmaceutical performance of the SMEDDS formulations was investigated using the dialysis bag method in reverse mode next to conventional in vitro release methodology. The results suggested that the measured concentration of the compounds inside the dialysis bag corresponded to solubility of the compound in the release medium, which suggested that the formation of micelles inside the dialysis bag was delayed or disturbed. Conventional in vitro release methodology with pH change from acidic to neutral appeared as a simple method which gives valuable information about the dispersion and the solubilization ability of the SMEDDS formulation at different pHs. In general, formulate-ability in SMEDDS was found to depend on the solubility of the drugs in the excipients and log P of the compounds (the optimal log P was found between 2 and 4).

Self-Assembly of Cyclodextrins and Their Complexes in Aqueous Solutions

Cyclodextrins (CDs) are enabling pharmaceutical excipients that can be found in numerous pharmaceutical products worldwide. Because of their favorable toxicologic profiles, CDs are often used in toxicologic and phase I assessments of new drug candidates. However, at relatively high concentrations, CDs can spontaneously self-assemble to form visible microparticles in aqueous mediums and formation of such visible particles may cause product rejections. Formation of subvisible CD aggregates are also known to affect analytical results during product development. How and why these CD aggregates form is largely unknown, and factors contributing to their formation are still not elucidated. The physiochemical properties of CDs are very different from simple amphiphiles and lipophilic molecules that are known to self-assemble and form aggregates in aqueous solutions but very similar to those of linear oligosaccharides. In general, negligible amounts of aggregates are formed in pure CD solutions, but the aggregate formation is greatly enhanced on inclusion complex formation, and the extent of aggregation increases with increasing CD concentration. The diameter of the aggregates formed is frequently less than about 300 nm, but visible aggregates can also be formed under certain conditions.

Preventing release in the acidic environment of the stomach via occlusion in ordered mesoporous silica enhances the absorption of poorly soluble weakly acidic drugs

This study aimed to assess the pharmaceutical performance of formulations consisting of either indomethacin or glibenclamide and the ordered mesoporous silica material SBA-15. Both compounds were loaded on SBA-15 via solvent impregnation. Adsorption in the SBA-15 mesopores was confirmed using nitrogen physisorption. Differential scanning calorimetry results suggested that both compounds were dispersed monomolecularly onto the SBA-15 surface. In in vitro experiments simulating the gastric-to-intestinal transition, the release of both compounds from SBA-15 remained under 1% in simulated gastric fluid (SGF, pH 1.2), whereas both drugs were completely released within 10 min after transfer to fasted state simulated intestinal fluid (FaSSIF, pH 6.5). As both drugs exhibited very rapid precipitation from the supersaturated state in SGF, the preferential release in FaSSIF--where conditions are more favourable by virtue of either much higher solubility (indomethacin) or more stable supersaturation (glibenclamide)--was considered crucial towards achieving optimal absorption. This hypothesis was confirmed by an in vivo study, where the extent of absorption of a glibenclamide-SBA-15 formulation was found to be more than fourfold higher than that of the commercial glibenclamide product Daonil®.

High-throughput study of phenytoin solid dispersions: formulation using an automated solvent casting method, dissolution testing, and scaling-up.

A high-throughput experimentation method for studying the dissolution of phenytoin, a poorly water soluble drug, was developed and validated. Solid dispersions with 12 excipients (7 polymers and 5 surfactants) were prepared and tested. Each excipient was screened with three drug loadings: 10, 20, and 40% (w/w). Each solid dispersion was prepared in triplicate, for a total of 108 samples. The drug dissolution was studied in simulated gastric fluid without pepsin plus 1% sodium laurylsulfate. This study led to the identification of three improved formulations, exhibiting an extent of dissolution higher than 90% after both 30 and 60 min. The HTE results could be reproduced at a larger scale using a conventional solvent evaporating method, proving the reliability of the HTE protocol.

The impact of guest compounds on cyclodextrin aggregation behavior: a series of structurally related parabens

Several studies have demonstrated the presence of aggregates in aqueous cyclodextrin containing solutions. The presence of guest compounds has been shown to influence this cyclodextrin aggregation process. In an attempt to gain insight into the effect of the physicochemical properties of the guest compound on 2-hydroxypropyl-β-cyclodextrin aggregation formation, a series of structurally related parabens was selected as model compounds. Using nuclear magnetic resonance spectroscopy and phase solubility studies, these parabens, differing only in side chain length, were demonstrated to form inclusion complexes with 2-hydroxypropyl-β-cyclodextrin. Additional techniques were subsequently applied to evaluate the aggregation behavior of this cyclodextrin in presence of the selected parabens. Solutions containing a broad range of 2-hydroxypropyl-β-cyclodextrin concentrations were saturated with the guest compounds and were used as test media. Results obtained from dialysis experiments, dynamic light scattering and mass spectrometry revealed a positive effect of the side chain length of the parabens on aggregate formation: in presence of heptylparaben, more and larger aggregates were observed than in presence of parabens with shorter side chains such as methyl- and butylparaben. No clear connection could be demonstrated between the cyclodextrin concentration and the extent of aggregate formation in presence of the guest compound.