Selective Interactions of Zein Microspheres with Different Class of Drugs: An In Vitro and In Silico Analysis

In this study, we have evaluated the interactions of zein microspheres with different class of drugs (hydrophobic, hydrophilic, and amphiphilic) using in vitro and in silico analysis. Zein microspheres loaded with aceclofenac, metformin, and promethazine has been developed by solvent evaporation technique and analyzed for its compatibility. The physical characterization depicted the proper encapsulation of hydrophobic drug in the microspheres. The in vitro release study revealed the sustaining ability of the microspheres in the following order: hydrophobic > hydrophilic > amphiphilic. In silico analysis also confirmed the better binding affinity and greater interactions of hydrophobic drug with zein. The above results revealed that zein is more suitable for hydrophobic drugs in the development of sustained drug delivery systems using solvent evaporation technique. The study therefore envisages a scope for identifying the most suitable polymer for a sustained drug delivery system in accordance with the nature of the drug.KEY WORDS: hydrophilic drugs, hydrophobic drugs, in silico analysis, protein-drug interactions, solvent evaporation, zein microspheres     

Raman characterization and chemical imaging of biocolloidal self-assemblies, drug delivery systems, and pulmonary inhalation aerosols: A review

This review presents an introduction to Raman scattering and describes the various Raman spectroscopy, Raman microscopy, and chemical imaging techniques that have demonstrated utility in biocolloidal self-assemblies, pharmaceutical drug delivery systems, and pulmonary research applications. Recent Raman applications to pharmaceutical aerosols in the context of pulmonary inhalation aerosol delivery are discussed. The "molecular fingerprint" insight that Raman applications provide includes molecular structure, drug-carrier/excipient interactions, intramolecular and intermolecular bonding, surface structure, surface and interfacial interactions, and the functional groups involved therein. The molecular, surface, and interfacial properties that Raman characterization can provide are particularly important in respirable pharmaceutical powders, as these particles possess a higher surface-area-to-volume ratio; hence, understanding the nature of these solid surfaces can enable their manipulation and tailoring for functionality at the nanometer level for targeted pulmonary delivery and deposition. Moreover, Raman mapping of aerosols at the micro- and nanometer level of resolution is achievable with new, sophisticated, commercially available Raman microspectroscopy techniques. This noninvasive, highly versatile analytical and imaging technique exhibits vast potential for in vitro and in vivo molecular investigations of pulmonary aerosol delivery, lung deposition, and pulmonary cellular drug uptake and disposition in unfixed living pulmonary cells.     

Biologically active human GM-CSF produced in the seeds of transgenic rice plants

Rice flour is a well-known and characterized source of pharmaceutical ingredients, which are gluten-free and incorporated in many drug delivery applications such as excipient starch. To further exploit this uniqueness, the synthetic capacity of rice endosperm tissue, the basis of rice flour, was extended by genetic transformation. Recombinant human GM-CSF, a cytokine used in treating neutropenia and with other potential clinical applications, has been expressed in transgenic rice seeds using a rice glutelin promoter. Rice seeds accumulated human GM-CSF to a level of 1.3% of total soluble protein. The rice seed-produced human GM-CSF was found to be biologically active when tested using a human cell line TF-1. Use of rice as a host plant offers not only attractive features of safe production in seeds but also self-containment of foreign genes, as rice is primarily a self-pollinated crop plant. Ravinder Sardana and Anil K. Dudani contributed equally to this work.     

Effect of sodium bicarbonate as a pharmaceutical formulation excipient on the interaction of fluvastatin with membrane phospholipids

Excipients in the pharmaceutical formulation of oral drugs are notably employed to improve drug stability. However, they can affect drug absorption and bioavailability. Passive transport through intestinal cell walls is the main absorption mechanism of drugs and, thus, involves an interaction with the membrane lipids. Therefore in this work, the effect of the excipient NaHCO₃ on the interaction of the anticholesterolemic drug fluvastatin sodium (FS) with membrane phospholipids was investigated by ¹H NMR and FTIR spectroscopy. Sodium bicarbonate is often combined with fluvastatin for oral delivery to prevent its degradation. We have used model DMPC/DMPS membranes to mimic the phospholipid content of gut cell membranes. The results presented in this work show a 100% affinity of FS for the membrane phospholipids that is not modified by the presence of the excipient. However, NaHCO₃ is shown to change the interaction mechanism of the drug. According to our data, FS enters the DMPC/DMPS bilayer interface by interacting with the lipids’ polar headgroups and burying its aromatic moieties into the apolar core. Moreover, lipid segregation takes place between the anionic and zwitterionic lipids in the membranes due to a preferential interaction of FS with phosphatidylserines. The excipient counteracts this favored interaction without affecting the drug affinity and location in the bilayer. This work illustrates that preferential interactions with lipids can be involved in passive drug permeation mechanisms and gives evidence of a possible nonpassive role of certain excipients in the interaction of drugs with membrane lipids.     

Recent applications of starch derivatives in nanodrug delivery

Starch has found use in industries as diverse as food, textiles, cosmetics, plastics, adhesives, paper, and pharmaceuticals. From a pharmaceutical standpoint, starch finds its value in solid-oral dosage forms, where it has been used as a binder, diluent, and disintegrant. However, only recently has the use of starch in nanotechnology started to make significant advances in biomedical applications, including newer drug delivery techniques. There has been a considerable effort to develop biodegradable nanoparticles as effective drug delivery systems. Being cheap, non-toxic, renewable, biodegradable and compatible with many other materials for industrial applications, starch is attracting the interest of drug delivery scientists. We have put together in a short and concise format, recent applications of starch derivatives in the emerging field of nanodrug delivery with the conclusion that a lot still needs to be done.     

Application of Supercritical Anti-Solvent Technologies for the Synthesis of Delivery Systems of Bioactive Food Components

To develop edible delivery systems suitable for food applications, regulations require that solvents and ingredients are either generally recognized as safe or listed by the Food and Drug Administration as processing aids. In this work, we studied a food grade polymer-corn zein, a category of alcohol-soluble proteins, as the carrier material for microencapsulating bioactives. Zein is insoluble in aqueous solutions; zein-based delivery systems may thus maintain the integrity in aqueous food products during processing and storage. Three alcohols, i.e., ethanol, methanol, and isopropanol, with an appropriate amount of water were used to dissolve zein. A supercritical anti-solvent process was applied to synthesize micro- and nanoparticles of zein for edible delivery systems of bioactive compounds. We studied critical variables during the particle formation: polymer concentration, CO₂ flow rate, and co-solvent chemistry. Particles were produced only when mass transfer was fast enough that the co-solvent in the atomized droplets could be extracted by the reservoir CO₂ and polymers could nucleate and grow into particles. Manipulation of the above variables enabled the production of micro- and nanoparticles, which can be used as bases for microencapsulating bioactives. Our results demonstrated promising applications of the supercritical anti-solvent technology to synthesize food grade delivery systems of bioactive food ingredients that can enhance the healthfulness, safety, and quality of food products.     

Zein adsorption to hydrophilic and hydrophobic surfaces investigated by surface plasmon resonance

Zein, the prolamine of corn, has been investigated for its potential as an industrial biopolymer. In previous research, zein was plasticized with oleic acid and formed into sheets/films. Physical properties of films were affected by film structure and controlled in turn by zein-oleic acid interactions. The nature of such interactions is not well understood. Thus, protein-fatty acid interactions were investigated in this work by the use of surface plasmon resonance (SPR). Zein adsorption from 75% aqueous 2-propanol solutions, 0.05% to 0.5% w/v, onto hydrophilic and hydrophobic self-assembled monolayers (SAMs) formed by 11-mercaptoundecanoic acid and 1-octanethiol, respectively, was monitored by high time resolution SPR. Initial adsorption rate and ultimate surface coverage increased with bulk protein concentration for both surfaces. The initial slope of plotted adsorption isotherms was higher on 11-mercaptoundecanoic acid than on 1-octanethiol, indicating higher zein affinity for hydrophilic SAMs. Also, maximum adsorption values were higher for zein on hydrophilic than on hydrophobic SAMs. Flushing off loosely bound zein in the SPR cell allowed estimation of apparent monolayer values. Differences in monolayer values for hydrophobic and hydrophilic surfaces were explained in terms of zein adsorption footprint.     

Nanotechnology and pharmaceutical inhalation aerosols

Pharmaceutical inhalation aerosols have been playing a crucial role in the health and well being of millions of people throughout the world for many years. The technology's continual advancement, the ease of use and the more desirable pulmonary-rather-than-needle delivery for systemic drugs has increased the attraction for the pharmaceutical aerosol in recent years. But administration of drugs by the pulmonary route is technically challenging because oral deposition can be high, and variations in inhalation technique can affect the quantity of drug delivered to the lungs. Recent advances in nanotechnology, particularly drug delivery field have encouraged formulation scientists to expand their reach in solving tricky problems related to drug delivery. Moreover, application of nanotechnology to aerosol science has opened up a new category of pharmaceutical aerosols (collectively known as nanoenabled-aerosols) with added advantages and effectiveness. In this review, some of the latest approaches of nano-enabled aerosol drug delivery system (including nano-suspension, trojan particles, bioadhesive nanoparticles and smart particle aerosols) that can be employed successfully to overcome problems of conventional aerosol systems have been introduced.     

Amino acid composition of zein molecular components

Zein extracted from maize endosperm has been fractionated into four polypeptide chains, having the following MWs 23 000, 21 000, 13 500 and 9600. By amino acid analysis the two smaller MW chains (representing 30% of total zeins) have been found to be zein-type molecules. These two chains are thought to be responsible for zein granule formation via -S-S- bridges. Zein is also highly heterogeneous in charge, and is resolved into at least 15 components, with pI's in the pH range 5–9. As demonstrated by amino acid analysis, part of this heterogeneity is due to spot mutations in some of the genes responsible for zein synthesis.     

Chitosan-based delivery systems for curcumin: A review of pharmacodynamic and pharmacokinetic aspects

Effective drug delivery is one of the most important issues associated with the administration of therapeutic agents that have low oral bioavailability. Curcumin is an active ingredient in the turmeric plant, which has low oral bioavailability due to its poor aqueous solubility. One strategy that has been considered for enhancing the aqueous solubility, and, thus, its oral bioavailability, is the use of chitosan as a carrier for curcumin. Chitosan is a biodegradable and biocompatible polymer that is relatively water-soluble. Therefore, various studies have sought to improve the aqueous solubility of chitosan. The use of different pharmaceutical excipients and formulation strategies has the potential to improve aqueous solubility, formulation processing, and the overall delivery of hydrophobic drugs. This review focuses on various methods utilized for chitosan-based delivery of curcumin.     

The Biodegradation of Zein <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> and its Application in Implants

A unique polymer-based sustained-release implant drug delivery system was prepared by using biocompatible and biodegradable Zein as the skeleton meterial. After preparing Zein colloids, the Zein-loaded implant rods were formulated by injection molding followed by evaporating the solvent, and being coated with poly(lactic-co-glycolic) acid (PLGA) solution. Drug release kinetics was examined by using Fluorouracil (5-FU) as model drug. Nearly zero-order release was achieved for the model drugs for a period of 0–25 days when the implants were incubated in distilled water at 37°C. And then the degradation kinetics of the rods in vivo and in vitro were evaluated, which indicated that Zein could be absorbed by body and has good degradation property. The effects of different ratios of Zein/5-FU and the rods’ diameter on drug release were studied, respectively. The plasma concentration of 5-FU in the implants were determined by HPLC after implanting a single dose of the implants in rats. All data were subsequently processed by using the computer program 3P97, and the values were showed as follows: the area under the plasma concentration–time curve (AUC) value was 321.88 (μg/ml) × day, and the mean residence time (MRT) value was 23.05 days. The sustained-release implants of Zein/5-FU were successfully formulated. The uniqueness of the article is that Zein has been used as a skeleton material in implant delivery system for the first time and zero-order release kinetics has been obtained successfully.     

Effect of Hydrophilic and Lipophilic Compounds on Zein Microstructures

Zein, the prolamine of corn, contains nearly an equal amount of hydrophilic and lipophilic amino acid residues. Its tertiary structure has a regular geometry measuring 17 × 4.5 × 1.2 nm. The structure of zein allows it to function as a polymeric amphiphile. Zein had been observed to self-assemble into periodic bilayer structures and nanotubes. This work investigated the structural development of zein self-assemblies as affected by the hydrophilic–lipophilic balance (HLB) of the system. The formation of several structures, including spheres, sponge, and lamellae, were identified. Images were obtained by SEM, AFM, and FIB/SEM. The radius of curvature of the observed assemblies was affected by the HLB of the components in the system. Thus, lipophilic flavor oils increased the curvature of zein spheres producing smaller spheres. Curvature decreased in the presence of amphiphilic fatty acids forming sponges with interconnected channels. Hydrophilic compounds decreased the curvature to the point of forming smooth films. The results of this study see a future in microencapsulation and controlled release systems for flavor and bioactive compounds in the food industry.     

Oral Delivery of Lactoferrin: A Review

Lactoferrin (Lf), as a therapeutic protein drug, has attracted much interest due to its many important roles in human and animal health and development. Oral delivery offers the most convenient way for supplementing Lf. However, the bioavailability of orally administered Lf is limited by a number of barriers associated with protein absorption. During the past decade, several oral delivery systems have been developed to preserve Lf stability in order to enhance gastric residence time and improve its bioavailability. This review summarizes various pharmaceutical strategies currently under investigation including: PEGylation, absorption enhancers, enzymatic inhibitors and advanced drug carrier systems.     

Lipid-based vehicle for oral drug delivery

With an increasing number of lipophilic drugs under development, homolipids and heterolipids have gained renewed interests as excipients for oral drug delivery systems. Oral administration has many advantages for chronic drug therapy. It is relatively safe, convenient for the patient and allows self administration. This article is not intended to review the broad area of lipid-based vehicle for oral drug delivery comprehensively. The rationale behind choosing lipids materials for pharmaceutical dosage forms and their applications is discussed. It also comments on the methods for monitoring the physicochemical properties of vehicles and formulations and describes a range of pharmacopoeial excipients suitable for these purposes. The excipients selected here are pharmacopoeial in European Pharmacopoeia 4th Ed., United States Pharmacopoeia 24th Ed./National Formulary 19th Ed. and Japanese Pharmacopoeia 13th Ed. or are drafted in Pharmaeuropa and Pharmacopoeial Forum. Widening availability of lipidic excipients with specific characteristics offer flexibility of application with respect to improving the bioavailability of poorly water-soluble drugs and manipulating release profiles.     

Isolation and evaluation of a polysaccharide from Prunus amygdalus as a carrier for transbuccosal delivery of Losartan potassium

An oral buccoadhesive drug delivery system for Losartan potassium using a hydrophilic polysaccharide, isolated from Prunus amygdalaus (Badam gum), was developed and evaluated for its potential to overcome the drawbacks associated with the conventional drug therapy. The results of the study indicate that the isolated polysaccharide has good physicochemical and morphological characteristics and is suitable for use as a mucoadhesive sustain release polymer in pharmaceutical dosage forms, to alleviate the drawbacks of the conventional drug therapy of Losartan potassium.     

Heterogeneity of zein mRNA and protein in maize

Zein, the prolamine fraction of maize, is localized in the endosperm in membrane-bound structures called protein bodies, which have polyribosomes on their surfaces. These polysomes or the mRNA fraction isolated from them will direct the synthesis of zein-like proteins in vitro. The in vitro products consist primarily of two molecular weight classes but show considerable charge heterogeneity when analyzed by isoelectric focusing. Although the molecular weight classes are very similar for different inbred lines, the isoelectric focusing patterns differ.Results given here suggest that the extensive charge heterogeneity of zein proteins does not result from the presence of a large number of totally distinct mRNAs. Zein proteins synthesized in vitro fall into several families related by sequence homologies in their mRNAs. In Illinois High Protein (IHP) the major zein mRNAs can be classified into three families based on their binding to cloned complimentary DNA copies of IHP zein mRNA. Each of three other lines we have studied (W22, Oh43, and W64A) has zein mRNAs that are related to those of IHP. Among these four lines the molecular weights of the members of a given family are generally similar, but the number of members in a family and their isoelectric points differ.     

Enhancement of naringenin bioavailability by complexation with hydroxypropoyl-β-cyclodextrin

The abundant flavonoid aglycone, naringenin, which is responsible for the bitter taste in grapefruits, has been shown to possess hypolipidemic and anti-inflammatory effects both in vitro and in vivo. Recently, our group demonstrated that naringenin inhibits hepatitis C virus (HCV) production, while others demonstrated its potential in the treatment of hyperlipidemia and diabetes. However, naringenin suffers from low oral bioavailability critically limiting its clinical potential. In this study, we demonstrate that the solubility of naringenin is enhanced by complexation with β-cyclodextrin, an FDA approved excipient. Hydroxypropoyl-β-cyclodextrin (HPβCD), specifically, increased the solubility of naringenin by over 400-fold, and its transport across a Caco-2 model of the gut epithelium by 11-fold. Complexation of naringenin with HPβCD increased its plasma concentrations when fed to rats, with AUC values increasing by 7.4-fold and C(max) increasing 14.6-fold. Moreover, when the complex was administered just prior to a meal it decreased VLDL levels by 42% and increased the rate of glucose clearance by 64% compared to naringenin alone. These effects correlated with increased expression of the PPAR co-activator, PGC1α in both liver and skeletal muscle. Histology and blood chemistry analysis indicated this route of administration was not associated with damage to the intestine, kidney, or liver. These results suggest that the complexation of naringenin with HPβCD is a viable option for the oral delivery of naringenin as a therapeutic entity with applications in the treatment of dyslipidemia, diabetes, and HCV infection.