Controlled Drug Delivery Applications Research Articles

A comparative study for nanoparticle production with passive mixers via solvent-displacement: Use of CFD models for optimization and design

Active and passive mixers, including a considerable variety of micro-devices, are nowadays widely used for the production of nanoparticles. Polymer nanoparticles for controlled drug delivery applications are investigated in this work with two specific objectives. The first one is to experimentally quantify the efficiency of confined impinging jets reactors and Tee-mixers in the production of nanoparticles constituted by two polymers: poly-ɛ-caprolactone and poly(methoxypolyethyleneglycolcyanoacrylate- co-hexadecylcyanoacrylate). The second objective is the development of a simple and reliable mathematical model to be used for the design, optimization and scale up of mixers for polymer nanoparticle production. Although the behaviour of the polymers investigated is quite different, it is possible to conclude that confined impinging jets reactors are more efficient than Tee-mixers, in converting the pressure drop into turbulent kinetic energy and as a consequence in producing smaller particles. The very simple modelling approach proposed here (based on the evaluation of the mixing time) seems to be able to correlate well experimental data obtained under different operating conditions, independently on the type of device used. Moreover, in the case of poly-ɛ-caprolactone it was also possible to successfully quantify the particle formation time with a simple power law, further exploiting the model.

Characterization of a novel lyophilized chitosan hydrogel complex for the controlled release of a highly water soluble drug, niacinamide.

The purpose of this research was to prepare and characterize a novel lyophilized chitosan-based hydrogel complex (termed CS-M) for controlled drug delivery applications using a highly water soluble model drug, niacinamide. Characterization studies were undertaken to evaluate the physical-chemical properties, polymer swelling, in vitro controlled release kinetics, tissue bioadhesion, intestinal permeability and stability of the novel chitosan complex. Additionally, a comparative analysis was conducted with commercial polymers namely, Carbopol 974P-NF® and hydroxypropyl methylcellulose (HPMC K4M). FT–IR and 1H NMR studies confirmed that despite alteration in physical structure and morphology of the chitosan complex the chemical properties remained unchanged, when compared to the parent chitosan compound. Polymer swelling studies showed consistency in the structural integrity and water uptake of CS-M compared to other polymers which showed inconsistent swelling and disintegration behavior over a 5 h period. In vitro controlled release profiles of CS-M showed a slower, more controlled release rate of niacinamide than other polymers indicating the influence of polymer swelling capacity on water uptake and subsequent drug release. CS-M demonstrated an overall increase in bioadhesion to intestinal tissue when compared to commercial polymers at same concentrations. Similarly, drug transport through everted sac intestinal tissue showed enhanced absorption properties of CS-M when compared to other polymers. Finally, a 3 month accelerated stability study showed all polymers including CS-M to be stable when formulated with niacinamide. Overall, the modified chitosan-based hydrogel polymer, CS-M, demonstrated enhanced characteristics indicating its potential to be used as a controlled release excipient in oral drug formulations. Keywords: Chitosan hydrogel complex, controlled drug delivery, niacinamide, lyophilization, Carbopol 974P-NF, HPMC K4M

Templated-assisted one-dimensional silica nanotubes: synthesis and applications

Silica (SiO2) is one of the most frequently used inorganic materials. This review covers the research progress in the synthesis of one-dimensional silica nanotubes as well as the newest aspects of silica nanotubes in applications where their structural attributes are exploited. The synthetic methods for well-defined silica nanotubes and a variety of specific silica nanotubes including hollow silica nanotubes, mesoporous silica nanotubes, chiral or helical silica nanotubes are summarized. One-dimensional tubular silica nanomaterials display structures that differ from those of other kinds of nanostructured silica materials and provide unique features such as very uniform diameter, open at both ends. In addition, sol–gel process and silane chemistry offer the reliable and robust surface modification or functionalization of silica nanotubes. Attractively, end functionalization of silica nanotubes may be able to control drug release, resulting in their wide applications in controlled drug and gene delivery; also their distinctive inner and outer surfaces can be differentially functionalized making silica nanotubes ideal multifunctional nanostructure candidates for biomedical applications in various areas such as biosensing, bioseparation and biocatalysis.

Thermo- and pH-responsive HPC- g-AA/AA hydrogels for controlled drug delivery applications

This paper describes smart hydrogels composed of pH-sensitive poly(acrylic acid) (PAA) and biodegradable temperature-sensitive hydroxypropylcellulose- g-acrylic acid (HPC- g-AA) for controlled drug delivery applications. In a pH-responsive manner, the hydrogels with the higher HPC- g-AA content resulted in the lower equilibrium swelling. Although temperature had little influence on the swelling of the hydrogels, optical transmittance of the hydrogels was changed as a function of temperature, which reflecting that the HPC parts of hydrogel became hydrophobic at temperature above the lower critical solution temperature (LCST). Scanning electron microscopic analysis revealed that the pore size and the morphology of the hydrogels could be controlled by changing the composition of AA and the crosslinking density. Using BSA as a model drug, in vitro drug release experiment was carried out in artificial gastric juice (pH = 1.2) for the first 2 h and then in artificial intestinal liquid (pH = 6.8) for the subsequent 6 h. The release profiles indicated that both HPC- g-AA and AA contents played important roles in the drug release behaviors. The temperature- and pH-responsive HPC- g-AA/AA hydrogels might be exploited for wide applications in controlled drug delivery.

Novel poly (diol-co-tricarballylate) biodegradable elastomers. What makes them excellent carriers for controlled drug delivery and tissue engineering applications?

Abstract In the past decade, biodegradable elastomeric polymers have gained considerable attention due to the renewed interest in their applications in the fields of biomedical tissue engineering and implantable drug delivery systems. Elastomers can be regarded as one of the best biomaterials for such applications because their mechanical properties can be manipulated in a manner that makes them as soft as body tissues, they have the ability to recover and withstand the mechanical challenges upon implantation in a mobile part of the body and they have also proven to be well suited to drug controlled drug delivery applications. Our lab has recently reported on the successful preparation and characterization of a novel family of poly (diol-co-tricarballylate) elastomers, using visible light photo initiated polymerization. This new patented family of elastomers possess many structural, mechanical and physicochemical properties that make them superior to the currently available biodegradable elastomers. The purpose of this presentation is to shed light on the preparation, characterization and in vivo animal biocompatibility studies conducted on these new elastomers. In addition, a short illustration on their application in controlled drug delivery and tissue engineering and the current and future scope of work planned utilizing the latest Qatar National Research Fund – National Priorities Research Program 3rd cycle support received will also to be presented.

Entrapment and release of drugs by a strict “on-off” mechanism in pullulan microspheres with pendant thermosensitive groups

Here, we report a new method to predict the appropriate size of drugs which can be entrapped in and released from a hydrogel with pendant thermosensitive units by a strict “on-off” mechanism. Moreover, the valve-type action of the thermosensitive arms has been investigated. Inverse size exclusion chromatography (ISEC) and environmental scanning electron microscopy (ESEM) have been used to characterize the extension and collapse of the pendant thermosensitive units, below and above the lower critical solution temperature (LCST) under physiological conditions, confirming the hypothesis postulated by the “arid” theoretical models.The functionalized pullulan (Pul) microspheres, here prepared, were coupled with thermoresponsive oligomers by reaction between the –NH2 end-group of oligomers and chlorine present on Pul microspheres. The Pul microspheres with temperature sensitive moieties were packed in a glass column and the elution volume of standard molecule with well-known molecular weights (radius of gyration) was determined below and above the LCST. FITC-Dextran 4000 diffused through the pores of Pul microspheres with short thermosensitive arms (Mw = 1500 g/mol) both below and above the LCST of the thermosensitive units. In contrast, Pul microspheres with long thermosensitive arms (Mw = 3300 g/mol) allowed the diffusion of FITC-Dextran 4000 only above the LCST of the thermosensitive units. Indeed, the long thermosensitive arms are extended below the LCST and FITC-Dextran 4000 is completely excluded from the pores. The loading/release profile of this model molecule follows an “on-off” mechanism, confirming the results obtained by ISEC. ESEM was used as a new technique, taking images of the surface of the thermosensitive pullulan microspheres in their natural swollen state, with no prior specimen preparation, below and above the LCST. The low toxicity of pullulan microspheres observed below and above the LCST of thermosensitive units at high concentrations (10 mg/ml) recommends their potential use for controlled drug delivery applications.

Facile synthesis of polyester-PEG triblock copolymers and preparation of amphiphilic nanoparticles as drug carriers

Novel amphiphilic triblock copolymers of poly(propylene succinate) (PPSu) and poly(ethylene glycol) (PEG) with different hydrophobic/hydrophilic ratios were synthesized using a facile one-pot procedure. The molecular weight of the copolymers was adjusted by varying the molecular weight of PPSu while keeping that of PEG constant. The copolymers exhibited glass transition temperatures between − 36.0 and − 38 °C and single melting points around 44 °C. WAXD data indicated that both blocks of the copolymers could crystallize. The mPEG–PPSu copolymers exhibited low in vitro toxicity against HUVEC cells. The synthesized copolymers were used to prepare core–shell nanoparticles with hydrophobic PPSu and hydrophilic PEG forming the core and shell, respectively. The drug loading efficiency and drug release properties of the mPEG–PPSu nanoparticles were investigated using two model drugs: the hydrophilic Ropinirole and the hydrophobic Tibolone. The mean size of the drug-loaded mPEG–PPSu nanoparticles ranged between 150 and 300 nm and increased with the molecular weight of the PPSu block. The drug loading efficiency of the nanoparticles was found to be dependent upon drug hydrophilicity and was much higher for the hydrophobic Tibolone. Drug release characteristics also depended on drug hydrophilicity: the hydrophilic Ropinirole was released at a much higher rate than the hydrophobic Tibolone. Contrary to Ropinirole, the profiles of Tibolone exhibited an early phase of burst release followed by a phase of slow release. By varying the composition (mPEG/PPSu ratio) of mPEG–PPSU copolymers, nanoparticles of different sizes and drug loading capacities can be synthesized exhibiting different drug release characteristics. Based on the results obtained, the proposed mPEG–PPSu copolymers can be useful in various controlled drug delivery applications, especially those involving relatively hydrophobic drugs.

Application of nanogel systems in the administration of local anesthetics

Nanogels are robust nanoparticles that could be used to deliver active drug compounds in controlled drug delivery applications. This review discusses the design, synthesis, loading, and release of local anesthetics using polymeric nanoparticles produced via various types of polymerization techniques. The strategy of using layer-by-layer approach to control the burst release of procaine hydrochloride (PrHy; a local anesthetic drug of the amino ester group) is described and discussed.

Formulation and Characterization of Novel Temperature Sensitive Polymer-Coated Magnetic Nanoparticles

The objective of this research was to develop novel polymer coated magnetic nanoparticles for controlled drug delivery applications. To form these novel nanoparticles, silane-coated magnetic nanoparticles (MNPs) were used as a template for a free radial polymerization of three monomers, N-isopropylacrylamide, acrylamide, and allylamine (NIPA-AAm-AH), on the surface of MNPs. Transmission electron microscope results indicated that the size of the NIPA-AAm-AH coated MNPs was approximately 100 nm. To investigate the chemical composition and chemical state of our nanoparticles, FTIR and XPS were used. Results from chemical analysis illustrated the presence of the constituent functional groups of the NIPA-AAm-AH coated MNPs. In addition, the magnetic properties of different layers on the MNPs, analyzed by SQUID, indicated a decrease in saturation magnetization after each layer of coating. The nanoparticles were successfully conjugated to fluorescent PEG to prolong their circulating half life. Furthermore, bovine serum albumin (BSA) was used in order to investigate the protein release profile of the nanoparticles as a function of the temperature. The protein release profile indicated that the NIPA-AAm-AH coated MNPs have a significantly higher percent release at 41 degrees C compared to those of 4 degrees C and 37 degrees C, which demonstrates their temperature sensitivity. In the future, the release profile of therapeutic drugs from nanoparticles at various temperatures and pHs as well as targeted capability of the synthesized nanoparticles for possible applications in controlled and targeted delivery will be investigated.

Synthesis and characterization of thermoresponsive poly(ethylene glycol)‐based hydrogels and their magnetic nanocomposites

AbstractTemperature‐responsive hydrogels are one of the most widely studied types of stimuli‐responsive hydrogel systems. Their ability to transition between their swollen and collapsed states makes them attractive for controlled drug delivery, microfluidic devices, and biosensor applications. Recent work has shown that poly(ethylene glycol) (PEG) methacrylate polymers are temperature‐responsive and exhibit a wide range of lower critical solution temperatures based on the length of ethylene glycol units in the macromer chain. The addition of iron oxide nanoparticles into the hydrogel matrix can provide the ability to remotely heat the gels upon exposure to an alternating magnetic field (AMF). In this work, diethylene glycol (n = 2) methyl ether methacrylate and PEG (n = 4.5) methyl ether methacrylate copolymers were polymerized into hydrogels with 5 mol % PEG 600 (n = 13.6) dimethacrylate as the crosslinker along with 5 wt % iron oxide nanoparticles. Volumetric swelling studies were completed from 22 to 80 °C and confirmed the temperature‐responsive nature of the hydrogel systems. The ability of the gels to collapse in response to rapid temperature changes when exposed to an AMF was demonstrated showing their potential use in biomedical applications such as controlled drug delivery and hyperthermia therapy. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3229–3235, 2010

APPLICATIONS OF ELECTROSPINNING TECHNIQUE IN DRUG DELIVERY

Electrospinning has proven to be a simple, versatile, and useful technique for fabricating nanofibers from a rich variety of functional materials. In the past few years, we have witnessed tremendous research progress in understanding electrospinning mechanisms and their applications in controlled drug releasing and delivery. In this review, a brief description of the electrospinning process and fiber formation mechanisms is first provided. Then, a detailed review and discussion are given of the creation of secondary structures on electrospun fibers, such as porous and core-shell or hollow fiber structures. Finally, the drug-loading methods and drug release control mechanisms for drug-loaded electrospun fibers are summarized and discussed.

Novel sol-gel organic-inorganic hybrid materials for drug delivery.

The aim of the present study was to synthetize and characterize novel sol-gel organic-inorganic hybrid materials to be used for controlled drug delivery application. Organic-inorganic hybrid class I materials based on poly(epsilon-caprolactone) (PCL 6, 12, 24 and 50 wt%) and zirconia-yttria (ZrO2-5%Y2O3) were synthesized by a sol-gel method, from a multicomponent solution containing zirconium propoxide [Zr(OC2H7)4], yttrium chloride (YCl3), PCL, water and chloroform (CHCl3). The structure of the hybrids was obtained by means of hydrogen bonds between the Zr-OH group (H-donor) in the sol-gel intermediate species and the carboxylic group (H-acceptor) in the repeating units of the polymer. The presence of hydrogen bonds between organic-inorganic components of the hybrid materials was suggested by Fourier transform infrared (FTIR) analysis, and strongly supported by solid-state NMR. A single-step, sol-gel process was then used to precipitate microspheres containing ketoprofen or indomethacin for controlled drug delivery applications. Release kinetics in a simulated body fluid (SBF) were subsequently investigated. The amount of drug released was detected by UV-VIS spectroscopy. Pure anti-inflammatory agents exhibited linear release with time, in contrast drugs entrapped in the organic-inorganic hybrids were released with a logarithmic time dependence, starting with an initial burst effect followed by a gradual decrease. The synthesis of amorphous materials containing drugs, obtained by sol-gel methods, helps to devise new strategies for controlled drug delivery system design.

Micellization and sustained drug release behavior of EC-g-PPEGMA amphiphilic copolymers

abstract The micellization and sustained drug release behavior of ethyl cellulose graft poly(poly(ethylene glycol)methyl ether methacrylate) (EC-g-PPEGMA) copolymers with well-defined structure were investigatedbyusingpyreneasthefluorescentprobeandmodeldrug.ItwasfoundthattheEC-g-PPEGMAcopolymershave a low critical micelle concentration (CMC) at about 5×10 −4 mg/mL. Drug loading experimentsindicate that a low graft density of the copolymers corresponds to a higher drug loading efficiency anda higher loading capacity of drug in the micelles. The release rate of the loaded pyrene depends on boththe length of the side chains and the loading capacity of pryene in the micelles. A shorter side chain ofthe copolymer and a higher ratio of the copolymer to the pyrene in the micelles correspond to a lowerrelease rate. The self-assembly system shows a potential application in controlled drug delivery.© 2010 Elsevier Ltd. All rights reserved. 1. IntroductionCellulose is the most abundant renewable biomacromoleculein nature. Cellulose and its derivatives have the advantagesof nontoxicity, biocompatibility, and biodegradability, and havebeen widely used in the fields of composites (CancheEscamilla,RodriguezTrujillo,HerreraFranco,Mendizabal,PHebeish,Waly,Abdel-Mohdy,ASrivastavaBWaly,Abdel-Mohdy,Aly, & Hebeish, 1998), drilling-mud additives (Zhang, Tan, & Li,1999), microfiltration membranes (Rajam & Ho, 2006), separation(Yu, Fu, Zhao, Liu, & He, 2006), absorbent resins (Pourjavadi &Mahdavinia, 2005), flocculants (Biswal & Singh, 2006), solid–solidphase change materials (Li, Liu, & Huang, 2008), and drug delivery(Dong et al., 2008).The micelle formation, as well as their application in the fieldsof medicine and biology has been investigated extensively in the

Advances and potential applications of chitosan derivatives as mucoadhesive biomaterials in modern drug delivery

Pharmaceutical technologists have been working extensively on various mucoadhesive polymeric systems to create an intimate and prolonged contact at the site of administration. Chitosan is one of the most promising polymers because of its non-toxic, polycationic biocompatible, biodegradable nature, and particularly due to its mucoadhesive and permeation enhancing properties. Due to its potential importance in controlled drug delivery applications, pharmaceutical scientists have exploited this mucoadhesive polymer. However, chitosan suffers from limited solubility at physiological pH and causes presystemic metabolism of drugs in intestinal and gastric fluids in the presence of proteolytic enzymes. These inherent drawbacks of chitosan have been overcome by forming derivatives such as carboxylated, various conjugates, thiolated, and acylated chitosan, thus providing a platform for sustained release formulations at a controlled rate, prolonged residence time, improved patient compliance by reducing dosing frequency, enhanced bioavailability and a significant improvement in therapeutic efficacy. We have explored the potential benefits of these improved chitosan derivatives in modern drug delivery.

Synthesis of poly(N-isopropylacrylamide)/poly(ethyl-2-cyanoacrylate) composite hollow particles

Recently, synthesis of hollow particles has received great interest due to their potential applications in controlled drug delivery, cosmetics, paint, electronic inks, heterogeneous catalytic or enzymatic reactions. In most cases, however, the syntheses include sacrificial templates and subsequent delicate removal steps, and which leads to detrimental effects such as, uses of toxic solvents, high impurities, and collapsed shell morphology. In order to resolve such drawbacks, several techniques have been developed. Among the techniques, the Shirasu Porous Glass (SPG) membrane emulsification seems not new but promising due to versatility in material selection, morphology control, energy cost, and mass productions. Herein, we aimed to fabricate monodisperse composite hollow particles of poly(N-isopropylacrylamide)/poly(ethyl-2cyanoacrylate) (namely, poly(NIPAAm)/ poly(E2CA)) by using SPG emulsification, ionic, and photo-polymerization techniques. Poly(NIPAAm) is well known biocompatible polymer exhibiting volume phase transition temperature (VPTT) near lower critical solution temperature (LCST) around 35 C. Poly(E2CA), known as one of ‘instant’ adhesive family, is both biocompatible and biodegradable. In this work, we found that shell morphology of the composite hollow particles was changed from semi-interpenetrating network (semi-IPN) to double shell structure depending on the mass ratio of NIPAAm and E2CA monomers.

Biomimetic and Smart Polymeric Surfaces for Biomedical and Biotechnological Applications

Surfaces and biointerfaces are recurrent when materials are used in bio-related applications. Bio-inspired concepts have been implemented in this field and gained increasing interest. In this context, stimuli-responsive surfaces have found applicability in a variety of subjects, including switchable surfaces to control protein immobilization or cell adhesion, porous membranes for controlled drug delivery applications, substrates and scaffolds for tissue engineering applications, biosensors, or membranes for bioseparation. Moreover, self-assembly strategies and hierarchical structures often found in Nature could inspire scientist and engineers to propose new solutions in the design and fabrication of surfaces with special features, such as wettability within extreme ranges, improved adhesion, optical and mechanical properties and specific bioactivity. In this work some aspects related to the use of stimuli-responsive and biomimetic surfaces in the field of biomedicine and biotechnology are highlighted and some examples are presented.

Spontaneous formation of temperature-responsive assemblies by molecular recognition of a β-cyclodextrin-containing block copolymer and poly(N-isopropylacrylamide)

We report the construction of novel temperature-responsive assemblies based on a double hydrophilic block copolymer (consisting of a PEG block and a β-cyclodextrin-containing block, PEG-b-PCD) and poly(N-isopropylacrylamide) (PNIPAm). Thus formed nano-assemblies exhibit a spherical morphology and have a temperature-responsive loose core. The driving force for the formation of these assemblies was found to be the inclusion complexation interaction between the hydrophobic cavity of β-cyclodextrin and the isopropyl group of PNIPAm. The particle size of these assemblies changed reversibly in response to the external temperature change. The particle size also changed with the PNIPAm/PEG-b-PCD weight ratio. A model hydrophobic drug (indomethacin) was loaded into these assemblies with a high efficiency. An in vitro release study showed that the payload could be released in a sustained manner after an initial burst release. The release rate could be switched between high and low in an ON/OFF fashion by temperature. These results demonstrate that the nano-assemblies have high potential for applications in controlled drug delivery and biomedicine when temperature responsiveness is desired.

Controlled drug release applications of the inclusion complex of peracetylated- β-cyclodextrin and water-soluble drugs formed in supercritical carbon dioxide

Supercritical carbon dioxide (scCO 2) processing was performed with mixtures of CO 2-soluble peracetylated- β-cyclodextrin (PAc- β-CD) heptakis(2,3,6-tri-O-acetyl)- β-cyclodextrin, and highly water-soluble drug molsidomine (MOL) to prepare inclusion complexes of MOL and PAc- β-CD. The MOL/PAc- β-CD inclusion complex was confirmed by differential scanning calorimetry, X-ray diffractometry, and 1H NMR analyses. The complexes were further investigated for their potential use in controlled drug delivery applications. The in-vitro release of MOL from the peanut oil suspensions into aqueous phase was found to be significantly retarded by the complexation with PAc- β-CD, mainly due to the hydrophobic properties associated with the PAc- β-CD.

Novel modified starch–xanthan gum hydrogels for controlled drug delivery: Synthesis and characterization

This work was intended to develop a new cross-linked gelatinized starch–xanthan gum hydrogel system, to characterize the properties of the new material, and to explore its potential applications in controlled drug delivery. Cross-linked starch–xanthan gum polymers were synthesized with varying levels of xanthan gum and sodium trimetaphosphate (STMP). The reaction of starch–xanthan gum polymers with STMP was examined using solid 31P NMR spectroscopy and FTIR. Morphology of the films made from the new polymers was studied by scanning electron microscopy. The swelling properties and the network parameters such as gel mesh size of the films were investigated. The permeation of solutes with various molecular weights and charges across the films was determined. 31P NMR and FTIR spectra showed that both starch and xanthan gum were reacted with STMP. The swelling ratio of the films was higher at higher STMP and xanthan gum levels. The gel mesh size increased with increasing swelling ratio varying from 2.84 to 6.74 nm. Permeability of anionic drugs across the polymeric films was significantly lower than their neutral form due mainly to the electrostatic repulsion between the negatively charged drugs and the polymer. The results suggest that the new cross-linked starch–xanthan gum hydrogels can be potentially used as a film-forming material in controlled release formulations.

Dual‐Responsive Supramolecular Hydrogels from Water‐Soluble PEG‐Grafted Copolymers and Cyclodextrin

Novel temperature and pH dual-responsive hydrogels were constructed by inclusion of poly(PEGMA)-co-poly(DMA) with alpha-cyclodextrin in aqueous solution. The temperature- or pH-induced sol/gel transition in the hydrogels was completely reversible. Studies on structure/property relationships show that chain uniformity, graft density and copolymer concentration affect the hydrogel behavior. A dual-responsive mechanism is proposed. The in vitro release of a model drug from this hydrogel was studied. It was found that the release kinetics were greatly accelerated at higher temperature and at acidic pH conditions, indicating potential applications in controlled drug delivery.