Immediate-Release Formulations Produced via Twin-Screw Melt Granulation: Systematic Evaluation of the Addition of Disintegrants.

The current study evaluated the effect of location and amount of various superdisintegrants on the properties of tablets made by twin-screw melt granulation (TSMG). Sodium-croscarmellose (CCS), crospovidone (CPV), and sodium starch glycolate (SSG) were used in various proportions intra- and extra-granular. Tabletability, compactibility, compressibility as well as friability, disintegration, and dissolution performance were assessed. The extra-granular addition resulted in the fasted disintegration and dissolution. CPV performed superior to CCS and SSG. Even if the solid fraction (SF) of the granules was lower for CPV, only a minor decrease in tabletability was observed, due to the high plastic deformation of the melt granules. The intra-granular addition of CPV resulted in a more prolonged dissolution profile, which could be correlated to a loss in porosity during tableting. The 100% intra-granular addition of the CPV resulted in a distinct decrease of the disintegration efficiency, whereas the performance of SSG was unaffected by the granulation process. CCS was not suitable to be used for the production of an immediate-release formulation, when added in total proportion into the granulation phase, but its efficiency was less impaired compared to CPV. Shortest disintegration (78 s) and dissolution (Q80: 4.2 min) was achieved with CPV extra-granular. Using CPV and CCS intra-granular resulted in increased disintegration time and Q80. However, at a higher level of appx. 500 s and appx. 15 min, only SSG showed a process and location independent disintegration and dissolution performance.

Effect of gamma sterilization on the properties of microneedle array transdermal patch system.

Soluble microneedles (MNs) of four different hydrophilic polymers namely sodium carboxymethyl cellulose (CMC), polyvinylpyrrolidone (PVP) K30, PVP K90 and sodium hyaluronate (HU) were fabricated by mold casting technique. When exposed to gamma radiation, a dose of 25 kilogray (kGy) was found to render the microneedle (MN) sterile. However, CMC was found to form MNs with poor mechanical properties, whereas PVP K30 MNs were drastically deformed upon exposure to applied dose as observed in bright field microscopy. Scanning electron microscopy (SEM) revealed that morphology of PVP K90 and HU MNs were not significantly affected at the applied dose. The appearances of characteristic peaks of irradiated MNs of PVP K90 and HU in Fourier-transform infrared spectra suggested structural integrity of the polymers on irradiation. Differential scanning calorimetry (DSC) indicated gamma irradiation failed to alter the glass transition temperature and thus mechanical properties of PVP K90 MNs. However, DSC and Powder X-ray Diffraction (PXRD) conclusively indicated that the degree in crystallinity of HU was substantially reduced on irradiation. In vitro dissolution profiles of sterile PVP K90 and HU MNs were similar to un-irradiated MNs with a similarity factor (f2) of 64 and 54, respectively. In vivo dissolution studies in human subjects indicated that sterile MNs of PVP K90 and HU exhibited dissolution of 78.45 ± 1.09 and 78.57 ± 0.70%, respectively, after 20 min. The studies suggested that PVP K90 and HU could be suitable polymers to fabricate soluble MNs as the structural, morphological, microstructural and dissolution properties remained unaltered post γ sterilization.

Graphene quantum dot cross-linked carboxymethyl cellulose nanocomposite hydrogel for pH-sensitive oral anticancer drug delivery with potential bioimaging properties.

Herein, graphene quantum dots (GQDs) were introduced as a novel and safe crosslinker for carboxymethyl cellulose to make biodegradable and biocompatible hydrogels. The casting was used as a simple method for the preparation of the CMC/GQDs films. Effects of the GQDs percentage on the physicochemical properties of the films were studied, and several characterizations were performed including Fourier transform infrared spectroscopy, UV-vis spectroscopy, scanning electron microscopy, gas permeability, and mechanical testing analysis. The CMC/GQDs showed a pH-sensitive swelling and degradation with improved tensile strength. Fluorescent properties were also studied to evaluate the potential of the prepared CMC/GQDs nanocomposite for fluorescent bioimaging applications. Drug delivery property of the CMC-GQDs were studied using doxorubicin (DOX) as a model anticancer drug. Cytotoxicity studies were carried out using human colon adenocarcinoma HT29 cells. The prepared CMC/GQDs exhibited biocompatibility and pH-sensitive drug delivery behavior which proposed the prepared nanocomposite hydrogel has the potential to be used as a pH-triggered site-specific drug delivery system.

Doxorubicin loaded carboxymethyl cellulose/graphene quantum dot nanocomposite hydrogel films as a potential anticancer drug delivery system.

Creating anticancer properties in the hydrogel film could make it as a candidate for treating cancer tissues. In this work, a novel hydrogel nanocomposite films with anticancer properties were designed via incorporation of graphene quantum dot (GQD) as a nanoparticle into carboxymethyl cellulose (CMC) hydrogel and using doxorubicin (DOX) as drug model with broad-spectrum anticancer properties. Drug release studies carried out at two different pHs and the MTT assay was evaluated for DOX-loaded CMC/GQD nanocomposite hydrogel films against blood cancer cells (K562). The prepared nanocomposite hydrogel films were characterized using Fourier transform infrared (FT-IR), UV-Vis spectroscopy, scanning electron microscopy (SEM), permeability and mechanical properties. The prepared CMC/GQD nanocomposite hydrogel films showed an improvement in vitro swelling, degradation, water vapor permeability and pH-sensitive drug delivery properties along with not significant toxicity against blood cancer cells (K562). According to the obtained results, this nanocomposite hydrogel films can be proposed to use as an anticancer film and drug delivery system.

Torsemide Fast Dissolving Tablets: Development, Optimization Using Box-Bhenken Design and Response Surface Methodology, In Vitro Characterization, and Pharmacokinetic Assessment.

The present study planed to develop new fast dissolving tablets (FDTs) of torsemide. Solid dispersions (SDs) of torsemide and sorbitol (3:1) or polyvinylpyrrolidone (PVP) k25 were prepared. The prepared SDs were evaluated for in-vitro dissolution. Fourier transform infrared spectroscopy and differential scanning calorimetry for SDs revealed no drug/excipient interactions and transformation of torsemide to the amorphous form. Torsemide/sorbitol SD was selected for formulation of torsemide FDTs by direct compression method. Box-Bhenken factorial design was employed to design 15 formulations using croscarmellose sodium and crospovidone at different concentrations. The response surface methodology was used to analyze the effect of changing these concentrations (independent variables) on disintegration time (Y1), percentage friability (Y2), and amount torsemide released at 10 min. The physical mixtures of torsemide and the used excipients were evaluated for angle of repose, Hausner's ratio, and Carr's index. The prepared FDTs tablets were evaluated for wetting and disintegration time, weight variation, drug content, percentage friability, thickness, hardness, and in vitro release. Based on the in-vitro results and factorial design characterization, F10 and F7 were selected for bioavailability studies following administration to Albino New Zealand rabbits. They showed significantly higher C max and (AUC0-12) and shorter T max than those obtained after administration of the corresponding ordinary commercial Torseretic ® tablets. Stability study was conducted for F10 that showed good stability upon storage at 30°C/75% RH and 40°C/75% RH for 3 months.

Experimental Design for Determination of Effects of Superdisintegrant Combinations on Liquisolid System Properties.

The preparation of liquisolid systems presents a promising and innovative possibility for enhancing dissolution profiles and improving the bioavailability of poorly soluble drugs. This study aims to evaluate the differences in the properties of liquisolid systems containing combinations of 3 commercially used superdisintegrants (sodium starch glycolate, crospovidone, and croscarmellose sodium). Multiple regression models and contour plots were used to study how the amount and the type of superdisintegrant used affected the quality parameters of liquisolid tablets. The results revealed that an increased amount of crospovidone in the mixture improves disintegration and wetting time and enhances drug release from the prepared liquisolid tablets. Moreover, it was observed that a binary blend of crospovidone and sodium starch glycolate improved tablet disintegration. Considering the obtained results, it could be stated that crospovidone showed the best properties to be used as superdisintegrant for the preparation of liquisolid systems containing rosuvastatin.

Enhancing Tumor Cell Response to Chemotherapy through the Targeted Delivery of Platinum Drugs Mediated by Highly Stable, Multifunctional Carboxymethylcellulose-Coated Magnetic Nanoparticles.

The fabrication of nanoparticles using different formulations, and which can be used for the delivery of chemotherapeutics, has recently attracted considerable attention. We describe herein an innovative approach that may ultimately allow for the selective delivery of anticancer drugs to tumor cells by using an external magnet. A conventional antitumor drug, cisplatin, has been incorporated into new carboxymethylcellulose-stabilized magnetite nanoparticles conjugated with the fluorescent marker Alexa Fluor 488 or folic acid as targeting agent. The magnetic nanocarriers possess exceptionally high biocompatibility and colloidal stability. These cisplatin-loaded nanoparticles overcome the resistance mechanisms typical of free cisplatin. Moreover, experiments aimed at the localization of the nanoparticles driven by an external magnet in a medium that mimics physiological conditions confirmed that this localization can inhibit tumor cell growth site-specifically.

A docetaxel-carboxymethylcellulose nanoparticle outperforms the approved taxane nanoformulation, Abraxane, in mouse tumor models with significant control of metastases.

Cellax is a PEGylated carboxymethylcellulose conjugate of docetaxel (DTX) which condenses into a 120-nm nanoparticle, and was compared against the approved clinical taxane nanoformulation (Abraxane®) in mouse models. Cellax increased the systemic exposure of taxanes by 37× compared to Abraxane, and improved the delivery specificity: Cellax uptake was selective to the tumor, liver and spleen, with a 203× increase in tumor accumulation compared to Abraxane. The concentration of released DTX in Cellax treated tumors was well above the IC50 for at least 10 d, while paclitaxel released from Abraxane was undetectable after 24h. In s.c. PC3 (prostate) and B16F10 (melanoma) models, Cellax exhibited enhanced efficacy and was better tolerated compared to Abraxane. In an orthotopic 4T1 breast tumor model, Cellax reduced the incidence of lung metastasis to 40% with no metastasic incidence in other tissues. Mice treated with Abraxane displayed increased lung metastasic incidence (>85%) with metastases detected in the bone, liver, spleen and kidney. These results confirm that Cellax is a more effective drug delivery strategy compared to the approved taxane nanomedicine.

Mechanochemically induced disordered structures of vincamine: the different mediation of two cross-linked polymers.

The aims of this research were to prepare highly bioavailable binary cogrounds (vincamine-AcDiSol(®) or PVP-Cl) by means of a mechanochemical process and to study the mediation of each polymer in the induction of physical transformations of the drug. From a set of fifteen cogrounds for each crosslinked polymer, two samples were selected in each group on the basis of the AUC of in vitro dissolution profiles with the help of a statistical comparison. The chosen samples were analysed by means of TEM, XRPD, Raman-spectroscopy/imaging, SSNMR, also including the study of (1)H spin-lattice relaxation times. The research encompassed in vivo oral absorption studies in rats, pharmacokinetic analysis and physical stability studies during 1 year. An intimate drug-polymer mixing was found in the coground samples with domain average dimensions smaller than 100 Å; this reflected in a remarkable enhancement of the in vitro and in vivo bioavailability. Different disordered states were detected in the coground samples as a function of cogrinding time and the type and amount of polymer used. Though both crosslinked polymers produced a remarkable enhancement of the oral bioavailability, coground systems based on AcDiSol(®) are preferable in terms of pharmacokinetic performance and physical stability.

Use of magnetic resonance imaging to assess blood-brain/blood-glioma barrier opening during conformal radiotherapy.

PURPOSE: For chemotherapy to act synergistically and safely with radiation against high-grade gliomas, drugs must pass the endothelial junctions of the blood-tumor barrier (BTB) to reach all tumor cells, and should not pass the blood-brain barrier (BBB) to cause toxicity to normal brain. The objective of this study was to assess BBB/BTB status using magnetic resonance imaging (MRI) during a course of radiotherapy of high-grade gliomas. PATIENTS AND METHODS: Sixteen patients with grade 3 or 4 supratentorial malignant glioma receiving conformal radiotherapy (RT) underwent contrast-enhanced MRI before, during, and after completion of RT. A gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) uptake index was analyzed with respect to the tumor and RT dose received. RESULTS: In the nonenhanced tumor region, contrast uptake increased significantly after the receipt of approximately 10 Gy (P < .01), and reached a maximum after the receipt of approximately 30 Gy. In the initially contrast-enhanced tumor region, contrast uptake decreased over the course of RT and became significant after completion of RT in patients without progressive disease. The healthy brain showed only nonsignificant changes during and after irradiation. CONCLUSION: Contrast MRI reveals increases in Gd-DTPA uptake in the initially nonenhanced tumor region but not in the remaining brain during the course of RT, suggesting opening of the BTB. This finding suggests that the effect of conformal radiation is more selective on the BTB than the BBB, and there may be a window extending from 1 week after the initiation of radiotherapy to 1 month after the completion of treatment during which a pharmaceutical agent has maximum access to high-grade gliomas.

Preventive effect of sialylglycopeptide-nondigestive polysaccharide conjugates on salmonella infection.

We have previously reported that sialylglycopeptide (SGP) and its derivatives isolated from egg yolk had a preventive effect on Salmonella infection in vivo; however, their retention time in the gut was rather short. To improve on this, SGP was conjugated with carboxymethyl cellulose (CMC) or carboxymethyl dextran (CMD). The conjugates inhibited the binding of Salmonella enteritidis and Escherichia coli to Caco-2 cells. Infection experiments with mice revealed that the SGP-CMD conjugate (SGP-CMD) had a strong protective effect against Salmonella infection. A turnover experiment in mice administered with radiolabeled SGP-CMD showed that SGP-CMD was more slowly absorbed into the blood and thus remained longer in the intestinal tract than SGP. SGP-CMD itself did not influence the production of tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta, or nitrite ion (NO(2)(-)) by macrophages, although it suppressed that of TNF-alpha and NO(2)(-) in zymosan-treated macrophages, suggesting no causative effects of inflammation in SGP-CMD. SGP-CMD is potentially useful as a food ingredient with a preventive effect on Salmonella infection.

Evaluation of the functional equivalence of crospovidone NF from different sources. II. Standard performance test.

Current NF monographs do not provide tests that reflect on the functionality of Crospovidone NF from multiple sources. Physical characterization studies such as particle size and distribution, surface area, porosity, and surface morphology revealed major differences among the crospovidones from different sources (Shah, U.; Augsburger, L.L. J. Pharm. Dev. Technol. 2001, 6 (1), 39-51). Differences in disintegration and dissolution were also observed for a model drug in an insoluble filler system (see Shah and Augsburger, 2001). The objective of this study was to determine the relationship between physical differences observed and disintegrant functionality and to develop standard performance test. Tests performed included settling volume studies, measurement of initial rate as well as extent of liquid uptake of the loose disintegrant powder, and simultaneous measurement of the axial and radial disintegrating forces along with the rate and extent of liquid uptake of the pure disintegrant compacts. Significant differences among the crospovidones were observed for all tests performed. Settling volume, liquid uptake, and disintegration force are recommended as standard performance tests to determine differences among crospovidones from different sources.

Dispersöes de carboximetilcelulose e hidroxietilcelulose como veículos estruturados esterilizados: comportamento reológico versus esterilizaçäo pelo calor úmido (AU) / Dispersions of carboxymethylcellulose and hidroxyethylcellulose as structured and sterilized vehicles: rheological behaviour versus moist heat Sterilization method (AU)

Investigou-se comparativamente o comportamento reológico de dispersöes de carboximetilcelulose sódica A.V. e Hidroxietilcelulose (cellosize-QP 15MH) a 0,5, 1,0, e 2,0 por cento, considerando o efeito produzido pelo aquecimento em processos de esterilizaçäo que aplicam calor úmido (vapor sob pressäo e vapor fluente). Procurou-se quantificar o comportamento reológico, antes e após processos de esterilizaçäo, objetivando qualificar os referidos produtos no que tange à sua aplicaçäo na forma de veículos estruturados esterilizados. Os resultados evidenciaram que: a) as dispersöes consideradas apresentaram uma similar perda de consistência independentemente do método de esterilizaçäo aplicado; b) apesar de diminuiçäo de consistência, as características reológicas, concernentes à pseudoplasticidade e tixotropia, foram relativamente bem mantidas; c) as dispersöes apresentaram diferentes graus de reversibilidade de consistência com nítidas vantagens para as dispersöes de hidroxietilcelulose