Development and characterization of different low methoxy pectin microcapsules by an emulsion–interface reaction technique

In the controlled release area, biodegradable microcapsules are one of the most useful devices to deliver materials in an effective, prolonged and safe manner. A new charged film microcapsular carrier system, using three different pectins, is described. The study utilized pectin microcapsules prepared by two encapsulation mechanisms of interfacial reaction explored through interaction of charged droplet–oil-anionic surfactant-calcium or oil-cationic surfactant with negatively charged pectin. A method for drug encapsulation was developed based on the type of pectin, surfactants and emulsification technique. Both types of surfactant, anionic sodium dodecyl sulphate (SDS) and cationic benzalkonium chloride (BzACl) promoted polymer film formation on the oil droplet surfaces, probably through cross-linking and electrostatic interaction, respectively. Microcapsules consisting of pectin as shell and hydrophobic oil as core were characterized. The resulting microcapsules were relatively small particles (d<3?µm), had high total particle number, specific surface area and drug encapsulation efficiency. They also demonstrated good stability with minimum particle aggregation. Correlation between physicochemical and drug release kinetic parameters were investigated with regard to the effect of pectin macromolecular structure and nature of surfactant used as a counterion in the manufacturing of microcapsules. The release rate of the encapsulated material (prednisolone) in three microcapsules can be controlled by manipulating the conformational flexibility of pectins in the presence of different counterions. As a result, biodegradable pectin microcapsules offer a novel approach for developing sustained release drug delivery systems that have potential for colonic drug delivery.     

pH-controlled drug loading and release from biodegradable microcapsules

Microcapsules made of biopolymers are of both scientific and technological interest and have many potential applications in medicine, including their use as controlled drug delivery devices. The present study makes use of the electrostatic interaction between polycations and polyanions to form a multilayered microcapsule shell and also to control the loading and release of charged drug molecules inside the microcapsule. Micron-sized calcium carbonate (CaCO3) particles were synthesized and integrated with chondroitin sulfate (CS) through a reaction between sodium carbonate and calcium nitrate tetrahydrate solutions suspended with CS macromolecules. Oppositely charged biopolymers were alternately deposited onto the synthesized particles using electrostatic layer-by-layer self-assembly, and glutaraldehyde was introduced to cross-link the multilayered shell structure. Microcapsules integrated with CS inside the multilayered shells were obtained after decomposition of the CaCO3 templates. The integration of a matrix (i.e., CS) permitted the subsequent selective control of drug loading and release. The CS-integrated microcapsules were loaded with a model drug, bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA), and it was shown that pH was an effective means of controlling the loading and release of FITC-BSA. Such CS-integrated microcapsules may be used for controlled localized drug delivery as biodegradable devices, which have advantages in reducing systemic side effects and increasing drug efficacy.     

beta-Estradiol biodegradable microspheres: effect of formulation parameters on encapsulation efficiency and in vitro release

The purpose of this work was to study the effect of organic solvent and surfactant type on the in vitro release behavior in general and on the burst release in particular of beta-estradiol from PLA/PLGA microspheres. Also the effect of these variables on the encapsulation efficiency was investigated. The microspheres were prepared by solvent evaporation technique using dichloromethane (DCM), ethyl acetate (EtAc), tetrahydrofuran (THF), chloroform (CHCl3) or acetone (AC) as organic solvent and polyvinyl alcohol (PVA), Tween 80, sodium lauryl sulfate (SLS) or benzalkonium chloride (BKCI) as surfactant. The obtained microspheres were tested for encapsulation efficiency and in vitro drug release using 50% methanol/buffer pH 7.4 as dissolution medium. EtAC and PVA formulations showed the highest encapsulation efficiency and the lowest burst release. These microspheres were further characterized for particle size distribution, SEM and zeta potential. The results suggested that these materials could be starting materials to prepare a beta-estradiol biodegradable controlled delivery system.     

Pectin–zein microspheres as drug delivery systems

The formation of microspheres from various pectin hydrogel complexes and corn zein in the presence of calcium and zinc ions has been studied. It is shown that the formation of microspheres and their loading capacity for a drug (piroxicam) depend on the type of biopolymers, their ratio, the sizes of the bivalent ions, and the molecular mass of the pectin. Complex formation between the two biopolymers results predominantly from bivalent metal cross-linking for low-methylated pectins and from hydrophobic interaction for high-methylated pectins. As a result, a series of microspheres have been prepared from biodegradable and biocompatible polymers and may find application as controlled-release drug delivery systems.     

Design of a pectin-based microparticle formulation using zinc ions as the cross-linking agent and glutaraldehyde as the hardening agent for colonic-specific delivery of resveratrol: In vitro and in vivo evaluations

The aim of this study was to develop a colon-specific microparticle formulation based on pectin. Resveratrol was used as a model drug due to its potential therapeutic efficacy on colitis and colon cancer. Microparticles were produced by cross-linking pectin molecules with zinc ions and with glutaraldehyde as hardening agent for pectins. Different microparticles were prepared by varying the formulation variables. Effect of these formulation variables were investigated on particle shape and size, moisture content and weight-loss during drying, encapsulation efficiency, swelling–erosion ratio, and drug release pattern of the formulated microparticles. Formulation conditions were optimized based on the in vitro drug release study. Morphology, Fourier transform infrared spectroscopy, stability, and in vivo pharmacokinetic study of the microparticles prepared at the optimized formulation conditions were performed. Microparticles were spherical with <1?mm diameter and encapsulation efficiencies of >94%. The glutaraldehyde-modified microparticles prepared at optimized formulation conditions revealed colon specific in vitro and in vivo drug release. Plasma appearance of drug was delayed for 4–5?h after their administration directly into stomach, but displayed comparable area under the curve to other controls in the experiment, indicating the potential of the developed formulation as a colon-specific drug delivery system.     

Emerging trend in nano-engineered polyelectrolyte-based surrogate carriers for delivery of bioactives

Importance of the field: In recent decades a new colloidal drug delivery system based on layer-by-layer (LbL) technology has emerged, which offers promising means of delivering bioactive agents, specifically biological macromolecules including peptides and DNA. Nano-engineered capsules specifically fabricated from biocompatible and biodegradable polyelectrolytes (PEs) can provide a better option for encapsulation of cells thereby protecting cells from immunological molecules in the body, and their selective permeability can ensure the survival of encapsulated cells.

Areas covered in this review: This review encompasses a strategic approach to fabricate nano-engineered microcapsules through meticulous selection of polyelectrolytes and core materials based on LbL technology. The content of the article provides evidence for its wide array of applications in medical therapeutics, as indicated by the quantity of research and patents in this area. Recent developments and approaches for tuning drug release, biocompatibility and cellular interaction are discussed thoroughly.

What the reader will gain: This review aims to provide an overview on the development of LbL capsules with specific orientation towards drug and macromolecular delivery and its integration with other drug delivery systems, such as liposomes.

Take home message: Selection of PEs for the fabrication of LbL microcapsules has a profound effect on stability, drug release, biocompatibility and encapsulation efficacy. The release can be easily modulated by varying different physicochemical as well as physiological conditions. Scale-up approaches for the fabrication of LbL microcapsules by means of automation must be considered to improve the possibility of application of LbL microcapsules on a large scale.     

A new family of folate-decorated and carbon nanotube-mediated drug delivery system: synthesis and drug delivery response

We describe here a new family of folate-decorated and carbon nanotube (CNT)-mediated drug delivery system that involves uniquely combining carbon nanotubes with anticancer drug (doxorubicin) for controlled drug release, which is gaining significant attention. The synthesis of nanocarrier involved attachment of doxorubicin (DOX) to CNT surface via π-π stacking interaction, followed by encapsulation of CNTs with folic acid-conjugated chitosan. The π-π stacking interaction, ascribed as a non-covalent type of functionalization, allows controlled release of drug. Furthermore, encapsulation of CNTs enhances the stability of the nanocarrier in aqueous medium because of the hydrophilicity and cationic charge of chitosan. The unique integration of drug targeting and visualization has high potential to address the current challenges in cancer therapy. Thus, it is attractive to consider the possibility of investigating a drug delivery system that combines the biodegradable chitosan and carbon nanotubes (CNTs).     

Onion phases of PEG-8 distearate

The aims of the present study were to formulate stable onion phases of the biodegradable surfactant PEG-8 Distearate (PEG8DS) and evaluate application of the onion phases in encapsulating sumatriptan succinate, a BCS class III potent antimigraine drug. Drug loaded and placebo onion phases were prepared by shearing lyotropic lamellar phases of the surfactant. Effect of drug/surfactant ratio, shear rate and shear time on particle size, and encapsulation efficiency were studied. The onion phases were characterized by polarized microscopy, small angle neutron scattering (SANS), NMR, rheology, and FTIR. Formation of onion phases of PEG8DS was confirmed by the presence of maltese crosses under a crosspolarized microscope and further by SANS studies. The onion phases revealed an increase of inter-bilayer spacing by 7 A after drug incorporation. NMR studies revealed location of drug in the aqueous phases of the multilamellar vesicles (MLVs). FTIR study revealed no interaction between drug and surfactant. Drug loaded onion phases exhibited high encapsulation efficiency ( approximately 90%) and rapid in vitro drug release (>90% in 10 min). Onion phases stored at 5 degrees C +/- 3 degrees C revealed no significant drug leakage at the end of 3 months suggesting adequate stability. Sumatriptan succinate loaded stable onion phases of PEG8DS with high entrapment efficiency and rapid drug release suggests potential application of the onion phases in drug delivery.     

Ethylcellulose microparticles: a review

Ethylcellulose (EC) based microencapsulated drug delivery systems are being extensively studied throughout the world for achieving extended drug release and protecting the core substance from degradation. The in vitro evaluation of EC microcapsules have elucidated that their particle characteristics are very useful to control drug release behavior, since these enable drugs to be released at a certain controlled release rate based on the characteristics of drug-EC linkage. This review encompasses microencapsulation techniques, core substances and other fundamentals involved in the preparation and characterization of EC microcapsules. EC microcapsules can be considered as mini-osmotic pumps. The release kinetics for EC microcapsules can be fine-tuned by altering osmolality of the dissolution medium or formulations and EC film mechanical characteristics by selecting appropriate EC molecular weights (viscosity), EC substitution grades, coating weights, and pore formers.     

Pulsatile Protein Release from Monodisperse Liquid-Core Microcapsules of Controllable Shell Thickness

Purpose

Pulsatile delivery of proteins, in which release occurs over a short time after a period of little or no release, is desirable for many applications. This paper investigates the effect of biodegradable polymer shell thickness on pulsatile protein release from biodegradable polymer microcapsules.

Methods

Using precision particle fabrication (PPF) technology, monodisperse microcapsules were fabricated encapsulating bovine serum albumin (BSA) in a liquid core surrounded by a drug-free poly(lactide-co-glycolide) (PLG) shell of uniform, controlled thickness from 14 to 19 μm.

Results

When using high molecular weight PLG (Mw 88 kDa), microparticles exhibited the desired core-shell structure with high BSA loading and encapsulation efficiency (55–65%). These particles exhibited very slow release of BSA for several weeks followed by rapid release of 80–90% of the encapsulated BSA within 7 days. Importantly, with increasing shell thickness the starting time of the pulsatile release could be controlled from 25 to 35 days.

Conclusions

Biodegradable polymer microcapsules with precisely controlled shell thickness provide pulsatile release with enhanced control of release profiles.     

Effect of alginate-pectin composition on drug release characteristics of microcapsules

Microencapsulation of model drug, acetylsalicylic acid into bio-based polymer, alginate-pectin matrix has been undertaken in this work to characterize the microcapsules based on their composition. Different proportions of the alginate-pectin solutions prepared with drug were homogenized and atomized using nitrogen gas into 1.0 M calcium chloride solution to form sol-gel microcapsules. Drug loaded microcapsules were dried using microwave energy under vacuum at low temperature. Average particle size of the microcapsules was found to be 90 micron. Scanning electron microscopy graphs and Fourier Transform Infrared Spectroscopy analysis on the microcapsules confirm the presence of drug in the polymer matrix. X-ray diffraction pattern showed that the microstructure was more like an amorphous pattern. Drug release of the microcapsules was tested in three different pH levels of 1.2, 7.4 and 8.2. Slow and controlled release of drug was observed at all the pH levels. Increase in pectin increased the drug release and also the release was more in acidic pH (1.2) as 75.6% for alginate: pectin-20:80.     

Studies on Amidated Pectins as Potential Carriers in Colonic Drug Delivery

Amidated pectins have been assessed, in-vitro, for their potential value in colonic drug delivery. The monitoring of the release of a model soluble drug, paracetamol, gives a sensitive indication of the behaviour of the pectins under simulated gastrointestinal conditions. Inclusion of calcium as a cross-linking agent increased the viscosities of amidated pectin gels to a maximum value. Further addition of calcium reduced gel viscosity and for pectin with a high extent of amidation this led to a reduction in drug release. Release was faster for pectin with less amidation in the presence of calcium; this could be related to matrix erosion. The results of the study suggest that the materials might be of value in colonic delivery either alone or in combination, possibly in the form of a coating.     

Preparation and in vitro dissolution of salbutamol sulphate microcapsules and tabletted microcapsules

Abstract

Salbutamol sulphate is a sympathomimetic amine having a rather short plasma half-life. Aiming to achieve sustained release of this drug through microencapsu-lation, the coacervation method with a 1:1 core-shell ratio was used. In vitro release rate experiments were performed on the microcapsules prepared using ethyl cellulose as the coating agent and compared to the results of intact drug, the tabletted microcapsules and a commercial tablet. The release rate of salbutamol sulphate could be controlled through microencapsulation. The time for the 50% release of the drug was 15 and 90 min for the tabletted microcapsules and microcapsules respectively. The specific surface area of the intact drug was 0.35m²/cc while it reduced to 0.06m²/cc after encapsulation.     

Preparation and characterization of methotrexate-loaded microcapsules

Abstract

Methotrexate (MTX) has toxic effect to healthy tissues. Microencapsulation coats particles with a functional coat to optimize storage stability and to modulate release. In the present study, a new MTX encapsulated microcapsules were synthesized for controlling MTX release. Controlled drug release provides releasing of efficient dose and prevent drug side effect to tissues and also protects MTX from oxygen, pH and other interactions. MTX was encapsulated through biocompatible hyaluronic acid (HA) and sodium alginate (SA) with an encapsulation system to reduce its toxicity and for controlled release. The microcapsules prepared by vibrating nozzle were cross-linked with SA, HA and calcium chloride. Nozzle diameter and MTX concentration were changed according to loaded MTX and encapsulation efficiency were determined using HPLC. For the reliability of the data, validation studies of the HPLC method were performed. The precision of the method was demonstrated using intra- and inter-day assay relative standard deviation (RSD) values which are less than 2% in all instances. For the characterization of microcapsules, particle size, drug loading and in vitro drug release studies were performed. Diameters of MTX-loaded microcapsules were acquired approximately 160, 400 and 800?µm. Surface morphology of encapsulated microcapsules were displayed with light microscope. Eighty-nine percent MTX encapsulation efficiencies were achieved. Encapsulated MTX microcapsules showed controlled release when compared to pure MTX. While powder MTX dissolved completely in 10?min in the dissolution medium, MTX release from encapsulated MTX microcapsules became 40?h in 0.1?M PBS pH 7.4, including NaCl. MTX release from MTX-loaded microcapsules was reached to 79%. Moreover, drug efficiency was examined in vitro cell culture tests. Viability of 5RP7 cells were decreased to 88.5% for 96?h. When MTX was given directly to 5RP7 cells, viability of 5RP7 cells was decreased to 49.7% for 96?h. Flow cytometry studies also showed that, MTX microcapsules induced apoptosis. The goal of this study is to provide controlled release of MTX and to reduce the toxic effect of MTX.     

Poly(D,L-lactide-co-glycolide) encapsulated poly(vinyl alcohol) hydrogel as a drug delivery system

Purpose. The efficiency of encapsulation of water-soluble drugs in biodegradable polymer is often low and occasionally these microcapsules are associated with high burst effect. The primary objective of this study is to develop a novel microencapsulation technique with high efficiency of encapsulation and low burst effect. Method. Pentamidine was used as a model drug in this study. Pentamidine/polyvinyl alcohol (PVA) hydrogel was prepared by freeze-thaw technique. Pentamidine loaded hydrogel was later microencapsulated in poly(lactide-co-glycolide) (PLGA) using solvent evaporation technique. The microcapsules were evaluated for the efficiency of encapsulation, particle size, surface morphology, thermal characteristic, and drug release. Results. Scanning Electron Microscope (SEM) studies revealed that the microcapsules were porous. The microcapsules were uniform in size and shape with the median size of the microcapsules ranging between 27 and 94 m. The samples containing 10% PLGA showed nearly three times increase in drug loading (18-53%) by increasing the hydrogel content from 0-6%. The overall drug release from the microencapsulated hydrogel, containing 3% and 6% PVA, respectively, was significantly lower than the control batches. Conclusions. The use of a crosslinked hydrogel such as PVA can significantly increase the drug loading of highly water-soluble drugs. In addition, incorporation of the PVA hydrogel significantly reduced the burst effect and overall dissolution of pentamidine.     

Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery

Considerable effort has been directed towards developing novel drug delivery systems. Microfluidics, capable of generating monodisperse single and multiple emulsion droplets, executing precise control and operations on these droplets, is a powerful tool for fabricating complex systems (microparticles, microcapsules, microgels) with uniform size, narrow size distribution and desired properties, which have great potential in drug delivery applications. This review presents an overview of the state-of-the-art multiphase flow microfluidics for the production of single emulsions or multiple emulsions for drug delivery. The review starts with a brief introduction of the approaches for making single and multiple emulsions, followed by presentation of some potential drug delivery systems (microparticles, microcapsules and microgels) fabricated in microfluidic devices using single or multiple emulsions as templates. The design principles, manufacturing processes and properties of these drug delivery systems are also discussed and compared. Furthermore, drug encapsulation and drug release (including passive and active controlled release) are provided and compared highlighting some key findings and insights. Finally, site-targeting delivery using multiphase flow microfluidics is also briefly introduced.     

Effect of surfactant on fabrication and characterization of paclitaxel-loaded polybutylcyanoacrylate nanoparticulate delivery systems

The feasibility of applying biodegradable polybutylcyanoacrylate (PBCA) nanoparticulate delivery systems (NDSs) for the controlled release of paclitaxel was investigated. Paclitaxel-loaded and unloaded PBCA-NDSs containing various surfactants (dextran 70, cholesterol, polyvinyl alcohol and lecithin) were prepared by anionic polymerization. The effects of surfactant (1% w/v), surfactant combination (1% w/v each), and surfactant concentration (0.05, 1.0 and 2.5% w/v) on PBCA-NDSs were evaluated and characterized by particle size, zeta potential, entrapment efficiency, and in-vitro paclitaxel release kinetics. The physicochemical characteristics of PBCA-NDSs incorporated with various surfactants were significantly improved compared with PBCA-NDS without any surfactant, by decreasing particle size at least 3-fold as well as by increasing the zeta potential up to 18-fold to minimize the agglomeration of nanoparticles. Moreover, PBCA-NDSs incorporated with various surfactants demonstrated higher entrapment efficiency of paclitaxel. Results from the in-vitro release kinetic studies indicated that a more controlled biphasic zero-order release pattern of paclitaxel was observed for PBCA-NDSs incorporated with various surfactants. Compared with dextran 70 and polyvinyl alcohol, the naturally occurring lipids, lecithin and cholesterol, indicated greater advantages in improving the physicochemical properties of PBCA-NDSs, in terms of smaller particle size, higher zeta potential and better drug entrapment efficiency, and better controlled release of paclitaxel, in terms of lower release rate and prolonged action from PBCA-NDSs.     

Porous biodegradable microparticles for delivery of pentamidine.

The primary objective of this study was to develop a method for the preparation of porous biodegradable controlled release formulation of poly(lactide/glycolide) (PLGA). The model drug used for this study was pentamidine. Scanning electron microscopy pictures showed that these microparticles are highly porous and spherical in shape. A comparison of particle size reveals a similar median particle size (54-68 microm) in all six batches. The particles are all smaller than 90 microm. Differential scanning calorimetry thermograms revealed that pentamidine was mostly present in the crystalline form in the microparticles and did not dissolve in PLGA. The efficiency of encapsulation of pentamidine was higher than 58% in all six batches. The amount of drug released from these microparticles was at least 12% within the first 60 min. At least 50% of the total drug was released within the first 4 h. Drug release from these microparticles continued for up to 12 h. This faster drug dissolution was due to the highly porous surface. This highly porous surface will allow large molecules to release at a much faster rate than the regular microcapsules/microspheres.     

Enhanced therapeutic effect of LK-423 in treating experimentally induced colitis in rats when administered in colon delivery microcapsules

LK-423 is a phthalimido-desmuramyl-dipeptide derivative with immunomodulating activity. In the present study the therapeutic efficacy of a colon-specific drug delivery system–LK-423 microcapsules–was examined in the 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced ulcerative colitis model in rats. The colon-specific delivery of the drug using microcapsules relies on the combination of pH (outer gastroresistant coating), time (inner retard coating of Eudragit® RS and RL) and enzyme (pectin core) controlled drug release mechanisms. The optimal in vitro dissolution profile for LK-423 delivery to the colon of rats was obtained after coating newly developed LK-423 loaded pectin cores with 20% w/w of retard coating with a Eudragit® RS/RL ratio of 8.5/1.5 and 30% w/w of enteric coating. Orally administered LK-423 microcapsules were therapeutically more beneficial in treating TNBS-induced ulcerative colitis in rats than orally or rectally administered LK-423 in the form of suspension. Clinical activity scores and colon weight to length ratio were insignificantly lower and the macroscopically estimated degree of healing was significantly greater. On the histological level, the administration of LK-423 microcapsules resulted in most physiological regeneration of intestinal mucosa, indicated by regular architecture of all mucosal tissue components, what is probably related to local drug delivery near the site of inflammation achieved using microcapsules. These results demonstrate that LK-23 colon delivery microcapsules enhance the therapeutic efficacy of the drug and therefore appear to be a useful approach for treating various inflammatory diseases in the large intestine.     

Development and in vitro evaluation of novel floating chitosan microcapsules for oral use: comparison with non-floating chitosan microspheres

Floating (F) microcapsules containing melatonin (MT) were prepared by the ionic interaction of chitosan and a negatively charged surfactant, sodium dioctyl sulfosuccinate (DOS). The DOS/chitosan complex formation was confirmed employing infrared spectroscopy, differential scanning calorimetry (DSC), solubility and X-ray diffraction analysis. The characteristics of the F microcapsules generated compared with the conventional non-floating (NF) microspheres manufactured from chitosan and sodium tripolyphosphate (TPP) were also investigated. The effect of various factors (crosslinking time, DOS and chitosan concentrations, as well as drug/polymer ratio) on microcapsule properties were evaluated. The use of DOS solution in coagulation of chitosan produced well-formed microcapsules with round hollow core and 31.2-59.74% incorporation efficiencies. Chitosan concentration and drug/polymer ratio had a remarkable effect on drug entrapment in DOS/chitosan microcapsules. The dissolution profiles of most of microcapsules showed near zero order kinetics in simulated gastric fluid (S.G.F: pH 1.2). Moreover, release of the drug from these microcapsules was greatly retarded with release lasting for several hours (t(50%) (S.G.F.): 1.75-6.7 h, depending on processing factors), compared with NF microspheres where drug release was almost instant. Most of the hollow microcapsules developed tended to float over simulated biofluids for more than 12 h. Swelling studies conducted on various drug-free formulations, clearly indicated that DOS/chitosan microcapsules showed less swelling and no dissolution in S.G.F. for more than 3 days, whereas, TPP/chitosan microspheres were markedly swollen and lost their integrity in S.G.F. within 5 h. Therefore, data obtained suggest that the F hollow microcapsules produced would be an interesting gastroretentive controlled-release delivery system for drugs.