Investigation of Need of Natural Bioenhancer for a Metabolism Susceptible Drug—Raloxifene,in a Designed Self-Emulsifying Drug Delivery System

Bioenhancers can increase the bioavailability of metabolism susceptible drugs. The present study was designed to understand the impact of bioenhancer on permeability and bioavailability of a biopharmaceutical drug disposition classification system (BDDCS) class II drug raloxifene (RLX). RLX undergoes extensive first pass metabolism by UGT enzymes in gastrointestinal tract (GIT) and has an oral bioavailability of about 2%. Self-emulsifying drug delivery system (SEDDS) of RLX was developed using a designed approach and this formulation was loaded with reported bioenhancers: quercetin and piperine. These formulations were tested for improvement in permeability and bioavailability of the RLX. The apparent permeability using everted gut sac (P _app) for SEDDS (5.26?±?1.10?×?10^?8 cm/s) was found to be similar to that of SEDDS with bioenhancers (5.11?±?1.05?×?10^?8 cm/s). In oral bioavailability study in rat, SEDDS demonstrated a 4-fold and 2.5-fold higher AUC_0–∞ than RLX suspension (control) and marketed product, respectively. No additional improvement in permeability and bioavailability was offered by inclusion of piperine and quercetin (bioenhancers) in the SEDDS.     

Porous Inorganic Drug Delivery Systems—a Review

Innovative methods and materials have been developed to overcome limitations associated with current drug delivery systems. Significant developments have led to the use of a variety of materials (as excipients) such as inorganic and metallic structures, marking a transition from conventional polymers. Inorganic materials, especially those possessing significant porosity, are emerging as good candidates for the delivery of a range of drugs (antibiotics, anticancer and anti-inflammatories), providing several advantages in formulation and engineering (encapsulation of drug in amorphous form, controlled delivery and improved targeting). This review focuses on key selected developments in porous drug delivery systems. The review provides a short broad overview of porous polymeric materials for drug delivery before focusing on porous inorganic materials (e.g. Santa Barbara Amorphous (SBA) and Mobil Composition of Matter (MCM)) and their utilisation in drug dosage form development. Methods for their preparation and drug loading thereafter are detailed. Several examples of porous inorganic materials, drugs used and outcomes are discussed providing the reader with an understanding of advances in the field and realistic opportunities.     

α-Acetal, ω-Alkyne Poly(ethylene oxide) as a Versatile Building Block for the Synthesis of Glycoconjugated Graft-Copolymers Suited for Targeted Drug Delivery

α-Acetal, ω-alkyne poly(ethylene oxide) was synthesized as building block of glycoconjugated poly(ε-caprolactone)-graft-poly(ethylene oxide) (PCL-g-PEO) copolymers. The alkyne group is indeed instrumental for the PEGylation of a poly(α-azido-ε-caprolactone-co-ε-caprolactone) copolymer by the Huisgen's 1,3 dipolar cycloaddition, i.e., a click reaction. Moreover, deprotection of the acetal end-group of the hydrophilic PEO grafts followed by reductive amination of the accordingly formed aldehyde with an aminated sugar is a valuable strategy of glycoconjugation of the graft copolymer, whose micelles are then potential. A model molecule (fluoresceinamine) was first considered in order to optimize the experimental conditions for the reductive amination. These conditions were then extended to the decoration of the graft copolymer micelles with mannose, which is a targeting agent of dendritic cells and macrophages. The bioavailability of the sugar units at the surface of micelles was investigated by surface plasmon resonance (SPR). The same question was addressed to nanoparticles stabilized by the graft copolymer. Enzyme linked lectin assay (ELLA) confirmed the availability of mannose at the nanoparticle surface.     

Chitosan–Chondroitin Sulfate Based Matrix Tablets for Colon Specific Delivery of Indomethacin

The different approaches for targeting orally administered drugs to the colon include coating with pH-dependent polymers, design of time-release dosage forms, and the utilization of carriers that are degraded exclusively by colonic bacteria. The aim of the present study was to develop a single unit, site-specific drug formulation allowing targeted drug release in the colon. Matrix tablets were prepared by wet granulation using cross-linked chitosan (ChI) and chondroitin sulfate (ChS) polysaccharides as binder and carrier. ChS was used to form polyelectrolyte complexes (PEC) with ChI, and its potential as a colon-targeted drug carrier was investigated. Indomethacin was used as a model drug. The ChI and ChS PEC was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffraction studies (XRD). The matrix tablets were tested in vitro for their suitability as colon-specific drug delivery systems. FTIR demonstrated that the PEC forms through an electrostatic interaction between the protonated amine (NH₃⁺) group of ChI with the free carboxylate (COO⁻) group and sulfate (SO₄²⁻) group of ChS. DSC and XRD indicated that the PEC has different thermal characteristics from ChI or ChS. The dissolution data demonstrates that the dissolution rate of the tablet is dependent upon the concentration of polysaccharide used as binder and matrix and time of cross-linking. The study confirmed that selective delivery of indomethacin to the colon can be achieved using cross-linked ChI and ChS polysaccharides.     

Melt-Extruded Eudragit® FS-Based Granules for Colonic Drug Delivery

The purpose of this study is to characterize the properties of Eudragit® FS-based granules prepared using melt extrusion process for colonic drug delivery. 5-Aminosalicylic acid (5-ASA), theophylline, and diclofenac sodium were used as the model compounds. Drug and polymer blends were melt-extruded into thin rods using a single screw extruder. Drugs were found to be dispersed as crystalline particles in the granules. A hammer mill was used to reduce the extrudate into 16–40 mesh granules, which were mixed with lactose and filled into hard gelatin capsules. Three-stage dissolution testing performed using USP paddle method was used to simulate drug release in gastrointestinal tract. In this study, melt extrusion has been demonstrated to be a suitable process to prepare granules for colonic delivery of 5-amino salicylic acid. At 30% drug loading, less than 25% 5-ASA was released from melt-extruded granules of 20–30 mesh in the first two stages (0.1 N hydrochloric acid solution and phosphate buffer pH 6.8) of the dissolution testing. All 5-ASA was released within 4 h when dissolution medium was switched to phosphate buffer pH 7.4. Drug loading, granule size, and microenvironment pH induced by the solubilized drug were identified as the key factors controlling drug release. Granules prepared with melt extrusion demonstrated lower porosity, smaller pore size, and higher physical strength than those prepared with conventional compression process. Eudragit® FS was found to be stable even when processed at 200°C.     

Transependymal Cerebrospinal Fluid Flow: Opportunity for Drug Delivery?

Drug delivery to the central nervous system (CNS) is complicated by the blood-brain barrier. As a result, many agents that are found to be potentially effective at their site of action cannot be sufficiently or effectively delivered to the CNS and therefore have been discarded and not developed further for clinical use, leaving many CNS diseases untreated. One way to overcome this obstacle is intracerebroventricular (ICV) delivery of the therapeutics directly to cerebrospinal fluid (CSF). Recent experimental and clinical findings reveal that CSF flows from the ventricles throughout the parenchyma towards the subarachnoid space also named minor CSF pathway, while earlier, it was suggested that only in pathological conditions such as hydrocephalus this form of CSF flow occurs. This transependymal flow of CSF provides a route to distribute ICV-infused drugs throughout the brain. More insight on transependymal CSF flow will direct more rational to ICV drug delivery and broaden its clinical indications in managing CNS diseases.     

Pollen as a vehicle for the escape of engineered genes?

Recent studies of pollen exchange between neighboring populations of plants have shown that interpopulation gene flow can proceed over much greater distances and at higher rates than hitherto believed. This means that the escape of engineered genes from crop plants to their wild relatives is not only possible, but also likely. The development of containment strategies, such as extra modifications for increased self-fertilization and decreased pollen longevity in engineered crop plants, will be necessary to safeguard against such escape.     

Metal–Organic Framework Composites for Theragnostics and Drug Delivery Applications

Among a plethora of nano-sized therapeutics, metal-organic frameworks (MOFs) have been some of the most investigated novel materials for, predominantly, cancer drug delivery applications. Due to their large drug uptake capacities and slow-release mechanisms, MOFs are desirable drug delivery vehicles that protect and transport sensitive drug molecules to target sites. The inclusion of other guest materials into MOFs to make MOF-composite materials has added further functionality, from externally triggered drug release to improved pharmacokinetics and diagnostic aids. MOF-composites are synthetically versatile and can include examples such as magnetic nanoparticles in MOFs for MRI image contrast and polymer coatings that improve the blood-circulation time. From synthesis to applications, this review will consider the main developments in MOF-composite chemistry for biomedical applications and demonstrate the potential of these novel agents in nanomedicine. It is concluded that, although vast synthetic progress has been made in the field, it requires now to develop more biomedical expertise with a focus on rational model selection, a major comparative toxicity study, and advanced targeting techniques.     

Synthesis of (−)‐DAPD

A new synthesis of (?)‐DAPD, suitable for large scale development, is described.     

Synthesis of D‐Altritol Nucleosides with a 3′‐O‐Tert‐Butyldimethylsilyl Protecting Group

Four D‐altritol nucleosides with a 3′‐O‐tert‐butyldimethylsilyl protecting group are synthesized (base moieties are adenine, guanine, thymine and 5‐methylcytosine). The nucleosides are obtained by ring opening reaction of 1,5:2,3‐dianhydro‐4,6‐O‐benzylidene‐D‐allitol. Optimal reaction circumstances (NaH, LiH, DBU, phase transfer, microwave irridation) for the introduction of the heterocycles are base‐specific. For the introduction of the 3′‐O‐silyl protecting group, long reaction times and several equivalents of tert‐butyldimethylsilyl chloride are needed.     

Turning a Drug Target into a Drug Candidate: A New Paradigm for Neurological Drug Discovery?

The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re-engineered to serve as a new candidate therapeutic agent. The L-glutamate-gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this exogenous, inhibitory, L-glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L-glutamate-induced hyper-excitation and toxicity. Variant GluCls, with their inhibitory responses to L-glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L-glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy.     

Synthesis and Antimicrobial Activity of a New Drug Based on a Retro-Analog of Cathelicidin—Polypeptide SE-33

Russian Journal of Bioorganic Chemistry - Polypeptide SE-33 (SETRPVLNRLFDKIRQVIRKFEKGIKEKSKRFF), which is a retro analog of natural antimicrobial protein cathelicidin LL-37...     

Micellar Delivery System for Dequalinium—A Lipophilic Cationic Drug with Anticarcinoma Activity

Abstract

Delocalized lipophilic cations (DLC) such as dequalinium (DQA) comprise a novel class of antitumor agents. They are more selectively toxic to carcinoma cells in comparison to non-transformed epithelial cells. In addition, DLC’s have also been shown to enhance the efficacy of existing anticancer modalities such as radiation and photodynamic therapies. A severe drawback of these attractive novel anticancer agents is their limited solubility in aqueous solutions. To overcome this obstacle, we tried to incorporate DQA into liposomes and micelles. We found that incorporation in liposomes does not seem to be possible at physiological salt concentrations. However, we succeeded in preparing micelles made of polyethylene glycol derivatives of phosphatidy-lethanolamine (PEG-PE) which stably bind up to 30 mol % DQA.     

Synthesis of Monomers Bearing at the 2′‐Position Cyanomethoxycarbonyl Group for Phosphoramidite Oligonucleotide Synthesis

A novel series of phosphoroamidites for the synthesis of 2′‐modified oligonucleotides was designed and synthesized on the base of 2′‐amino uridine and 2′‐amino arabinoadenosine. The amino groups in these compounds were acidified by bis‐cyanomethyl esters of different dicarbonic acids. Generated reactive linker groups containing cyanomethoxycarbonyl groups are stable under conditions of oligonucleotide synthesis but could be easily functionalised in post‐synthetic stage by treatment with compounds bearing primary amino groups.     

Cell Surface Engineering of a β-Galactosidase for Galactooligosaccharide Synthesis

A novel gene encoding transglycosylating β-galactosidase (BGase) was cloned from Penicillium expansum F3. The sequence contained a 3,036-bp open reading frame encoding a 1,011-amino-acid protein. This gene was subsequently expressed on the cell surface of Saccharomyces cerevisiae EBY-100 by galactose induction. The BGase-anchored yeast could directly utilize lactose to produce galactooligosaccharide (GOS), as well as the by-products glucose and a small quantity of galactose. The glucose was consumed by the yeast, and the galactose was used for BGase expression, thus greatly facilitating GOS synthesis. The GOS yield reached 43.64% when the recombinant yeast was cultivated in yeast nitrogen base-Casamino Acids medium containing 100 g/liter initial lactose at 25°C for 5 days. The yeast cells were harvested and recycled for the next batch of GOS synthesis. During sequential operations, both oligosaccharide synthesis and BGase expression were maintained at high levels with GOS yields of over 40%, and approximately 8 U/ml of BGase was detected in each batch.Galactooligosaccharides (GOS) are beneficial for human health as prebiotics that maintain the balance of normal flora in the intestine, enhance lactose tolerance and the digestibility of milk products, reduce serum cholesterol levels, increase Ca²⁺ absorption, synthesize B-complex vitamins, and reduce the risk of cancer (15, 18). Recently, a great deal of attention has been devoted to GOS synthesis, especially via enzymatic transglycosylation, since chemical synthesis of GOS is very tedious (16). GOS can be synthesized by β-galactosidase (BGase) from lactose by glycosyl transfer of one or more galactosyl units onto a galactose moiety of lactose or other structurally related galactosides (10). Both free and immobilized BGases from different microorganisms have been employed for GOS synthesis (12). Based on previous studies, using free enzymes has been associated with limitations, such as low stability and nonreusability of the enzymes. Using immobilized enzymes could overcome these problems, but there are still some drawbacks, including low recovery rates of enzyme activity, the gradual loss of enzyme during the reaction process, finite immobilized carriers, and large mass transfer resistance between some immobilized enzymes and substrates.Recently, an alternative strategy to conventional enzyme immobilization was proposed in which the enzyme is anchored on the cell surfaces of engineered microorganisms, such as Escherichia coli and Saccharomyces cerevisiae (8, 13). S. cerevisiae is a highly advantageous host for cell surface display, as it may allow the accurate folding and glycosylation of recombinant proteins. It is generally regarded as safe in its applications in different fields. Yeast cell surface engineering has been demonstrated using the α-agglutinin receptor of S. cerevisiae to display foreign proteins on the cell surface. There were certain advantages to using cell surface-engineered yeast as an immobilized biocatalyst, e.g., the enzyme was anchored covalently on the cell surface without enzyme loss or additional treatments for immobilization, and the mass transfer resistance between the enzyme and the substrate was sharply reduced in contrast to conventional immobilization methods (17). Several studies have successfully used engineered yeast with immobilized target enzymes as a biocatalyst for a single use, such as the cell surface engineering of a β-glucosidase from Aspergillus oryzae for isoflavone aglycone production and a chitosanase from Paenibacillus fukuinensis for chitooligosaccharide production (7, 19). However, there have been no reports of the use of engineered yeast for consecutive batch production without loss of enzyme activity during the reaction process.The objective of this work was to present a novel approach for GOS synthesis by anchoring BGase from Penicillium expansum F3 on the cell surface of S. cerevisiae as an immobilized enzyme. Figure ​Figure11 shows the main principle of this strategy. The BGase that was cell surface engineered and anchored to yeast (BGase-anchored yeast) could directly utilize lactose for GOS synthesis in batches without loss of enzyme activity. The carbon source (glucose) for cell growth and the inducer (galactose) for enzyme production were the by-products of lactose. The yield of GOS was greatly increased because of the removal of glucose and the continuous expression of BGase. The results showed that this method was especially suitable for GOS synthesis, and it has great promise for industrial oligosaccharide production in the future.Open in a separate windowFIG. 1.Schematic of GOS synthesis by BGase-anchored yeast. The BGase-anchored yeast is represented by modified ovals. The surface BGase converted lactose into GOS, glucose, and a small quantity of galactose. The undesirable glucose was consumed by the yeast for cell growth, and the galactose induced the continuous expression of BGase. Thus, BGase-anchored yeast cells were grown and successively utilized lactose to produce GOS. After a batch reaction, BGase-anchored yeast with higher BGase activity could be harvested and recycled for another batch of GOS synthesis under the same cultivation conditions as the first batch.     

Synthesis of a small library of bivalent α-D-mannopyranosides for lectin cross-linking

A small library of bivalent α-D-mannopyranosides having rigid linkers was constructed in order to evaluate the effects of inter-saccharide distances upon multivalent binding interactions with plant and bacterial lectins. To this end, iodoaryl and propargyl α-D-mannopyranosides were synthesized and the former treated with TMS-acetylene under palladium chemistry to provide their corresponding ethynylaryl derivatives. A library of 15 dimeric members was then obtained using Lewis acid catalyzed glycosidation, aryl-aryl homocoupling, transition metal catalyzed Sonogashira cross-coupling reactions, and oxidative Glaser homocoupling.     

Emulsifiers’ Composition Modulates Venous Irritation of the Nanoemulsions as a Lipophilic and Venous Irritant Drug Delivery System

In this study, a nanoemulsion (NE) system was investigated for intravenous delivery of lipophilic and venous irritant drugs. NEs were prepared to deliver diallyl trisulfide (DT) for systemic therapy of bacterial and fungal infection, egg phospholipid was chosen as the main emulsifier, and two co-emulsifiers were also incorporated, including Poloxamer 188 (P188) and Solutol HS 15 (S15). Soybean oil was used as the dispersed phases, forming stable DT NEs with small particle sizes. The venous irritation of DT NEs was evaluated by in vitro human umbilical cord endothelial cells (CRL 1730) compatibility model with the intracellular adenosine triphosphate (ATP) and guanosine triphosphate (GTP) concentrations as the indices. The intracellular ATP and GTP reduction changed with the incorporation of a variety of co-emulsifiers, which varied in a free DT concentration-dependent manner. It was deduced that the free DT concentrations of NEs containing co-emulsifiers were determined by the partition coefficient of DT between oil and surfactant buffer solution. In conclusion, NE was an appropriate delivery system for lipophilic and venous irritant drug, and optimization of the composition of emulsifiers was an effective method to alleviate the venous irritation of DT NEs.     

Synthesis,Specific Intracellular Delivery and Biological Activity of Novel Stabilized (2′-5′)(A)n Analogues

Abstract

5’ and 2’ stabilized (2′-5′)(A)_n analogues were synthesized by chemical modifications of enzymatically polymerized (2′-5′)(A)_n oligomers. They exhibit an increased antiviral activity after micro-injection in HeLa cell cytoplasm in agreement with their augmented metabolic stability. Their specific in vitro delivery to mouse leukemia cells after encapsulation in targetted liposomes leads to a transient inhibition of protein synthesis and an antiviral activity.