A correlative model to predict in vivo AUC for nanosystem drug delivery with release rate-limited absorption

Purpose. Drug release from nanosystems at the sites of either absorption or effect biophase is a major determinant of its biological action. Thus, in vitro drug release is of paramount importance in gaining insight for the systems performance in vivo. Methods. A novel in vitro in vivo correlation, IVIVC, model denoted as double reciprocal area method was presented and applied to 19 drugs from 55 nano formulations with total 336 data, gathered from literature. Results. The proposed model correlated the in vitro with in vivo parameters with overall error of 12.4 ± 3.9%. Also the trained version of the model predicted the test formulations with overall error of 15.8 ± 3.7% indicating the suitability of the approach. A theoretical justification was provided for the model considering the unified classical release laws. Conclusion. The model does not necessitate bolus intravenous drug data and seems to be suitable for IVIVC of drugs with release rate-limited absorption

Collapsibility Prediction of Stabilized Soil with Styrene-Butadiene Rubber Polymer Using ANFIS

Collapsible soils are among the problematic soils in nature that, due to moisture content increasing and under the same stress, show a high rate of decrease in volume. This volume reduction leads to loss of soil structure and ultimately to significant subsidence. Such soils in many parts of the world, including the Kerman province of Iran, necessitate researches regarding the collapsible soils\u27 behavior and characteristics. This study aims to investigate the effect of butadiene rubber on the stabilization of collapsible soils. The tested fine-grained soils that have been sampled from two different sites were stabilized through injecting different percentages of butadiene (the number of experiments was 84). The ASTM D5333 Double-Consolidation Method was applied to examine the stabilized soils on intact soil samples. The results show that the penetrations of butadiene rubber and the formation of butadiene rubber columns have led to a reduction in soil collapse. Considering the development of intelligent systems using the prediction behavior of stabilized collapsible soils, the adaptive neural-fuzzy inference system (ANFIS) model was used to predict the degree of collapsibility of soil samples stabilized by injection of Styrene Butadiene Rubber

Development and Characterization of Solid Dispersion for Dissolution Improvement of Furosemide by Cogrinding Method

Purpose: The purpose of this study was to prepare and characterize solid dispersion formulation of furosemide to enhance dissolution rate. Methods: Solid dispersions with different drug: carrier ratios were prepared by cogrinding method using crospovidone and microcrystalline cellulose as carrier. The physical state and interactions between the drug and carrier were characterized by Fourier transform infrared spectroscopic (FT-IR) and X ray diffraction (XRD). Results: Solid dispersions (especially with drug: Carrier ratio of 1:2) showed a higher dissolution rate than their respective physical mixture and pure furosemide. Dissolution rate in pH 5.8 was also higher than pH 1.2. The XRD analysis showed that crystalline form was changed to the amorphous state in the solid dispersions. FT-IR analysis did not show any physicochemical interactions in the solid dispersion formulations. Release kinetic of formulations were fitted best to the Weibull and Wagner log probability (linear kinetic) as well as suggested 2 and Gompertz (non-linear kinetic) models. Conclusion: The dissolution properties of furosemide were improved with the use of hydrophilic carriers in solid dispersions due to change in the crystalline form of the drug and more intimate contact between drug and carriers which was dependent on the type and ratio of carrier as well as dissolution medium pH

Design and Evaluation of Delayed-Release Osmotic Capsule of Acetaminophen: Delayed-release osmotic capsule of acetaminophen

Hard gelatin capsule filled with acetaminophen, osmotic agent (sorbitol), a release promoter (sodium dodecyl sulfate), coated with a semipermeable cellulose acetate membrane containing a hydrophobic plasticizer (castor oil) and sealed with white bees wax plug was designed. When placed in the sink water penetrates the membrane, dissolves the osmotic agent and increases the osmotic pressure inside the capsule. The increased osmotic pressure enhances the water imbibition and consequently increases the hydrostatic pressure inside the capsule and when the latter pressure is high enough it expels out the plug and the drug release commences. With cellulose acetate concentration constant in membrane forming solution, 11% (w/w), the factors affecting the onset of the drug release, i.e. the lag time (tL), were thickness of semipermeable membrane (0.033-0.112 mm) and plug thickness (2.40-3.40 mm) although the influence of semipermeable membrane thickness was more important than plug thickness in delaying the onset of release. As the statistical analysis revealed, castor oil concentrations in the range of 3-4% (w/w) did not affect the lag time. With the control of the membrane thickness, the onset of release could be adjusted from 2 to 7 h. The formulations with tL of 3.9 and 5.8 h may have practical benefits in that if such systems are administered simultaneously with conventional forms the 6 and 4 times daily drug dosage frequency would be reduced to 3 and 2 times regimens, respectively. A theoretical justification was provided for the observed nonlinear relationship between the onset and/or tL of drug release and thickness of the semipermeable membrane. After the lag time, the drug release fromthe systems conformed to the USP requirements

Treatment and outcomes of oligometastatic colorectal cancer limited to lymph node metastases

Introduction: The optimal management of isolated distant lymph node metastases (IDLNM) from a colorectal primary, is not clearly established. We aimed to analyze the outcomes of patients with IDLNM treated with systemic therapies plus locoregional therapy with curative intent versus systemic therapies with palliative intent. Materials & Methods: Clinical data were collected and reviewed from the Treatment of Recurrent and Advanced Colorectal Cancer registry, a prospective, comprehensive registry for metastatic colorectal cancer (mCRC) treated at multiple tertiary hospitals across Australia. Clinicopathological characteristics, treatment modalities and survival outcomes were analyzed in patients with IDLNM and compared to patients with disease at other sites. Results: Of 3408 mCRC patients diagnosed 2009 to 2020, with median follow-up of 38.0 months, 93 (2.7%) were found to have IDLNM. Compared to mCRC at other sites, patients with IDLNM were younger (mean age: 62.1 vs. 65.6 years, P = .02), more likely to have metachronous disease (57.0% vs. 38.9%, P < .01), be KRAS wild-type (74.6% vs. 53.9%, P< .01) and BRAF mutant (12.9% vs. 6.2%, P = .01). Amongst mCRC patients with IDLNM, 24 (25.8%) received treatment with curative intent and had a significantly better overall median survival than those treated with palliative intent (73.5 months vs. 23.2 months, P = .01). These 24 patients had an overall median survival similar (62.7 months, P = .82) to patients with isolated liver or lung metastases also treated with curative intent. Conclusion: Curative treatment strategies (radiotherapy or surgery), with or without systemic therapy, should be considered for mCRC patients with IDLNM where appropriate as assessed by the multidisciplinary team

Metastasectomy and BRAF mutation; an analysis of survival outcome in metastatic colorectal cancer

Abstract Background: Resection of oligometastases improves survival in metastatic colorectal cancer (mCRC). It is unclear whether the benefit is consistent for BRAF V600E mutant (MT) and wild type (WT) mCRC. This retrospective analysis explores the influence of BRAF MT on survival after metastasectomy. Methods: Overall survival (OS) and recurrence-free survival (RFS) for BRAF MT and WT mCRC were evaluated. Survival was also analyzed in the cohort of BRAF MT with or without metastasectomy. Results: Five hundred and thirteen patients who had undergone metastasectomy were identified, 6% were BRAF-MT. Median age 63. Median OS in BRAF MT vs WT: 25.7 vs 48.5 months (hazard ratio [HR] 1.95; 1.18-3.22). However, difference was not significant in a multivariate model. Right primary tumor, intact primary, >1 metastatic site, non-R0 resection, peritoneal metastasis, and synchronous metastasis were independent predictors of worse OS. Among 364 patients with RFS data there was no difference between BRAF MT and WT (16 vs 19 months, p=0.09). In another cohort of 158 BRAF-MT patients, OS was significantly better after metastasectomy compared to “no metastasectomy” (HR 0.34; 0.18-0.65, P= 0.001). Proficient mismatch repair status showed a trend toward worse survival after metastasectomy in BRAF MT (HR 1.71, P = 0.08). Conclusion: OS did not differ after metastasectomy between BRAF MT and WT in a multivariate model. Median OS was >2 years in this study after metastasectomy among BRAFV600E MT patients suggesting a survival benefit of metastasectomy in this group where systemic therapeutic options are limited. Metastasectomy may be considered in carefully selected BRAF-MT patients.Roche Products Pty Limited has provided financial assistance for the development, installation, and maintenance of the BioGrid-TRACC registry. The South Australian State Government has provided support for the maintenance of the SA Metastatic Colorectal Cancer Registr