Pharmaceutical Development and Technology最新文献

Chemotherapeutic drug delivery systems are commonly limited by their short half-lives, poor bioavailability, and unsuccessful targetability. Herein, pH-responsive hybrid NPs consist of benzimidazole-coated mesoporous silica nanoparticles (BZ-MSN) loaded with naturally occurring flavonoid quercetin (QUE-BZ-MSN). The NPs were further capped with beta-cyclodextrin (BCD) to obtain our desired BCD-QUE-BZMSN, with a zeta potential around 7.05 ± 2.37 mV and diameter about 115.2 ± 19.02 nm. The abundance of BZ onto the nanoparticles facilitates targeted quercetin chemotherapy against model lung and liver cancer cell lines. FTIR, EDX, and NMR analyses revealed evidence of possible surface functionalizations. Powder XRD analysis showed that our designed BCD-QUE-BZMSN formulation is amorphous in nature. The UV and SEM showed that our designed BCD-QUE-BZMSN has high drug entrapment efficiency and a nearly spherical morphology. In vitro, drug release assessments show controlled pH-dependent release profiles that could enhance the targeted chemotherapeutic response against mildly acidic regions in cancer cell lines. The obtained BCD-QUE-BZMSN nanovalve achieved significantly higher cytotoxic efficacy as compared to QUE alone, which was evaluated by in vitro cellular uptake against liver and lung cancer cell lines, and the cellular morphological ablation was further confirmed via inverted microscopy. The outcomes of the study imply that our designed BCD-QUE-BZMSN nanovalve is a potential carrier for cancer chemotherapeutics.

Given the extensive first pass metabolism of rizatriptan in oral administration and its delayed absorption during a migraine attack as a result of gastric stasis, focus has been on transdermal delivery. The main purpose of this study is to prepare and assess transdermal formulation of rizatriptan, loaded on hydrogel microneedles delivery system, to avoid first pass metabolism and also improve its percutaneous permeation rate. Rizatriptan hydrogel microneedles were prepared using micromolding method and evaluated in terms of mechanical strength, encapsulation efficiency, permeation and in-vivo skin absorption. Different formulations of rizatriptan microneedles (F1-F5) were successfully prepared using different concentrations of carboxymethyl cellulose and gelatin type A. Rizatriptan hydrogel microneedles demonstrated favorable mechanical properties, including withstanding insertion forces, thereby enhancing its skin insertion ability. In permeation study, the percent cumulative drug released after 24 h ranged between 93.1-100% which means that microneedles were able to deliver the drug effectively. For in-vivo study, F3 formulation was selected due to its superior characteristics over other formulations as it exhibited the highest swelling capacity, and demonstrated favorable mechanical properties. Furthermore, F3 showcased the most controlled drug release over a 24-hour period. Relative bioavailability of F3 microneedles was 179.59% compared to oral administration based on the AUC_0-24. The observed AUC_0-24 in F3 microneedles was statistically significant and 1.80 times greater than that in oral administration. The higher rizatriptan level in the microneedle demonstrated adequate drug permeability through the rat skin, suggesting the potential of microneedles for enhanced therapeutic effectiveness.

Objectives: Furosemide (FSM), a potent loop diuretic, is used to treat edema due to hypertension, congestive heart failure, and liver and renal failures. FSM applications are limited by its low bioavailability. Our aim is to use different nanoencapsulation strategies to control the release of FSM and enhance its pharmacokinetic properties.

Methods: Two types of FSM-loaded nanocapsules, namely FSM-loaded lipid nanocapsules (LNCs) and polymeric nanocapsules (PNCs), were developed, physicochemically characterized, and subjected to pharmacokinetic and pharmacodynamic studies. Lipid nanocapsules were prepared by the simple phase inversion method using Labrafac^TM lipid, while the polymeric nanocapsules were prepared by nanoprecipitation method using polycaprolactone polymer.

Results: Transmission electron microscopy ascertains spherical structures, corroborating the nanometric diameter of both types of nanocapsules. The particle size of the optimized FSM-loaded LNCs and FSM-loaded PNCs was 32.19 ± 0.72 nm and 230.7 ± 5.13 nm, respectively. The percent entrapment efficiency was 63.56 ± 1.40% of FSM for the optimized PNCs. The in vitro release study indicated prolonged drug release compared to drug solutions. The two loaded nanocapsules systems succeeded in enhancing the pharmacokinetic parameters in comparison to the marketed FSM solution with superior diuretic activity (p < 0.05). The results of the stability study and the terminal sterilization by autoclave indicated the superiority of LNCs over PNCs in maintaining the physical parameters under storage conditions and the drastic conditions of sterilization.

Conclusions: LNCs and PNCs are considered promising nanosysems for improving the diuretic effect of FSM.

Hot melt extrusion by a co-rotating twin screw extruder is an important process in the pharmaceutical industry. Especially for quality by design aspects, a comprehensive process understanding is indispensable. The performance of conveying elements was determined as critical process parameter, and therefore an experimental and numerical framework was developed to analyze and compare variations. A test rig capable of measuring volume flow, pressure and torque with high accuracy and precision was designed and built. The 3D simulation was performed using computational fluid dynamics (CFD). A stationary model with impulse transmission and an apparent motion of the screws was applied. The experimental data were fitted to the model of Pawlowski, and parameters for the pressure (A₁, A₂) and power characteristics (B₁, B₂) were determined. Good agreement between experimental data and the model was observed. The simulation was significantly faster compared to common methods, and the results were consistent with the literature. Systematic investigations of a native and worn screw were performed with CFD resulting in a transport capacity increase and a pressure build up decrease for all tested screw elements. An experimental and simulation setup was generated to assess the performance of co-rotating twin screw elements. The experiments provided high-quality data, and the simulations exhibited high flexibility with low computational effort.

Dwell time is an important parameter responsible for the material deformation and the mechanical and biopharmaceutical properties of the tablet. Thus, it is widely used for scale-up purposes. The geometric dwell time (GDT) can be assumed based on the shape of the punch head and the diameter and speed of the turret. This research is aimed to compare compaction simulator-recorded dwell time according to force (DTF) and the GDT calculated for the simulated rotary tablet press using the microcrystalline cellulose and calcium phosphate mixtures (CEOLUS™ UF-711 and DI-CAFOS^® A60) in different proportions. Tablets were prepared, and DTF was analyzed with a compaction simulator (STYL'One Nano and Alix software) upon simulating a small rotary press at 70 rpm and a compression pressure of 10-50 kN (100-500 MPa). While GDT comprised of 14.4 ms, DTF was compression force and formulation dependent. The differences between the DTF values of the formulations decreased as the compression force increased, which was most pronounced at compression forces of 10 and 15 kN.

Doxorubicin (DOX) is a chemotherapeutic with considerable efficacy, but its application is limited due to cardiotoxicity. Nanoparticles can improve DOX efficacy and prevent its adverse effects. Herein, DOX-loaded extracellular vesicles (DOX-EVs) were prepared using different loading methods including incubation, electroporation, and sonication in different hydration buffers to permeabilize nanostructures or desalinize DOX for improved entrapment. Different protein:drug (µg:µg) ratios of 1:10, 1:5, and 1:2, and incubation parameters were also investigated. The optimal formulation was characterized by western blotting, electron microscopy, Zetasizer, infrared spectroscopy, and release study. The cellular uptake and efficacy were investigated in MCF-7 spheroids via MTS assay, spheroid formation assay (SFA), confocal microscopy, and flow cytometry. The percentage of entrapment efficiency (EE) of formulations was improved from 1.0 ± 0.1 to 22.0 ± 1.4 using a protein:drug ratio of 1:2 and sonication in Tween 80 (0.1%w/v) containing buffer. Characterization studies verified the vesicles' identity, spherical morphology, and controlled drug release properties. Cellular studies revealed the accumulation and cytotoxicity of DOX-EVs in the spheroids, and SFA and confocal microscopy confirmed the efficacy and cellular localization. Flow cytometry results revealed a comparable and amplified efficacy for DOX-EV formulations with different cell origins. Overall, the EV formulation of DOX can be applied as a promising alternative with potential advantages.

The appearance of an extrudate formulation was monitored during hot-melt extrusion (HME) continuous manufacturing over 3 days. The formulation matrix consisted of a polymeric component, copovidone, and a low molecular weight surfactant, polysorbate 80. Based on studies prior to the continuous manufacturing, the desired appearance of the target extrudate is translucent. Although process parameters such as feed rate and screw speed were fixed during the continuous manufacturing, the extrudate appearance changed over time from turbid to translucent. For root-cause investigation, the extrudates were analyzed offline by differential scanning calorimetry (DSC) and advanced polymer chromatography (APC^™). Although the polysorbate 80 content of both turbid and translucent extrudates was within target, the glass transition temperature of the turbid extrudate was 2 °C above expected value. The observed turbidity was traced to lot-to-lot variability of the polysorbate 80 used in the continuous manufacturing, where APC^™ analysis revealed that the relative content of the low molecular weight component varied from 23% to 27% in correlation with the evolution from turbid to translucent extrudates. This work stresses the importance of taking feeding material variability into account during continuous manufacturing.

Letrozole (LTZ) is used as first-line treatment for hormone-positive breast cancer (BC) in postmenopausal women. However, its poor aqueous solubility and permeability have reduced its clinical efficacy. Herein, we developed LTZ-nanotransferosomes (LTZ-NT) to address above mentioned issues. The LTZ-NT were optimized statistically using Design Expert^® followed by their characterization via dynamic light scattering (DLS), Transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and Differential scanning calorimetry (DSC). The optimized LTZ-NT was incorporated into 1% chitosan-gel to develop LTZ-NTG. Moreover, in vitro drug release and ex vivo permeation of LTZ-NTG were performed and compared with LTZ-dispersion and LTZ-NT. Additionally, skin irritability and histopathology of LTZ-NTG were investigated. Furthermore, in vitro antitumor study of LTZ-NTG was investigated in BC cell lines. The optimized LTZ-NT showed suitable zeta potential (30.4 mV), spherical size (162.5 nm), and excellent entrapment efficiency (88.04%). Moreover, LTZ-NT exhibited suitable thermal behavior and no interactions among its excipients. In addition, LTZ-NTG had an optimal pH (5.6) and a suitable viscosity. A meaningfully sustained release and improved permeation of LTZ was observed from LTZ-NTG. Additionally, LTZ-NTG showed significantly enhanced cell death of MCF-7 and MCC-7 cells. It can be concluded that LTZ-NTG has the potential to deliver chemotherapeutic agents for possible treatment of BC.

The purpose of this study was to investigate the impact of different functional stabilizers on in vitro/in vivo drug performances after oral administration of drug nanocrystals. Quercetin nanocrystals (QT-NCs) respectively stabilized by five types of functional stabilizers, including hydroxypropyl methyl cellulose E15 (HPMC E15), poloxamer 407 (P407), poloxamer 188 (P188), D-α-tocopherol polyethylene glycol succinate (TPGS), and glycyrrhizin acid (GL), were fabricated by wet media milling technique. The particle size, morphology, physical state, drug solubility, drug dissolution in vitro, and orally pharmacokinetic behaviors of all QT-NCs were investigated. All QT-NCs with similar particle size about 200 nm were obtained by controlling milling speed and milling time. No significant differences in particles shape and crystalline nature were found for QT-NCs stabilized by different functional stabilizers. But the solubility and dissolution of QT-NCs were significantly influenced by the different functional stabilizers. The AUC_0∼t of all QT-NCs after oral administration was in the following order: QT-NCs/P188 ≈ QT-NCs/HPMC E15 > QT-NCs/GL > QT-NCs/P407 ≈ QT-NCs/TPGS, and the C_max showed an order of QT-NCs/P407 > QT-NCs/P188 ≈ QT-NCs/GL > QT-NCs/HPMC E15 > QT-NCs/TPGS. Both of QT-NCs/P407 and QT-NCs/TPGS exhibited faster oral absorption with T_max at 0.5 h and 0.83 h, respectively, while the other three QT-NCs (QT-NCs/P188, QT-NCs/GL and QT-NCs/HPMC E15) showed a relatively slow absorption with same T_max at 5.33 h. The longest MRT_0∼t (11.72 h) and t_1/2z (32.22 h) were observed for QT-NCs/HPMC E15. These results suggested that the different functional stabilizers could significantly influence on drug solubility, drug dissolution in vitro and orally pharmacokinetic behavior of QT-NCs, and it is possible to alter the drug dissolution in vitro, oral absorption and drug retention in vivo by changing the type of functional stabilizers in NCs preparation.

In order to overcome the poor bioavailability of paclitaxel (PTX), in this study, self-assembled paclitaxel silk fibronectin nanoparticles (PTX-SF-NPs) were encapsulated with outer membrane vesicles of Escherichia coli (E. coil), and biofilm-encapsulated paclitaxel silk fibronectin nanoparticles (OMV-PTX-SF-NPs) were prepared by high-pressure co-extrusion, the size and zeta potential of the OMV-PTX-SF-NPs were measured. The antitumor effects of OMV-PTX-SF-NPs were evaluated by cellular and pharmacodynamic assays, and pharmacokinetic experiments were performed. The results showed that hydrophobic forces and hydrogen bonding played a major role in the interaction between paclitaxel and filipin proteins, and the size of OMV-PTX-SF-NPs was 199.8 ± 2.8 nm, zeta potential was -17.8 ± 1.3 mv. The cellular and in vivo pharmacokinetic assays demonstrated that the OMV-PTX-SF-NPs possessed a promising antitumor effect. Pharmacokinetic experiments showed that the AUC0-∞ of OMV-PTX-SF-NPs was 5.314 ± 0.77, which was much larger than that of free PTX, which was 0.744 ± 0.14. Overall, we have successfully constructed a stable oral formulation of paclitaxel with a sustained-release effect, which is able to effectively increase the bioavailability of paclitaxel, improve the antitumor activity, and reduce the adverse effects.