Influence of talc and hydrogenated castor oil on the dissolution behavior of metformin-loaded pellets with acrylic-based sustained release coating.

Multi-unit pellet system (MUPS) is of great interest as it is amenable to customization. MUPS comprises multi-particulates, usually as pellets or spheroids, which can be coated with diffusion barrier coatings. One commonly used diffusion barrier coating is the methacrylic acid copolymer, which can be used as a taste masking, enteric or sustained release polymer. While the versatility of methacrylic acid copolymers makes them pliable for pellet coating, there are impediments associated with their use. Additives commonly required with this polymer, including plasticizer and anti-adherent, have been shown to weaken the film strength. The objective of this study was to investigate the impact of osmotic pressure within the core on the sustained release coat integrity and functionality. Hydrogenated castor oil (HCO) was chosen as the additive to be studied. Metformin-loaded pellets, prepared via extrusion-spheronization, were coated with ethyl acrylate and methyl methacrylate copolymer (Eudragit RS 30 D) containing talc, talc-HCO, or HCO to different coat thicknesses. Drug release was investigated using the USP dissolution apparatus 2 and an ultraviolet imager. The swelling of the pellets when wetted was monitored by video imaging through a microscope. When coated to 7.5 % coat weight gain, coats with HCO slowed down drug release more than the other pellets. The pellets also swelled the most, which suggests that they were more resistant to the osmotic pressure exerted by metformin. For drugs which exert high osmotic pressure, HCO can serve as an efficient alternative to talc in the preparation of methacrylic acid copolymer coatings.

An approach for predicting the true density of powders based on in-die compression data.

Helium pycnometry, a commonly used technique for measuring the true density of powders, is sensitive to the release of volatiles during measurement. This can lead to over-estimated true density, and as such, an accurate method for determining the true density of powders containing volatile components is needed. Here, a method based on in-die compression data obtained with a compaction simulator was assessed. Specifically, the stress transmission coefficient (STC), measured using an instrumented die, was used to predict the in-die Heckel mean yield pressure (Py). A true density was derived by repeatedly performing a Heckel analysis using iteratively estimated true density values until the predicted Py value from the measured STC value is obtained from in-die density - pressure data. This novel method was validated using a set of water-free powders. Using crystalline hydrates, we further showed that the calculated true densities were closer to values calculated from crystal structure than those from helium pycnometry. Hence, this method may be used for determining the true density of powders from their STC values.

Albendazole-loaded cubosomes interrupt the ERK1/2-HIF-1α-p300/CREB axis in mice intoxicated with diethylnitrosamine: A new paradigm in drug repurposing for the inhibition of hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. It was suggested that albendazole (ABZ) is a powerful inhibitor of several carcinoma types. However, the bioavailability of ABZ is very poor. Additionally, the mechanisms underlying the antitumor effects of ABZ may go beyond its tubulin-inhibiting activity. Therefore, we aimed to examine the effects of ABZ suspension (i.p. and p.o.) and ABZ-loaded cubosomes (LC) on the diethylnitrosamine-induced HCC in mice. ABZ-loaded nanoparticles exhibited a mean particle size of 48.17 ± 0.65 nm and entrapped 93.26 ± 2.48% of ABZ. The in vivo absorption study confirmed a two-fold improvement in the relative bioavailability compared with aqueous ABZ suspension. Furthermore, the oral administration of ABZ cubosomal dispersion demonstrated regression of tumor production rates that was comparable with ABZ (i.p.). ABZ relieved oxidative stress, improved liver function, and decreased necroinflammation score. The antiangiogenic activity was evident as ABZ effectively downregulated tissue expression of CD34, mRNA expression of CD309 and VEGF at the protein expression level. Besides, lower levels of MMP-9 and CXCR4 indicated antimetastatic activity. ABZ showed a considerable level of apoptotic activity as indicated by increased mRNA expression level of p53 and the increased Bax/BCL-2 ratio and active caspase-3. Additionally, Ki-67 expression levels were downregulated showing an antiproliferative potential. These protective effects contributed to increasing survival rate of diethylnitrosamine-treated mice. These effects found to be mediated via interrupting ERK1/2-HIF-1α-p300/CREB interactions. Therefore, our findings revealed that disrupting ERK1/2-HIF-1α-p300/CREB interplay might create a novel therapeutic target for the management of HCC.

Cushioning pellets based on microcrystalline cellulose - Crospovidone blends for MUPS tableting.

Compaction of multiple-unit pellet system (MUPS) tablets has been extensively reported to be potentially challenging. Thus, there is a need for non-segregating cushioning agents to mitigate the deleterious effect of the compaction forces. This study was designed to investigate the use of porous pellets as cushioning agents using different drying techniques to prepare pellets of various porosities and of different formulations. The pellets fabricated were characterized for their porosity and crushing strength. Subsequently, MUPS tablets were prepared using blends of polymer-coated pellets and custom-designed cushioning pellets by compacting at different pressures. The effects of pellet volume fraction and dwell time on the pellet coat damage, as well as the tensile strength of the resultant MUPS tablets were also investigated. Compacts with coated pellet volume fraction of 0.21 exhibited the best cushioning effect when tableted at different compression speeds with both gravity and force feeders. The findings from this study showed that cushioning pellet porosity was highest when drying was carried out by freeze drying, followed by fluid bed drying and oven drying. There was an inverse relationship between cushioning pellet porosity and strength. The tensile strength of tablets prepared from freeze dried pellets was highest. The protective effect of the cushioning pellets was principally dependent on their porosity. Also, pellet volume fraction in the compacts and compaction pressure used had remarkable effect on pellet coat damage. When unprocessed powders were compacted by automatic die filling, capping and lamination problems were observed. However, tablets of reasonable quality were made with the cushioning pellets. Freeze dried pellets containing crospovidone were found to be promising as cushioning agents and had enabled the production of MUPS tablets even at higher compaction pressures, beyond the intrinsic crushing strength of the coated pellets.

Influence of the surface tension of wet massing liquid on the functionality of microcrystalline cellulose as pelletization aid.

This study designed to investigate the impact of surface tension of moistening liquid on the functionality of MCC as pelletization aid. For this purpose, sodium dodecyl sulfate (SDS), poloxamer 188 (PL), di-potassium hydrogen phosphate (K2HPO4) and combinations thereof were incorporated into the powder blend comprised of MCC and dicalcium phosphate (DCP) at different levels. Physical mixture (PM) and co-processed composite (Cop) of MCC and sodium carboxymethyl cellulose (SCMC) replaced MCC as pelletization aids. The pellets prepared were characterized for their median diameter (D50), particle size distribution (PSD), sphericity, porosity, tensile strength and disintegration. SDS induced a drop in the surface tension of water from 68.7 to 23.7 mN/m at 0.1% (w/w). In contrast, the surface tension values of PL and K2HPO4 solutions were 2.08- and 3.07-fold higher than that of SDS solutions, respectively. MCC based pellets obtained with SDS showed wider PSD and lower sphericity than those made with PL, K2HPO4 and their combinations. In addition, the PSD and porosity increased with rise of SDS concentration from 0.05 to 0.25% (w/w). It was thus inferred that a critical surface tension of moistening liquid was essential for functionality of MCC as pelletization aid but not for PM and Cop.

Influence of the porosity of cushioning excipients on the compaction of coated multi-particulates.

The compaction of multiple unit-pellet system (MUPS) tablets poses considerable challenges due to potential compaction-induced damage to the functional polymer coat and segregation of pellets from other excipients during the tableting process. This study was designed to investigate the impact of porous pellets as cushioning agent without issues related to segregation while tableting. Different drying techniques were applied to produce microcrystalline cellulose (MCC) pellets with various porosities. Sodium chloride was also added to the pellet formulation as a pore forming agent to generate a porous skeleton after production and aqueous extraction. The pellets fabricated were characterized for their porosity, crushing strength and yield pressure. Tablets were prepared using unlubricated pellets and their tensile strengths determined. Blends containing polymer-coated pellets and cushioning pellets of various porosities were compacted at different compaction pressures. The porous pellets exhibiting the best cushioning effect were used for MUPS tableting at different compression speeds with both gravity and force feeders. The findings from this study showed that pellet porosity was highest when drying was carried out in a freeze dryer, followed by fluid bed and least porous from the oven. There was an inverse relationship between pellet porosity and strength. The protective effect of cushioning pellets was mainly dependent on their porosity. The porosity of pellets manufactured by leaching NaCl from MCC-NaCl (1:1) pellets were 2.14-, 2.57- and 4.88-fold higher than that of MCC PH101 only pellets for oven, fluid bed and freeze dried pellets, respectively. Although the porosity of MCC PH101-NaCl (1:3) pellets was highest, they exhibited less cushioning effect than MCC PH101-NaCl (1:1). It was inferred that a good balance between porosity and bulk density of cushioning pellets was essential to be effective at protecting the coated pellets from damage during compaction. Compared with MUPS tablets prepared using unprocessed MCC PH105, the tablets prepared with the porous freeze dried MCC PH101 (NaCl fraction leached) pellets had improved drug content uniformity and were mechanically stronger.

Application of the Modified Tangential Spray-Fluidized Bed to Produce Nonpareils from Primary Crystals.

Coating of fine primary drug particles by a fluidized bed processor has been reported to be potentially challenging. This work aimed to develop a spray layering process to produce nonpareils by a side spray fluid bed with swirling air flow. The first part examined the effects of various parameters for producing lactose nonpareils by using Box-Behnken design. The factors considered were atomizing air pressure, spray rate, and fluidizing air temperature. This was followed by an in-depth investigation on the effects of inlet airflow rate, air temperature, and spray rate on properties of the product, in addition to process optimization. The results indicated a negative correlation between atomizing air pressure and D90 (particle size at 90th percentile in the cumulative undersize plot) as well as span (size distribution). Temperature had a positive correlation with D90 and span while spray rate affected span. Both atomizing air pressure and temperature correlated negatively with span. It was also found that spray rate negatively affected roundness at different coat weight gain levels across the study design space. Inlet airflow rate was found to correlate negatively with roundness at 15%, w/w coat weight gain. The mean useful yield of the optimized runs was about 91%. In the second part of this study, the metformin hydrochloride crystals as starter seeds were converted into nearly spherical shaped spheroids with 1:1 crystals to coat weight deposition over a processing time of about 3.5 h. The processor studied shows promise for direct spheronization of crystals into spherical seeds.

Fast disintegrating tablets of nisoldipine for intra-oral administration.

Nisoldipine is a calcium channel blocker with low and variable oral bioavailability. This was attributed to slow dissolution and presystemic metabolism. Accordingly, the objective of this work was to enhance the dissolution rate of nisoldipine to formulate fast disintegrating tablets with rapid dissolution. Binary solid dispersions (SD) were prepared for the drug with hydroxypropyl methyl cellulose E5 (HPMC), polyvinylpyrrolidone (PVP), Pluronic F68 or polyethylene glycol 6000 (PEG 6000). SD formation increased the dissolution rate compared to pure drug with the corresponding physical mixtures failing to provide the same dissolution enhancement. This indicates that the SD enhanced dissolution is not due to the solubilizing effect of the polymer and can be due to physical change in the drug crystal which was confirmed by thermal analysis. SD with HPMC and PVP were selected for preparation of fast disintegrating tablets as they liberated most of the drug in the first 5 min. HPMC-based tablets disintegrated rapidly and released most of the drug in the first 2 min which correlated with the corresponding SD. In contrast, PVP-based tablets disintegrated slowly with gradual dissolution. This can be attributed to the binding effect of PVP. The study developed fast disintegrating tablet for intra-oral administration.