Untangling the influence of abiotic and biotic factors on leaf C, N, and P stoichiometry along a desert-grassland transition zone in northern China.

Plant elemental composition and stoichiometry are useful tools for understanding plant nutrient strategy and biogeochemical cycling in terrestrial ecosystems. However, no studies have examined how plant leaf carbon (C), nitrogen (N), and phosphorus (P) stoichiometry responds to abiotic and biotic factors in the fragile desert-grassland ecological transition zone in northern China. Then a systematically designed 400 km transect was established to investigate the C, N, and P stoichiometry of 870 leaf samples of 61 species from 47 plant communities in the desert-grassland transition zone. At the individual level, plant taxonomic groups and life forms rather than climate or soil factors determined the leaf C, N, and P stoichiometry. In addition, leaf C, N, and P stoichiometry (except leaf C) was significantly influenced by soil moisture content in the desert-grassland transition zone. At the community level, leaf C content showed a considerable interspecific variation (73.41 %); however, the variation in leaf N and P content, as well as C:N and C:P ratios, was mainly due to intraspecific variation, which was in turn driven by soil moisture. We suggested that intraspecific trait variation played a key role in regulating community structure and function to enhance the resistance and resilience of plant communities to climate change in the desert-grassland transition zone. Our results highlighted the role of soil moisture content as a critical parameter for modeling the biogeochemical cycling in dryland plant-soil systems.

Sharp bounds on the relative treatment effect for ordinal outcomes.

For ordinal outcomes, the average treatment effect is often ill-defined and hard to interpret. Echoing Agresti and Kateri, we argue that the relative treatment effect can be a useful measure, especially for ordinal outcomes, which is defined as γ=pr{Yi(1)>Yi(0)}-pr{Yi(1)

Solubility and bioavailability enhancement study of lopinavir solid dispersion matrixed with a polymeric surfactant - Soluplus.

As a biopharmaceutical classification system Class IV drug, lopinavir (LPV) shows relatively poor water solubility and permeation in vivo. In the study, we developed novel solid dispersions (SD) of LPV to improve its bioavailability and to describe their overall behaviors. By employing solvent evaporation for a preliminary formulation screening, the SDs of LPV-polymer-sorbitan monolaurate (SBM, as the wetting agent) at 1:4:0.4 (w/w) dramatically enhanced the LPV dissolution in a non-sink medium, and then hot-melt extrusion (HME) was applied to improve the dissolution further. A hydrophilic polymer - Kollidon VA 64 (VA64) and a polymeric surfactant Soluplus were employed as matrix respectively in the optimized formulations. The dissolution profiles of extrudates were significantly higher than those of SDs prepared with solvent-evaporation method. It was attributed to the stronger intermolecular interactions between LPV and the polymers in the HME process, which was also supported by the stability analysis after 6 months storage under 25 °C/60% RH. The differential scanning calorimetry, fourier transform infrared spectroscopy and equilibrium studies showed VA64 only created hydrogen bonding (H-bond) with LPV, but Soluplus generated both H-bond and micelle thanks to its amphiphilic structure. In addition, the bioavailability of LPV in Soluplus matrixed extrudate was 1.70-fold of VA64 matrixed extrudate and 3.70-fold of LPV crystal. In situ permeability and Caco-2 cell transport studies revealed that Soluplus significantly enhanced the permeability of LPV through rat intestine and Caco-2 cell monolayers by P-glycoprotein (P-gp) inhibition. Herein, Soluplus matrixed extrudate improved the LPV bioavailability through three mechanisms: H-bond with LPV, micelle formation in water and P-gp inhibition in vivo. These unique advantages of Soluplus suggested it is a promising carrier for poorly water soluble drugs, especially the substrates of P-gp.

Sharpening randomization-based causal inference for 22 factorial designs with binary outcomes.

In medical research, a scenario often entertained is randomized controlled 22 factorial design with a binary outcome. By utilizing the concept of potential outcomes, Dasgupta et al. proposed a randomization-based causal inference framework, allowing flexible and simultaneous estimations and inferences of the factorial effects. However, a fundamental challenge that Dasgupta et al.'s proposed methodology faces is that the sampling variance of the randomization-based factorial effect estimator is unidentifiable, rendering the corresponding classic "Neymanian" variance estimator suffering from over-estimation. To address this issue, for randomized controlled 22 factorial designs with binary outcomes, we derive the sharp lower bound of the sampling variance of the factorial effect estimator, which leads to a new variance estimator that sharpens the finite-population Neymanian causal inference. We demonstrate the advantages of the new variance estimator through a series of simulation studies, and apply our newly proposed methodology to two real-life datasets from randomized clinical trials, where we gain new insights.

A note on Type S/M errors in hypothesis testing.

Motivated by the recent replication and reproducibility crisis, Gelman and Carlin (2014, Perspect. Psychol. Sci., 9, 641) advocated focusing on controlling for Type S/M errors, instead of the classic Type I/II errors, when conducting hypothesis testing. In this paper, we aim to fill several theoretical gaps in the methodology proposed by Gelman and Carlin (2014, Perspect. Psychol. Sci., 9, 641). In particular, we derive the closed-form expression for the expected Type M error, and study the mathematical properties of the probability of Type S error as well as the expected Type M error, such as monotonicity. We demonstrate the advantages of our results through numerical and empirical examples.

Melt Extrusion for a High Melting Point Compound with Improved Solubility and Sustained Release.

The objective of the current study was to develop an amorphous solid dispersion for a high melting point compound, griseofulvin (GRF), with an enhanced solubility and a controlled release pattern utilizing hot melt extrusion (HME) technology. Hypromellose acetate succinate (HPMCAS, Shin-Etsu AQOAT®, medium particle size) was explored as the polymeric carrier, while hypromellose (HPMC, Metolose® SR) was chosen as the release rate control agent. GRF presented an HPMCAS grade-dependent solubility: AS-HMP > AS-MMP > AS-LMP. At 10 wt.% loading, the release of GRF was prolonged to 6 h with the incorporation of 10% HPMC 90SH-100SR, while its solubility was enhanced up to sevenfold. Fourier transform infrared spectroscopy (FT-IR) identified the H-bonding between drug and polymers. Element analysis utilizing X-ray photoelectron spectroscopy (XPS) discovered that less GRF aggregated on the surface of binary powders compared with ternary powders containing HPMC, indicating the relatively poor wettability of the latter one. The morphology of extrudates was observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM), illustrating a much smoother and uniform surface of binary extrudates. Immediate release tablets including 10% super-disintegrant L-HPC were able to achieve identical dissolution profile as the powders of extrudates.

Solid-state characterization of Felodipine-Soluplus amorphous solid dispersions.

The aim of the current study is to develop amorphous solid dispersion (SD) via hot melt extrusion technology to improve the solubility of a water-insoluble compound, felodipine (FEL). The solubility was dramatically increased by preparation of amorphous SDs via hot-melt extrusion with an amphiphilic polymer, Soluplus® (SOL). FEL was found to be miscible with SOL by calculating the solubility parameters. The solubility of FEL within SOL was determined to be in the range of 6.2-9.9% (w/w). Various techniques were applied to characterize the solid-state properties of the amorphous SDs. These included Fourier Transform Infrared Spectrometry spectroscopy and Raman spectroscopy to detect the formation of hydrogen bonding between the drug and the polymer. Scanning electron microscopy was performed to study the morphology of the SDs. Among all the hot-melt extrudates, FEL was found to be molecularly dispersed within the polymer matrix for the extrudates containing 10% drug, while few small crystals were detected in the 30 and 50% extrudates. In conclusion, solubility of FEL was enhanced while a homogeneous SD was achieved for 10% drug loading.

Conjugation of Hot-Melt Extrusion with High-Pressure Homogenization: a Novel Method of Continuously Preparing Nanocrystal Solid Dispersions.

Over the past few decades, nanocrystal formulations have evolved as promising drug delivery systems owing to their ability to enhance the bioavailability and maintain the stability of poorly water-soluble drugs. However, conventional methods of preparing nanocrystal formulations, such as spray drying and freeze drying, have some drawbacks including high cost, time and energy inefficiency, traces of residual solvent, and difficulties in continuous operation. Therefore, new techniques for the production of nanocrystal formulations are necessary. The main objective of this study was to introduce a new technique for the production of nanocrystal solid dispersions (NCSDs) by combining high-pressure homogenization (HPH) and hot-melt extrusion (HME). Efavirenz (EFZ), a Biopharmaceutics Classification System class II drug, which is used for the treatment of human immunodeficiency virus (HIV) type I, was selected as the model drug for this study. A nanosuspension (NS) was first prepared by HPH using sodium lauryl sulfate (SLS) and Kollidon® 30 as a stabilizer system. The NS was then mixed with Soluplus® in the extruder barrel, and the water was removed by evaporation. The decreased particle size and crystalline state of EFZ were confirmed by scanning electron microscopy, zeta particle size analysis, and differential scanning calorimetry. The increased dissolution rate was also determined. EFZ NCSD was found to be highly stable after storage for 6 months. In summary, the conjugation of HPH with HME technology was demonstrated to be a promising novel method for the production of NCSDs.

Investigation of phase diagrams and physical stability of drug-polymer solid dispersions.

Solid dispersion technology has been widely explored to improve the solubility and bioavailability of poorly water-soluble compounds. One of the critical drawbacks associated with this technology is the lack of physical stability, i.e. the solid dispersion would undergo recrystallization or phase separation thus limiting a product's shelf life. In the current study, the melting point depression method was utilized to construct a complete phase diagram for felodipine (FEL)-Soluplus® (SOL) and ketoconazole (KTZ)-Soluplus® (SOL) binary systems, respectively, based on the Flory-Huggins theory. The miscibility or solubility of the two compounds in SOL was also determined. The Flory-Huggins interaction parameter χ values of both systems were calculated as positive at room temperature (25 °C), indicating either compound was miscible with SOL. In addition, the glass transition temperatures of both solid dispersion systems were theoretically predicted using three empirical equations and compared with the practical values. Furthermore, the FEL-SOL solid dispersions were subjected to accelerated stability studies for up to 3 months.

Influence of processing parameters and formulation factors on the bioadhesive, temperature stability and drug release properties of hot-melt extruded films containing miconazole.

This study investigated the processing parameters and formulation factors on the bioadhesive properties, temperature stability properties, and drug release properties of miconazole in PolyOx® and Klucel® matrix systems produced by Hot-melt Extrusion (HME) technology. Miconazole incorporated into these matrix systems were found to be stable for 8 months by X-ray diffraction (XRD). The addition of miconazole increased area under the curve (AUC) at contact time intervals of 30 and 60 sec, while the bioadhesion decreased with an increase in processing temperatures. The release profiles suggest that a sustained release of miconazole was observed from all of the tested HME film formulations for approximately 10 h. The release from the optimal HME film extruded at 205°C was found to be significantly different than that extruded at 190°C. Therefore, this matrix system may address the present shortcomings of currently available therapy for oral and pharyngeal candidiasis.

Melt extrusion with poorly soluble drugs.

Melt extrusion (ME) over recent years has found widespread application as a viable drug delivery option in the drug development process. ME applications include taste masking, solid-state stability enhancement, sustained drug release and solubility enhancement. While ME can result in amorphous or crystalline solid dispersions depending upon several factors, solubility enhancement applications are centered around generating amorphous dispersions, primarily because of the free energy benefits they offer. In line with the purview of the current issue, this review assesses the utility of ME as a means of enhancing solubility of poorly soluble drugs/chemicals. The review describes major processing aspects of ME technology, definition and understanding of the amorphous state, manufacturability, analytical characterization and biopharmaceutical performance testing to better understand the strength and weakness of this formulation strategy for poorly soluble drugs. In addition, this paper highlights the potential advantages of employing a fusion of techniques, including pharmaceutical co-crystals and spray drying/solvent evaporation, facilitating the design of formulations of API exhibiting specific physico-chemical characteristics. Finally, the review presents some successful case studies of commercialized ME based products.

Melt extrusion: process to product.

INTRODUCTION: Niche applicability and industrial adaptability have led hot melt extrusion (HME) techniques to gain wide acceptance and have, therefore, solidified their place in the array of pharmaceutical research and manufacturing operations. Melt extrusion's momentum has resulted in extensive research publications, reviews and patents on the subject for over a decade. Currently, > 50% of the new drug candidates are speculated to be highly lipophilic and thus poorly bioavailable. HME is a key technology for these and other formulation and processing issues. AREAS COVERED: Various approaches have been addressed using HME in developing solid molecular dispersions and have demonstrated viability to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. This review provides a holistic perspective on HME from equipment, processing and materials to its varied applications in oral delivery (immediate release, sustained release, taste masking, enteric and targeted release, as well as trans-drug delivery), oral mucosal, dermal, ungual and intravaginal systems. EXPERT OPINION: Interest in HME as a pharmaceutical process continues to grow and the potential of automation and reduction of capital investment and labor costs has earned this technique a necessary consideration as a drug delivery solution.