Engineered Site-specific Vesicular Systems for Colonic Delivery: Trends and Implications.

Steering drug-loaded, site-specific, coated lipid vesicles to the target receptor sites have the potential of plummeting adverse effects and improving the pharmacological response in diverse pathologies of the large bowel, especially the colon. Colonic delivery via oral route has its own challenges, often governed by several glitches such as drug degradation or absorption in the upper GIT, instability of proteins/peptides due to high molecular weight, and peptidase activity in the stomach. Consequently, colon-specific coated liposomal systems (CSLS) offer a potential alternate for not only site-specificity, but protection from proteolytic activity, and prolonged residence time for greater systemic bioavailability. On the other hand, liposomal delivery via the oral route is also cumbersome owing to several barriers such as instability in GIT, difficulty in crossing membranes, and issues related to production at the pilot scale. New advancements in the field of CSLS have successfully improved the stability and permeability of liposomes for oral delivery via modulating the compositions of lipid bilayers, adding polymers or ligands. Despite this ostensible propitiousness, no commercial oral CSLS has advanced from bench to bedside for targeted delivery to the colon as yet. Nevertheless, CSLS has quite fascinated the manufacturers owing to its potential industrial viability, simplistic and low-cost design. Hence, this review aims to decipher the convolutions involved in the engineering process of industrially viable CSLS for colonic delivery.

Strategizing biodegradable polymeric nanoparticles to cross the biological barriers for cancer targeting.

The biological barriers in the body have been fabricated by nature to protect the body from foreign molecules. The successful delivery of drugs is limited and being challenged by these biological barriers including the gastrointestinal tract, brain, skin, lungs, nose, mouth mucosa, and immune system. In this review article, we envisage to understand the functionalities of these barriers and revealing various drug-loaded biodegradable polymeric nanoparticles to overcome these barriers and deliver the entrapped drugs to cancer targeted site. Apart from it, tissue-specific multifunctional ligands, linkers and transporters when employed imparts an effective active delivery strategy by receptor-mediated transcytosis. Together, these strategies enable to deliver various drugs across the biological membranes for the treatment of solid tumors and malignant cancer.

Aspartic acid tagged carbon nanotubols as a tool to deliver docetaxel to breast cancer cells: Reduced hemotoxicity with improved cytotoxicity.

The present study aimed to explore the potential of hydroxylated carbon nanotubes (CNTnols) conjugated with aspartic acid for the delivery of docetaxel (DTX) to breast cancer cells. The conjugate was well-characterized by FT-IR, NMR, XRD and FE-SEM. The nanoconjugate offered a hydrodynamic diameter of 86.31 ±â€¯1.02 nm, with a PDI of 0.113 and zeta potential of -41.6 ±â€¯0.17 mV. The designed nanosystem offered a controlled & pH dependent release vouching release of drug in the cancerous cytosol, not in blood, assuring delivery of the pay-load to the site of action. The carriers offered substantial hemocompatibility and lower plasma protein binding, ensuring more drug available at the site of action. The in-vitro cell viability studies in MDA MB-231 cells inferred approx. 2.8 times enhancement in the cytotoxicity potential of the conjugate vis-à-vis plain drug. Pharmacokinetic studies also corroborated the superiority of the designed nanoconjugate in terms of enhanced bioavailable fractions, reduced clearance and longer bioresidence to that of plain docetaxel. The present studies, successfully provide a workable nanomedicine, loaded with a BCS class-IV drug, for improved efficacy and safety in breast cancer.

QbD-Based Development of Cationic Self-nanoemulsifying Drug Delivery Systems of Paclitaxel with Improved Biopharmaceutical Attributes.

The present studies describe quality-by-design-based design and characterization of cationic self-nanoemulsifying formulations of paclitaxel for improving its biopharmaceutical attributes. Solubility and phase titration experiments were designed to select the lipidic and emulsifying excipients. Two different types of lipidic nanoformulations were developed using medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs). The nanoformulations were optimized by mixture designs and subjected to evaluation for globule size, zeta potential, drug release, and intestinal permeability. Following apt mathematical modeling, the optimum nanoformulation was earmarked using numerical optimization. Further, cationic formulations were developed for both LCT- and MCT-containing formulations and subjected to performance evaluation. The optimized formulations were extensively evaluated, where an in vitro drug release study indicated 2.7-fold improvement in dissolution rate from optimized cationic nanoformulations over powder pure drug. Ex vivo and in situ evaluation performed on Wistar rats exhibited nearly six- to eightfold enhancement in permeation and absorption parameters of the drug for the optimized cationic nanoformulation as compared to the pure paclitaxel. Pharmacokinetic studies indicated nearly 13.4-fold improvement in AUC and Cmax, along with 1.8-fold reduction in Tmax of the drug from cationic nanoformulations as compared to the pure drug suspension. Moreover, nanoformulation containing long-chain lipids exhibited superior performance (1.18-fold improvement in drug absorption) over medium-chain lipids. Cytotoxicity evaluation of cationic nanoformulations on MCF-7 cells revealed significant reduction in growth vis-à-vis the pure drug. Overall, the current paper reports successful systematic development of paclitaxel-loaded cationic self-nanoemulsifying systems with distinctly improved biopharmaceutical performance.

Clathrin-mediated endocytic uptake of PUFA enriched self-nanoemulsifying lipidic systems (SNELS) of an anticancer drug against triple negative cancer and DMBA induced preclinical tumor model.

The current studies envisage unravelling the underlying cellular internalisation mechanism of the systematically developed docetaxel (DTH) polyunsaturated fatty acid (PUFA) enriched self-nanoemulsifying lipidic micellar systems (SNELS). The concentration-, time- and cytotoxicity-related effects of DTH-SNELS on triple negative breast cancer (TNBC) MDA-MB-231 and non-TNBC MCF-7 cell lines were assessed through Presto-blue assay. Subsequently, rhodamine-123 (Rh-123) loaded SNELS were employed for evaluating their internalisation through flow cytometry and fluorescence microscopy, establishing it to be "clathrin-mediated" endocytic pathway. Apoptosis assay (65% cell death) and cell cycle distribution (47% inhibition at G2/M phase) further corroborated the cytotoxicity of DTH-SNELS towards cancerous cells. Biodistribution, histopathology and haematology studies indicated insignificant toxicity of the optimized formulation on vital organs. Preclinical anticancer efficacy studies using 7,12-dimethylbenzantracene (DMBA)-induced model construed significant reduction in breast tumor-volume. Overall, extensive in vitro and in vivo studies indicated the intracellular localization and cytotoxicity, suggesting DTH-SNELS as promising delivery systems for breast tumor therapeutics including TNBC.

Improving the biopharmaceutical attributes of mangiferin using vitamin E-TPGS co-loaded self-assembled phosholipidic nano-mixed micellar systems.

The current research work encompasses the development, characterization, and evaluation of self-assembled phospholipidic nano-mixed miceller system (SPNMS) of a poorly soluble BCS Class IV xanthone bioactive, mangiferin (Mgf) functionalized with co-delivery of vitamin E TPGS. Systematic optimization using I-optimal design yielded self-assembled phospholipidic nano-micelles with a particle size of < 60 nm and > 80% of drug release in 15 min. The cytotoxicity and cellular uptake studies performed using MCF-7 and MDA-MB-231 cell lines demonstrated greater kill and faster cellular uptake. The ex vivo intestinal permeability revealed higher lymphatic uptake, while in situ perfusion and in vivo pharmacokinetic studies indicated nearly 6.6- and 3.0-folds augmentation in permeability and bioavailability of Mgf. In a nutshell, vitamin E functionalized SPNMS of Mgf improved the biopharmaceutical performance of Mgf in rats for enhanced anticancer potency.

Administration of antioxidants in cancer: debate of the decade.

Several randomized clinical trials have divulged that administration of antioxidants during chemotherapy decreases the effectiveness of treatment. Hence, the characteristic feature of this article is extensive assessment of putative benefits and potential risks of natural and synthetic antioxidant supplementation, administered with chemotherapy, based upon the available preclinical and clinical data. After analyzing mixed results, it was concluded that current FDA guidelines should be followed before supplementing antioxidants during cytotoxic treatment. Nevertheless, contradictory experimental animal models opposing human clinical trials discourage the concurrent administration of antioxidants ostensibly owing to the possibility of tumor protection and reduced survival.

Development of a validated liquid chromatographic method for quantification of sorafenib tosylate in the presence of stress-induced degradation products and in biological matrix employing analytical quality by design approach.

The current research work envisages an analytical quality by design-enabled development of a simple, rapid, sensitive, specific, robust and cost-effective stability-indicating reversed-phase high-performance liquid chromatographic method for determining stress-induced forced-degradation products of sorafenib tosylate (SFN). An Ishikawa fishbone diagram was constructed to embark upon analytical target profile and critical analytical attributes, i.e. peak area, theoretical plates, retention time and peak tailing. Factor screening using Taguchi orthogonal arrays and quality risk assessment studies carried out using failure mode effect analysis aided the selection of critical method parameters, i.e. mobile phase ratio and flow rate potentially affecting the chosen critical analytical attributes. Systematic optimization using response surface methodology of the chosen critical method parameters was carried out employing a two-factor-three-level-13-run, face-centered cubic design. A method operable design region was earmarked providing optimum method performance using numerical and graphical optimization. The optimum method employed a mobile phase composition consisting of acetonitrile and water (containing orthophosphoric acid, pH 4.1) at 65:35 v/v at a flow rate of 0.8 mL/min with UV detection at 265 nm using a C18 column. Response surface methodology validation studies confirmed good efficiency and sensitivity of the developed method for analysis of SFN in mobile phase as well as in human plasma matrix. The forced degradation studies were conducted under different recommended stress conditions as per ICH Q1A (R2). Mass spectroscopy studies showed that SFN degrades in strongly acidic, alkaline and oxidative hydrolytic conditions at elevated temperature, while the drug was per se found to be photostable. Oxidative hydrolysis using 30% H2 O2 showed maximum degradation with products at retention times of 3.35, 3.65, 4.20 and 5.67 min. The absence of any significant change in the retention time of SFN and degradation products, formed under different stress conditions, ratified selectivity and specificity of the systematically developed method.

Potential of Natural Biomaterials in Nano-scale Drug Delivery.

BACKGROUND: The usage of natural biomaterials or naturally derived materials intended for interface with biological systems has steadily increased in response to the high demand of amenable materials, which are suitable for purpose, biocompatible and biodegradable. There are many naturally derived polymers which overlap in terms of purpose as biomaterials but are equally diverse in their applications. METHODS: This review examines the applications of the following naturally derived polymers; hyaluronic acid, silk fibroin, chitosan, collagen and tamarind polysaccharide (TSP); further focusing on the biomedical applications of each as well as emphasising on individual novel applications. RESULTS: Each of the polymers was found to demonstrate a wide variety of successful biomedical applications fabricated as wound dressings, scaffolds, matrices, films, sponges, implants or hydrogels to suit the therapeutic need. Interestingly, blending and amelioration of polymer structures were the two selection strategies to modify the functionality of the polymers to suit the purpose. Further, these polymers have shown promise to deliver small molecule drugs, proteins and genes as nano-scale delivery systems. CONCLUSION: The review highlights the range of applications of the aforementioned polymers as biomaterials. Hyaluronic acid, silk fibroin, chitosan, collagen and TSP have been successfully utilised as biomaterials in the subfields of implant enhancement, wound management, drug delivery, tissue engineering and nanotechnology. Whilst there are a number of associated advantages (i.e. biodegradability, biocompatibility, non-toxic, nonantigenic as well as amenability) the selected disadvantages of each individual polymer provide significant scope for their further exploration and overcoming challenges like feasibility of mass production at a relatively low cost.

Enhancing biopharmaceutical performance of an anticancer drug by long chain PUFA based self-nanoemulsifying lipidic nanomicellar systems.

The aim of this study was to develop polyunsaturated fatty acid (PUFA) long chain glyceride (LCG) enriched self-nanoemulsifying lipidic nanomicelles systems (SNELS) for augmenting lymphatic uptake and enhancing oral bioavailability of docetaxel and compare its biopharmaceutical performance with a medium-chain fatty acid glyceride (MCG) SNELS. Equilibrium solubility and pseudo ternary phase studies facilitated the selection of suitable LCG and MCG. The critical material attributes (CMAs) and critical process parameters (CPPs) were earmarked using Placket-Burman Design (PBD) and Fractional Factorial Design (FFD) for LCG- and MCG-SNELS respectively, and nano micelles were subsequently optimized using I- and D-optimal designs. Desirability function unearthed the optimized SNELS with Temul <5min, Dnm <100nm, Rel15min >85% and Perm45min >75%. The SNELS demonstrated efficient biocompatibility and energy dependent cellular uptake, reduced P-gp efflux and increased permeability using bi-directional Caco-2 model. Optimal PUFA enriched LCG-SNELS exhibited distinctly superior permeability and absorption parameters during ex vivo permeation, in situ single pass intestinal perfusion, lymphatic uptake and in vivo pharmacokinetic studies over MCG-SNELS.

Stimuli-Responsive Systems with Diverse Drug Delivery and Biomedical Applications: Recent Updates and Mechanistic Pathways.

With the advent of "intelligent" polymeric systems, the use of stimuli-responsive in situ gelling systems has been revolutionized. These interesting polymers exist as free-flowing aqueous solutions before administration and undergo a phase transition to form a viscoelastic gel in a physiological environ through various stimuli such as temperature, pH, solvent, biochemical, magnetic, electric, ultrasound, and photo-polymerization. These smart polymers are endowed with numerous merits such as ease of administration, sustained release, reduced frequent administration with improved patient compliance, and targeted and spatial delivery of a drug with reduced frequency of side effects. Concerted efforts are being made to modify these polymers synthetically because they hold immense potential in various fields such as polymer chemistry, materials science, pharmaceutics, bioengineering medicine, and chemical engineering. In addition to novel drug delivery, these smart polymeric systems have exhibited tremendous applications in tissue engineering, regenerative biomedicine, molecular imprinting, cancer therapy, gene delivery, theranostic and other applications. The current review mainly focuses on the fundamental principles involved during in situ gelling, use of various "smart" drug-delivery formulation systems through diverse routes for their administration, as well as their well-documented biomedical applications. The pertinent literature, marketed formulations, and recent advances on these stimuli-responsive sol-gel-transforming systems are also discussed.

Exploring and validating physicochemical properties of mangiferin through GastroPlus® software.

AIM: Mangiferin (Mgf), a promising therapeutic polyphenol, exhibits poor oral bioavailability. Hence, apt delivery systems are required to facilitate its gastrointestinal absorption. The requisite details on its physicochemical properties have not yet been well documented in literature. Accordingly, in order to have explicit insight into its physicochemical characteristics, the present work was undertaken using GastroPlus™ software. RESULTS: Aqueous solubility (0.38 mg/ml), log P (-0.65), Peff (0.16 × 10-4 cm/s) and ability to act as P-gp substrate were defined. Potency to act as a P-gp substrate was verified through Caco-2 cells, while Peff was estimated through single pass intestinal perfusion studies. Characterization of Mgf through transmission electron microscopy, differential scanning calorimetry, infrared spectroscopy and powder x-ray diffraction has also been reported. CONCLUSION: The values of physicochemical properties for Mgf reported in the current manuscript would certainly enable the researchers to develop newer delivery systems for Mgf.

Investigating the potential of Tamarindus indica pectin-chitosan conjugate for reducing recovery period in TNBS induced colitis.

The present study was aimed at exploiting the wound healing applications and tablet coating potential of Tamarindus indica pectin-chitosan (PCH) conjugate for reducing recovery period from TNBS induced colitis. The PCH (60:40, 3% w/v) solution when spray coated followed by drying at 50°C created hydrophobic surface, that may be due to interaction of pectin with chitosan as evident from temperature ramping rheological investigations. Further, the 15% w/v coating was sufficient to prevent Mesalamine (Ma) release in pH 1.2. The AUC and AUMC of PCH coated tablets were 1.98 and 17.69 fold increased as compared to uncoated tablets. A synergistic therapeutic effect of PCH conjugate with Ma was evident from the colon/body weight ratio, clinical activity and damage score. Overall, the findings suggested PCH and Ma (20mg) reduces the recovery period from 5 to 4days with reduction in dose.

Elucidation of stress-induced degradation products of mangiferin: Method development and validation.

The degradation behavior of mangiferin, under various ICH Q1A(R2) recommended stress conditions, was studied using an isocratic elution with mobile phase (pH 2.4), composed of acetonitrile and 1% orthophosphoric acid (12:88 v/v) at a flow rate of 1.0 mL/min, with λmax 262 nm. It was suitably adapted for LC-MS studies by replacing with 1% acetic acid (ACN-1% acetic acid; 18:82) and the pH was adjusted to 3.0. Extensive degradation was found to occur during alkaline medium stress studies at 2.31 min of retention time at λmax of 235 nm. The mass spectrum of mangiferin, 3 h after treatment with 0.1 M NaOH, clearly shows the rupture of the tricyclic ring, indicating that a fragment at m/z - 269 was formed. Furthermore, the results were supported by nuclear magnetic resonance as well. However, no degradation was observed in other stress conditions.

Enhancing biopharmaceutical attributes of phospholipid complex-loaded nanostructured lipidic carriers of mangiferin: Systematic development, characterization and evaluation.

Mangiferin (Mgf), largely expressed out from the leaves and stem bark of Mango, is a potent antioxidant. However, its in vivo activity gets tremendously reduced owing to poor aqueous solubility and inconsistent gastrointestinal absorption, high hepatic first-pass metabolism and high P-gp efflux. The current research work, therefore, was undertaken to overcome the biopharmaceutical hiccups by developing the Mgf-phospholipid complex (PLCs) loaded in nanostructured lipidic carriers (NLCs). The PLCs and NLCs were prepared using refluxing, solvent evaporation and hot emulsification technique, respectively with three molar ratios of Mgf and Phospholipon 90G, i.e., 1:1; 1:2; and 1:3. The complex was evaluated for various physicochemical parameters like drug content (96.57%), aqueous solubility (25-fold improved) and oil-water partition coefficient (10-fold enhanced). Diverse studies on the prepared complex using FTIR, DSC, PXRD and SEM studies ratified the formation of PLCs at 1:1 ratio. The PLCs were further incorporated onto NLCs, which were systematically optimized employing a face centered cubic design (FCCD), while evaluating for particle size, zeta potential, encapsulation efficiency and in vitro drug release as the CQAs. Caco-2 cell line studies indicated insignificant cytotoxicity, and P-gp efflux, while bi-directional permeability model and in situ perfusion studies specified enhanced intestinal permeation parameters. In vivo pharmacokinetic studies revealed notable increase in the values of Cmax (4.7-fold) and AUC (2.1-fold), respectively, from PLCs-loaded NLCs vis-à-vis Mgf solution. In a nutshell, the promising results observed from the present research work signify enhanced biopharmaceutical attributes of the novel PLCs-loaded NLCs for potentially augmenting the therapeutic efficacy of Mgf.

Systematic Development and Validation of a Thin-Layer Densitometric Bioanalytical Method for Estimation of Mangiferin Employing Analytical Quality by Design (AQbD) Approach.

The present work aims at the systematic development of a simple, rapid and highly sensitive densitometry-based thin-layer chromatographic method for the quantification of mangiferin in bioanalytical samples. Initially, the quality target method profile was defined and critical analytical attributes (CAAs) earmarked, namely, retardation factor (Rf), peak height, capacity factor, theoretical plates and separation number. Face-centered cubic design was selected for optimization of volume loaded and plate dimensions as the critical method parameters selected from screening studies employing D-optimal and Plackett-Burman design studies, followed by evaluating their effect on the CAAs. The mobile phase containing a mixture of ethyl acetate : acetic acid : formic acid : water in a 7 : 1 : 1 : 1 (v/v/v/v) ratio was finally selected as the optimized solvent for apt chromatographic separation of mangiferin at 262 nm withRf 0.68 ± 0.02 and all other parameters within the acceptance limits. Method validation studies revealed high linearity in the concentration range of 50-800 ng/band for mangiferin. The developed method showed high accuracy, precision, ruggedness, robustness, specificity, sensitivity, selectivity and recovery. In a nutshell, the bioanalytical method for analysis of mangiferin in plasma revealed the presence of well-resolved peaks and high recovery of mangiferin.

QbD-Enabled Development of Novel Stimuli-Responsive Gastroretentive Systems of Acyclovir for Improved Patient Compliance and Biopharmaceutical Performance.

The current studies entail systematic quality by design (QbD)-based development of stimuli-responsive gastroretentive drug delivery systems (GRDDS) of acyclovir using polysaccharide blends for attaining controlled drug release profile and improved patient compliance. The patient-centric quality target product profile was defined and critical quality attributes (CQAs) earmarked. Risk assessment studies, carried out through Ishikawa fish bone diagram and failure mode, effect, and criticality analysis, helped in identifying the plausible risks or failure modes affecting the quality attributes of the drug product. A face-centered cubic design was employed for systematic development and optimization of the concentration of sodium alginate (X 1) and gellan (X 2) as the critical material attributes (CMAs) in the stimuli-responsive formulations, which were evaluated for CQAs viz. viscosity, gel strength, onset of floatation, and drug release characteristics. Mathematical modeling was carried out for generation of design space, and optimum formulation was embarked upon, exhibiting formulation characteristics marked by excellent floatation and bioadhesion characteristics along with promising drug release control up to 24 h. Drug-excipient compatibility studies through FTIR and DSC revealed absence of any interaction(s) among the formulation excipients. In vivo pharmacokinetic studies in Wistar rats corroborated extension in the drug absorption profile from the optimized stimuli-responsive GR formulations vis-à-vis the marketed suspension (ZOVIRAX®). Establishment of in vitro/in vivo correlation (IVIVC) revealed a high degree of correlation between the in vitro and in vivo data. In a nutshell, the present investigations report the successful development of stimuli-responsive GRDDS of acyclovir, which can be applicable as a platform approach for other drugs too.

Quantum Dots and their Potential Role in Cancer Theranostics.

The emergence of cancer nanomedicine is the result of fruitful advances in the fields of nanotechnology, bioimaging, formulation development, and molecular biology. Quantum dots (QDs) are the luminescent nanocrystals (NCs) that provide a multifunctional platform for imaging the biosystems following controlled delivery of therapeutic drugs, proteins, peptides, oligonucleotides, and genes. These engineered fluorescent probes with integrated imaging and carrier functionalities have become excellent tools for molecular diagnostics and delivery of therapeutics molecules. Flexible surface chemistry, unique optical properties, high sensitivity, and multiplexing capabilities of QDs certainly make them a most promising tool for personalized medicine. This review focuses on state-of-art advances in synthesizing QDs and highlights the approaches used for functionalization of QDs with desired ligands for targeted carriage to specific sites. Discussed is the role of QDs in antitumor therapy through drug delivery and gene delivery and the recently emerged photodynamic therapy (PDT). We also endeavor to critically address the major impediments in the clinical development of these multifunctional nanoplatforms, with a special focus on plausible advancements for the near future.

Emerging Strategies and Challenges for Controlled Delivery of Taxanes: A Comprehensive Review.

Taxanes introduction in the mid 90 s leads to significant advancement as well as superlative improvement in the treatment of cancer. Since then, several strategies have been designed to enhance therapeutic potential of these agents by overcoming the limitations in drug delivery and pharmacokinetic constraints associated with conventional delivery. In this regard, controlled drug delivery systems for taxanes have contributed enormously by altering the pharmacokinetic profile, thus ultimately enhancing their therapeutic response. With their conferred stellar merits, controlled drug delivery systems have been able to surmount many of the challenges associated with conventional drug delivery systems. The altered absorption, resistance, low toxicity and cellular uptake profiles that lead to better safety from variegated carrier systems like nanocarriers, liposomes, solid lipid nanoparticles, nanoemulsions, nanocapsules, hydrogels and micelles for controlled delivery of taxanes call for an exhaustive review for future progressive work. Therefore, this review focuses on the altered pharmacokinetic, pharmacodynamic and toxicity patterns achieved from various controlled drug delivery approaches, with the latter half highlighting the clinical profile set ups and commercial aspects of controlled release drug delivery systems.

Multifaceted role of clay minerals in pharmaceuticals.

The desirable physical and physiochemical properties of clay minerals have led them to play a substantial role in pharmaceutical formulations. Clay minerals like kaolin, smectite and palygorskite-sepiolite are among the world's most valuable industrial minerals and of considerable importance. The elemental features of clay minerals which caused them to be used in pharmaceutical formulations are high specific area, sorption capacity, favorable rheological properties, chemical inertness, swelling capacity, reactivity to acids and inconsiderable toxicity. Of course, these are highly cost effectual. This special report on clay minerals provides a bird's eye view of the chemical composition and structure of these minerals and their influence on the release properties of active medicinal agents. Endeavor has been made to rope in myriad applications depicting the wide acceptability of these clay minerals.