Biomedical potential of clay nanotube formulations and their toxicity assessment

ABSTRACT

Introduction: Halloysite clay nanotubes (HNTs) are a naturally abundant and biocompatible aluminosilicate material with a structure able to encapsulate 10–20% of drugs. These features are attractive toward the clinical application in controlled drug delivery, tissue engineering and regenerative medicine.

Areas covered: We describe the application of HNTs as a viable method for clinical purposes, particularly developing formulations for prophylaxis, diagnosis and therapeutics, having a special attention to these nanotubes bio-safety. HNTs may be used for pharmaceuticals, biopharmaceuticals, wound healing, bone regeneration, dental repair, hair surface engineering and biomimetic applications.

Expert opinion: HNTs are a versatile, safe and biocompatible nanomaterial used for drug encapsulation for numerous clinical applications. The studies here reviewed confirm the HNTs biocompatibility, describing their low toxicity. Further developments will be made regarding the long-term efficacy of halloysite-based treatments in humans, concentrating mostly on topical applications.     

Proteomic profiling of halloysite clay nanotube exposure in intestinal cell co‐culture

Halloysite is aluminosilicate clay with a hollow tubular structure with nanoscale internal and external diameters. Assessment of halloysite biocompatibility has gained importance in view of its potential application in oral drug delivery. To investigate the effect of halloysite nanotubes on an in vitro model of the large intestine, Caco‐2/HT29‐MTX cells in monolayer co‐culture were exposed to nanotubes for toxicity tests and proteomic analysis. Results indicate that halloysite exhibits a high degree of biocompatibility characterized by an absence of cytotoxicity, in spite of elevated pro‐inflammatory cytokine release. Exposure‐specific changes in expression were observed among 4081 proteins analyzed. Bioinformatic analysis of differentially expressed protein profiles suggest that halloysite stimulates processes related to cell growth and proliferation, subtle responses to cell infection, irritation and injury, enhanced antioxidant capability, and an overall adaptive response to exposure. These potentially relevant functional effects warrant further investigation in in vivo models and suggest that chronic or bolus occupational exposure to halloysite nanotubes may have unintended outcomes. Copyright © 2013 John Wiley & Sons, Ltd.     

Composite polymer-bioceramic scaffolds with drug delivery capability for bone tissue engineering

Introduction: Next-generation scaffolds for bone tissue engineering (BTE) should exhibit the appropriate combination of mechanical support and morphological guidance for cell proliferation and attachment while at the same time serving as matrices for sustained delivery of therapeutic drugs and/or biomolecular signals, such as growth factors. Drug delivery from BTE scaffolds to induce the formation of functional tissues, which may need to vary temporally and spatially, represents a versatile approach to manipulating the local environment for directing cell function and/or to treat common bone diseases or local infection. In addition, drug delivery from BTE is proposed to either increase the expression of tissue inductive factors or to block the expression of others factors that could inhibit bone tissue formation. Composite scaffolds which combine biopolymers and bioactive ceramics in mechanically competent 3D structures, including also organic–inorganic hybrids, are being widely developed for BTE, where the affinity and interaction between biomaterials and therapeutic drugs or biomolecular signals play a decisive role in controlling the release rate.

Areas covered: This review covers current developments and applications of 3D composite scaffolds for BTE which exhibit the added capability of controlled delivery of therapeutic drugs or growth factors. A summary of drugs and biomolecules incorporated in composite scaffolds and approaches developed to combine biopolymers and bioceramics in composites for drug delivery systems for BTE is presented. Special attention is given to identify the main challenges and unmet needs of current designs and technologies for developing such multifunctional 3D composite scaffolds for BTE.

Expert opinion: One of the major challenges for developing composite scaffolds for BTE is the incorporation of a drug delivery function of sufficient complexity to be able to induce the release patterns that may be necessary for effective osseointegration, vascularization and bone regeneration. Loading 3D scaffolds with different biomolecular agents should produce a codelivery system with different, predetermined release profiles. It is also envisaged that the number of relevant bioactive agents that can be loaded onto scaffolds will be increased, whilst the composite scaffold design should exploit synergistically the different degradation profiles of the organic and inorganic components.     

In situ gel systems as ‘smart’ carriers for sustained ocular drug delivery

Introduction: In situ gel systems refer to a class of novel delivery vehicles, composed of natural, semisynthetic or synthetic polymers, which present the unique property of sol–gel conversion on receipt of biological stimulus.

Areas covered: The present review summarizes the latest developments in in situ gel technology, with regard to ophthalmic drug delivery. Starting with the mechanism of ocular absorption, the review expands on the fabrication of various polymeric in situ gel systems, made up of two or more polymers presenting multi-stimuli sensitivity, coupled with other interesting features, such as bio-adhesion, enhanced penetration or sustained release. Various key issues and challenges in this area have been addressed and critically analyzed.

Expert opinion: The advent of in situ gel systems has inaugurated a new transom for ‘smart’ ocular delivery. By virtue of possessing stimuli-responsive phase transition properties, these systems can easily be administered into the eye, similar to normal eye drops. Their unique gelling properties endow them with special features, such as prolonged retention at the site of administration, followed by sustained drug release. Despite the superiority of these systems as compared with conventional ophthalmic formulations, further investigations are necessary to address the toxicity issues, so as to minimize regulatory hurdles during commercialization.     

Deterred drug abuse using superabsorbent polymers

ABSTRACT

Objective: This study aimed to determine whether selected superabsorbent polymers (SAPs) could be used as a suitable alternative to thwart extraction, filtration, and syringeability attempts for abuse. Many abuse-deterrent formulations (ADFs) rely on high molecular weight polymers such as poly(ethylene oxide) to provide crush and extraction resistance. However, these polymers suffer from slow dissolution kinetics, and are susceptible to a variety of abuse conditions.

Methods: Several commercially available SAPs were evaluated for swelling behavior in extraction solvents, and tableting properties. Post-compaction abuse properties were evaluated by recoverable volume and syringeability after solvent extraction. Drug release and percent drug extraction were conducted using tramadol HCl as a model drug.

Results: Certain SAPs had the ability to rapidly imbibe solvent and effectively stop extraction processes in a variety of solvents, including water and water/alcohol mixtures. Tablets containing SAP and drug showed no effect on drug release in vitro.

Conclusions: SAPs possess adequate properties for tableting, and maintain their high and fast swelling properties after compaction. The fast and extensive interactions of SAPs with aqueous medium are a major advantage over non-crosslinked high molecular weight viscosifying agents such as poly(ethylene oxide).     

Modulating drug release profiles by lipid semi solid matrix formulations for BCS class II drug – an in vitro and an in vivo study

Abstract

The main objective of the study was to alter the dissolution profile of a practically insoluble Biopharmaceutics Classification System class II drug, aceclofenac, by formulating into lipid semisolid matrix (SSM) formulations using liquid filling technology in hard gelatin capsules, for both immediate and sustained release. SSM formulations of aceclofenac were prepared by melt fusion technique, using Gelucires (44/14, 50/13, 33/01 and 43/01), polyethylene glycols (4000 and 6000) and Poloxamer 188 at different levels. Role of additives like docusate sodium, Tween 80, Aerosil 200 and polyvinylpyrrolidone K-30 in enhancement of drug release was investigated. The optimized immediate and sustained SSM capsules were characterized in terms of assay, in vitro drug release, moisture uptake and differential scanning calorimetry. More than 80% of the drug was released within 15?min in various dissolution media studied, from Gelucire 44/14-based immediate release formulations. Incorporation of docusate sodium and Tween 80 provided further enhancement in drug dissolution when compared to plain drug and marketed tablet. SSM formulations based on Gelucire blends of 50/13 and 43/01 and 44/14 and 43/01 sustained the release of the drug for a period of 24?h following zero-order kinetics. The in vivo study of the optimized immediate release and sustained release formulations revealed significant enhancement in anti inflammatory activity (p?<?0.01) in rats. From these findings, liquid fill technique in hard gelatin capsules using Gelucire and their blends might be an efficacious approach for designing immediate or sustained drug release profiles for poorly soluble drugs like aceclofenac.     

Formulation development and optimization of bilayer tablets of aceclofenac

Objective: The objective of the present study was to develop bilayer tablets of aceclofenac that are characterized by initial burst drug release followed by sustained release of drug.

Methods: The fast-release layer of the bilayer tablet was formulated using microcrystaline cellulose (MCC) and HPMC K4M. The amount of HPMC E4M (X₁) and MCC (X₂) was used as independent variables for optimization of sustained release formulation applying 3² factorial design. Three dependent variables were considered: percentage of aceclofenac release at 1 h, percentage of aceclofenac release at 12 h, and time to release 50% of drug (t_50%). The composition of optimum formulation of sustained release tablets were employed to formulate double layer tablets.

Results: The results indicate that X₁ and X₂ significantly affected the release properties of aceclofenac from sustained release formulation. The double layer tablets containing fast-release layer showed an initial burst drug release of more than 30% of its drug content during first 1 h followed by sustained release of the drug for a period of 24 h.

Conclusion: The double layer tablets for aceclofenac can be successfully employed as once-a-day oral-controlled release drug delivery system characterized by initial burst release of aceclofenac for providing the loading dose of drug.     

Pharmacokinetic/Pharmacodynamics Modeling of Drug-Loaded PLGA Nanoparticles Targeting Heterogeneously Vascularized Tumor Tissue

Purpose

Combination chemotherapy is gradually receiving more attention because of its potential synergistic effect and reduced drug doses in clinical application. However, how to precisely control drug release dose and time using vehicles remains a challenge. This work developed an efficient drug delivery system to combat breast cancer, which can enhance drug effects despite reducing its concentration.

Methods

Controlled-release poly-lactic-co-glycolic acid (PLGA) scaffolds were fabricated by E-jet 3D printing to deliver doxorubicin (DOX) and cisplatin (CDDP) simultaneously.

Results

This drug delivery system allowed the use of a reduced drug dosage resulting in a better effect on the human breast cancer cell apoptosis and inhibiting tumor growth, compared with the effect of each drug and the two drugs administrated without PLGA scaffolds. Our study suggested that DOX-CDDP-PLGA scaffolds could efficiently destroy MDA-MB-231 cells and restrain tumor growth.

Conclusions

The 3D printed PLGA scaffolds with their time-programmed drug release might be useful as a new multi-drug delivery vehicle in cancer therapy, which has a potential advantage in a long term tumor cure and prevention of tumor recurrence.

     

Nanovesicular carriers as alternative drug delivery systems: ethosomes in focus

Introduction: The application of vesicular carrier formulations has generated promise of overcoming some problems associated with drug delivery arising from not only the physicochemical properties of the drug but also those of the biological barriers, such as the membrane linings of various body tissues and the skin. This review article discusses the importance of various vesicular carriers, namely liposomes, niosomes, transfersomes and ethosomes in drug delivery with greater emphasis on ethosomes.

Areas covered: The nature, mechanism of drug delivery, methods of preparation as well as characterization of vesicular carriers was discussed with a focus on ethosomes. An overview of their potential applications was provided with discussions on the future prospects and challenges of achieving enhanced drug delivery using ethosomes.

Expert opinion: Vesicular carriers offer controlled and sustained drug release, improved permeability and protection of the encapsulated bioactives. Ethosomes offer more efficient and enhanced bioavailability better than the older dosage forms owing to the high ethanol content. Ethosomes have potential applications in the development of nanomedicines, including phytomedicines, for the treatment of challenging diseases ravaging the world today. The future holds great prospects in the utilization of vesicular carriers, especially ethosomes, in overcoming peculiar problems of drug delivery.     

Future of nanomedicines for treating respiratory diseases

Introduction: Nanoparticles are under discussion in drug delivery for more than 20 years now, but examples for nanoparticulate formulations in the treatment of respiratory diseases are rare and mostly limited to the administration of sub-micron drug particles (ultrafine particles). However, nanoparticles may also carry specific benefits for respiratory treatment. Are nanoparticles the next-generation drug carrier system to facilitate systemic delivery, sustained release and cancer treatment in the lungs?

Areas covered: This review will look into the promises and opportunities of the use of nanoparticles in the treatment of respiratory diseases. Important aspects to discuss are the fate of nanoparticles in the lung and mechanisms for reproducible delivery of nanoparticulate formulations to the lungs. Examples are given where nanoparticles may be advantageous over for traditional formulations and further aspects to explore are mentioned.

Expert opinion: The benefit of nanoparticulate systems for respiratory delivery adds to the portfolio of possible formulation strategies, depends on the intended functionality and needs more exploration. Advantages of such systems are only seen in special cases.     

Floating microspheres of carvedilol as gastro retentive drug delivery system: 32 full factorial design and in vitro evaluation

Abstract

Context: Designing a sustained release system for Carvedilol to increase its residence time in the stomach.

Objective: Preparation of floating microsphere by the emulsion solvent diffusion method, studying the effect of various process parameters and optimize the formulation using full factorial design.

Methods: Different microsphere formulations were prepared by varying the ratio ethanol:dichloromethane (1:0 to 1:1.5), ethyl cellulose:hydroxypropyl methyl cellulose and stirring speed (800–1600?rpm). The effect of these variables on particle size, encapsulation parameters, surface topography, in vitro floatability and drug release were evaluated.

Results: 3² full factorial design was used for the optimization of the formulation. Drug entrapment efficiency, particle size and in vitro drug release were dependent on concentration of ethyl cellulose and stirring speed. Microspheres remained buoyant for more than 10?h and showed sustained release of the drug.

Conclusion: Floating microspheres of Carvedilol with good floating ability and sustained release were developed.     

pH- and ion-sensitive polymers for drug delivery

Introduction: Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body.

Areas covered: Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations.

Expert opinion: Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.     

Anti-inflammatory and pharmacokinetics evaluation of PEGylated ibuprofen tablet formulation

Abstract

To develop a novel PEGylated ibuprofen tablet formulations and evaluate its anti-inflammatory activity and pharmacokinetics profile in an animal model. Six batches of PEGylated ibuprofen tablets were prepared by direct compression using Avicel® and lactose as the binder diluents. In vivo anti-inflammatory activity of the tablets was carried out as well as the pharmacokinetics profiles. The PEGylated ibuprofen tablet reduced carrageenan-induced inflammation in experimental animals and sustained its anti-inflammatory action for over 10?h. The pharmacokinetics profile of the optimized formulations were greater than that of the marketed sample and the pure drug sample. In conclusion, PEGylation of ibuprofen conferred a high level of anti-inflammatory activity and slowed plasma clearance level, indicating sustained release. Thus, further exploration of this novel formulation to be used as an alternative carrier for this drug is required.     

Challenges in SN38 drug delivery: current success and future directions

Introduction: Clinical use of SN38 is limited by its poor aqueous solubility and hydrolysis of the lactone ring at pH > 6 to inactive carboxylate form. A variety of drug delivery systems have been developed to improve the solubility and stability of SN38, and reduce its toxicity. A few noteworthy formulations with some success in initial phases of clinical trials are reported.

Areas covered: This work aims to provide a comprehensive review on the various techniques and strategies employed (physical, chemical and biological methods) to improve physicochemical properties and to deliver the drug efficiently to the cancer cells. Physical methods such as nanoparticle encapsulation, cyclodextrin complexation; chemical methods such as prodrugs, polymer-, albumin- and immunoconjugates; and enzyme activated prodrug therapy are discussed.

Expert opinion: The challenges in SN38 drug delivery may be overcome by two ways: ensuring multiple layers of protection against degradation and slow but sustained release of therapeutically effective drug concentrations. It may also be achieved by preparing a polymer–drug conjugate and further encapsulating the conjugate in suitable carrier system; tumor-targeted SN38 delivery by using immunoconjugates, enzyme-activated prodrug therapy and antibody-directed nanoparticle delivery. However, selection of a suitable ligand for tumor targeting and use of safe and biocompatible nanoparticle systems play an important role in realizing this goal.     

Chitosan: a potential polymer for colon-specific drug delivery system

Introduction: There is an enormous growth and awareness of the potential applications of natural polymers for colon delivery of therapeutic bioactives. Chitosan (CH), a cationic polysaccharide, has a number of vital applications in the field of colon delivery and has attracted a great deal of attention from formulation scientists, academicians and environmentalists due to its unique properties.

Areas covered: CH has been widely explored for the delivery of drugs, peptides, proteins and genes to the colon for different therapeutic applications. Sustained and controlled delivery can be achieved with CH-based formulations like CH-coated tablets, capsules, beads, gels, microparticles and nanoparticles. This review mainly focuses on various aspects of CH-based formulations, particularly development of colon-specific delivery of drug.

Expert opinion: The vital properties of CH make it a versatile excipient, not only for sustained/controlled release applications but also as biodegradable, biocompatible, bioadhesive polymer. The colon is recognized as the preferred absorption site for orally administered protein and peptide drugs. The main problem associated with CH is limited solubility at higher pH due to reduced cationic nature, which also reduces mucoadhesiveness. The application of newer targeting moiety with CH-based formulations for highly site-specific delivery of bioactive has to be evaluated for further improvement of therapeutic index (bioavailability).     

One-step microencapsulation and spraying of pesticide formulations for improved adhesion and sustained release

Abstract

Aim: To reduce the contamination arising from abuse of commercial pesticide formulations, the coaxial electrospray (CES) method was used for one-step microencapsulation and spraying of pesticides.

Methods: After optimisation of process parameters, polymeric microcapsules with different structures were fabricated as the carriers of azoxystrobin (AZS). For the resultant microcapsules, the sustained pesticide release was verified in vitro and the adhesion properties were investigated through a normalised rinsing test.

Results: The maximum encapsulation efficiency of the fabricated AZS-loaded microcapsules was 99.14%. Compared to commercial AZS aqueous suspension, the microcapsules fabricated by the CES method exhibited improved sustained release performance of AZS, which could be readily controlled by adjusting the shell thicknesses. Moreover, highly enhanced adhesion performance was observed for the AZS-loaded microcapsules directly sprayed in CES process.

Conclusions: The CES process is promising to be applied as a one-step microencapsulation and spraying technology for improving pesticide utilisation and reducing environmental pollution.     

Advances in ocular drug delivery: emphasis on the posterior segment

Introduction: Recent advances in pharmacological therapies to treat ocular diseases such as glaucoma, age-related macular degeneration, diabetic macular edema and retinal vascular occlusions have greatly improved the prognosis for these diseases. Due to these advances in pharmacological therapy, there is a great deal of interest in minimally invasive delivery methods, which has generated rapid developments in the field of ocular drug delivery.

Areas covered: This review will summarize currently available and recent developments for ocular drug delivery to both the anterior and posterior segments. Modes of delivery, including topical, systemic, transcleral/periocular and intravitreal, will be discussed and corresponding examples will be given. This review will highlight the advantages and disadvantages of each mode of delivery and discuss strategies to address these issues.

Expert opinion: An ideal therapy should maintain effective levels of drug for the intended duration of treatment following a single application, yet a significant number of months of therapy may be required. There are numerous approaches under investigation to improve treatment options. From the use of novel biomaterial implants and depots for sustained release, to prodrug formations, to iontophoresis to improve drug delivery, the main emphasis will continue to be placed on less invasive, longer acting, sustained release formulations in the treatment of numerous ocular disorders.     

Dual sustained release delivery system for multiple route therapy of an antiviral drug

Abstract

Context: The first successful molecule against herpes infections was Acyclovir, which competes with new generations in the market, with its potential activity. The major physicochemical constraints and pharmacokinetics of Acyclovir such as low solubility, poor permeability, less half-life, high dose has initiated many researchers to develop diverse modified release dosage forms.

Objective: The objective of this work was to design polymeric nanoparticles of Acyclovir and then incorporate the drug-loaded nanoparticles within an in situ gelling system to provide dual sustained release effect, whereby the duration of action and bioavailability through different routes of administration could be improved.

Materials and methods: The formulation was designed through 3² factorial design, first developing the nanoparticles using Polycaprolactone and Pluronic F127 by Solvent evaporation process, followed by dispersion of the suspended nanoparticles into thermosensitive in situ gelling system of Pluronic F127 with Carbopol.

Results and discussion: The characterization of the nanoparticles and its sol-gel system performed through zeta sizer, SEM, XRD, TG-DSC, FTIR and rheology helped to optimize the formulation. The drug release could be sustained to 60% and 30% at eight hours, for the nanoparticles and their in situ gel systems, respectively, with non-Fickian diffusion mechanism of drug release. The test for % cell viability with NIH3T3 cell line revealed low level of toxicity for the nanoparticles.

Conclusion: The statistical significance obtained for the trail formulations experimentally proved its suitability for this dosage form design to achieve desired level of drug release.     

Design and evaluation of sustained release mucoadhesive film of sumatriptan succinate containing grafted co-polymer as the platform

PurposeThe primary goal of this research is to improve the bioavailability and efficacy of Sumatriptan succinate by incorporating it in the mucoadhesive film for the treatment of migraine. Mucoadhesive film offers an excellent substitute to deliver the drug in the systemic circulation and eliminate the chance of first-pass metabolism.MethodUsing central composite design (CCD), various formulations were created by incorporating polymer, plasticizer, and water, and an optimized preparation was created using statistical screening. The optimization has been performed by applying a 3⁴ factorial method based on dependent variables such as Drug content (%), Swelling index (%), Folding endurance (Number of times), and Mucoadhesive strength (g).ResultsThe actual experimental values obtained were compared with those predicted by the mathematical models. Formulation S9 was selected as an optimized formulation because it showed the lowest standard deviation between predicted and actual values compared to other formulations. In the case of the S9 formulation, approximately 77.12% of the drug was released within 24 h, but initially, it showed burst release. In addition, the in-vitro release of pure drug suspension showed 99.32% drug release within 2 h. That signified that the developed formulation provides sustained release due to presence of grafted co-polymer.ConclusionFormulation holding drug-loaded grafted film showed decent sustained and controlled drug release characteristics compared to a pure drug suspension. S9 formulation showed better results than other formulations in drug content, swelling index, folding endurance, and mucoadhesive strength, which is further used to treat migraine.     

Chitosan–sodium alginate blended polyelectrolyte complexes as potential multiparticulate carrier system: colon-targeted delivery and gamma scintigraphic imaging

Objectives: The objective of this study is to develop stable, biodegradable chitosan–sodium alginate-based dual, ionic cross-linked multiparticulate system (microbeads) of tinidazole for targeted colon delivery and sustained drug release for the treatment of amoebiasis and thereby evaluating its targeting approach through in vivo gamma scintigraphic imaging technique.

Methods: The chitosan–sodium alginate-based multiparticulate system developed was producing sustained effect by virtue of its mechanical strength using double ionotropic gelation method utilizing calcium chloride and sodium sulfate as first and second cross-linkers respectively. Prepared formulations were evaluated for percent yield, drug entrapment efficiency, particle size, degree of swelling, in vitro kinetics, and in vivo targeting potentials using gamma scintigraphic imaging technique.

Results: The obtained particulates were spherical, free flowing, and had a mean particle size ranging from 1.422 mm to 1.881 mm, whereas percent yield and percent drug entrapment efficiency was found to be in between 72.61 to 82.43% and 63.25 to 79.32% respectively.

Conclusion: The prepared multiparticulate system showed better sustained release property and in vivo ability to target colon for drug delivery. Hence, the developed multiparticulate system could be a promising device to achieve greater site-specificity to colon.