Controlled Drug Delivery Devices Research Articles

Developments in the use of rare earth metal complexes as efficient catalysts for ring-opening polymerization of cyclic esters used in biomedical applications

AbstractBiodegradable polymers represent a class of particularly useful materials for many biomedical and pharmaceutical applications. Among these types of polyesters, poly(ε-caprolactone) and polylactides are considered very promising for controlled drug delivery devices. These polymers are mainly produced by ring-opening polymerization of their respective cyclic esters, since this method allows a strict control of the molecular parameters (molecular weight and distribution) of the obtained polymers. The most widely used catalysts for ring-opening polymerization of cyclic esters are tin- and aluminium-based organometalliccomplexes; however since the contamination of the aliphatic polyesters by potentially toxic metallic residues is particularly of concern for biomedical applications, the possibility of replacing organometallic initiators by novel less toxic or more efficient organometallic complexes has been intensively studied. Thus, in the recent years, the use of highly reactive rare earth initiators/catalysts leading to lower polymer contamination has been developed. The use of rare earth complexes is considered a valuable strategy to decrease the polyester contamination by metallic residues and represents an attractive alternative to traditional organometallic complexes.

Fabrication of graphene oxide-β-cyclodextrin nanoparticle releasing doxorubicin and topotecan for combination chemotherapy

Controlled delivery of dual chemical drugs may increase the efficiency of chemotherapy. In this work, doxorubicin (DOX) was bound to adamantanecarboxylic acid (AD-COOH) through covalent linkage to form AD-DOX, while graphene oxide (GO) was modified by ethylenediamino-β-cyclodextrin (EDA-CD) to form graphene oxide-β-cyclodextrin (GO-CD), then GO-CD was assembled with as-produced AD-DOX via host–guest interaction. In contrast to the conjugation of DOX via covalent linkage, topotecan (TPT) was loaded onto GO through π–π stacking interaction. It was found that TPT/GO-CD/AD-DOX nanoparticles synchronised the delivery of DOX and TPT, and pH value played a critical role in determining the release profiles of dual drugs. Moreover, in vitro cellular investigations proved that TPT/GO-CD/AD-DOX nanoparticles were superior to free drugs and single-drug loaded nanoparticles in inhibiting the growth of HeLa cells. As a kind of injectable biomaterials, this controlled drug delivery device offers a solution to simultaneous delivery of dual chemical drugs in cancer lesion positions. Authors expect that this platform can be exploited for controlled delivery of various drug combinations for combination chemotherapy.

Formation of silk fibroin hydrogel and evaluation of its drug release profile

ABSTRACTSilk hydrogels are interesting materials to be used as matrix in controlled drug delivery devices. However, methods to accelerate fibroin gelation and allow the drug incorporation during the hydrogel preparation are needed in literature. In this article we report the preparation of silk fibroin hydrogels with addition of several contents of ethanol, used to accelerate fibroin gelation kinetics, and we also evaluate the potential of these hydrogels to be used as matrices for drug delivery. Chemical and conformational properties did not change despite the amount of ethanol incorporated in the hydrogel. Hydrogels containing diclofenac sodium dissolved in ethanol showed a faster initial release of the drug than hydrogels with the drug dissolved in water but equilibrium was reached later. This indicates a more sustained drug delivery from hydrogels in which the model drug was dissolved in ethanol. Fibroin hydrogels confirm their promising use as biopolymeric matrices for controlled drug release. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41802.

Calcium Phosphate Nanoparticles and their Biomedical Potential

Calcium Phosphate Nanoparticles and their Biomedical Potential Nanodimensional and nanocrystalline calcium phosphates (in the form of apatites) of a biological origin are the basic inorganic building blocks of bones and teeth of mammals. The application and potential use of calcium phosphates for clinical repair of damaged bones and teeth to controlled drug delivery devices, multi-modal imaging, and bone regeneration is gaining importance. Calcium phosphate nanoparticles are rigid, biocompatible, biodegradable, bioactive, resorbable and non-immunogenic. Nanostructured calcium phosphates with various morphologies including spherical nanoparticles, plate-like nanocrystals, nano-needles, whiskers/ fibers/wires, mesoporous, nanotubes, nano-blades, and powders with three-dimensional structures have been synthesized by various methods including mechanochemical synthesis, reverse microemulsion, hydrothermal approach, co-precipitation, spraydrying technique, in-situ deposition technique, wet chemical precipitation, gas phase ablation and biomimetic coating. Nanostructured calcium phosphates are promising biomaterials for applications in biomedical areas, such as tissue engineering scaffolds, drug/gene delivery systems, vaccine adjuvants, contrast agents for imaging and multi-modal imaging, nanosystems for photodynamic therapy and antifungal/antibacterial agents.

Pharmacokinetics of intravitreal antibiotics in endophthalmitis.

Intravitreal antibiotics are the mainstay of treatment in the management of infectious endophthalmitis. Basic knowledge of the commonly used intravitreal antibiotics, which includes their pharmacokinetics, half-life, duration of action and clearance, is essential for elimination of intraocular infection without any iatrogenic adverse effect to the ocular tissue. Various drugs have been studied over the past century to achieve this goal. We performed a comprehensive review of the antibiotics which have been used for intravitreal route and the pharmacokinetic factors influencing the drug delivery and safety profile of these antibiotics. Using online resources like PubMed and Google Scholar, articles were reviewed. The articles were confined to the English language only. We present a broad overview of pharmacokinetic concepts fundamental for use of intravitreal antibiotics in endophthalmitis along with a tabulated compendium of the intravitreal antibiotics using available literature. Recent advances for increasing bioavailability of antibiotics to the posterior segment with the development of controlled drug delivery devices are also described.

Synthesis ofGum tragacanthand acrylic acid based hydrogel: its evaluation for controlled release of antiulcerative drug pantoprazole sodium

In this work, natural polymer was used as matrix for preparing hydrogel to improve the performance of the material in biomedical sector. Gum tragacanth and acrylic acid [Gt-cl-poly(AA)] based hydrogel was prepared by graft copolymerization of natural Gum tragacanth with acrylic acid using ascorbic acid–potassium persulfate as an initiator and glutaraldehyde as cross-linker. Synthesized hydrogel was evaluated as a device for colon-specific controlled drug delivery. The results indicated that higher drug release was found at pH 9.2 followed by pH 7.0 and 2.0. Non-Fickian diffusion mechanism was exhibited at pH 9.2 and Case II diffusion mechanism was found in the case of pH 2.0 and 7.0.

Immunosuppressive agent leflunomide: A SWNTs-immobilized dihydroortate dehydrogenase inhibitory effect and computational study of its adsorption properties on zigzag single walled (6, 0) carbon and boron nitride nanotubes as controlled drug delivery devices

Leflunomide [HWA 486 or RS-34821, 5-methyl-N-(4trifluoromethylphenyl)-4-isoxazole carboximide] is an immunosuppressive agent effective in the treatment of rheumatoid arthritis. Dihydroortate dehydrogenase (DHODH, EC 1.3.3.1) immobilization on the nanotubes was carried out and biochemical characterization of free and immobilized enzyme was determined. In comparison with free enzyme, the immobilized DHODH showed improved stability and reusability for investigation of inhibition pattern of drugs such as leflunomide. The experimental data showed that, DHODH was inhibited by the active metabolite of leflunomide (RS-61980) with a Ki and KI of 0.82 and 0.06mM, respectively. Results exhibited mixed-type inhibition kinetics towards dihydroorotate as a substrate in the free and immobilized enzyme. Furthermore, the behavior of anticancer drug leflunomide adsorbed on the external surface of zigzag single walled (6,0) carbon and boron nitride nanotubes (SWCNT and SWBNNT) was studied by means of DFT calculations at the B3LYP/6-31G* level of theory. The larger adsorption energies and charges transfer showed that the adsorption of leflunomide onto SWBNNT is more stable than that the adsorption of leflunomide onto SWCNT. Frontier molecular orbitals (HOMO and LUMO) suggest that adsorption of leflunomide onto SWBNNT behave as charge transfer compounds with leflunomide as an electron donor and SWBNNT as an electron acceptor. Thus, nanotubes (NTs) have been proposed and actively explored as multipurpose innovative carriers for drug delivery and diagnostic application. The AIM theory has been also applied to analyze the properties of the bond critical points: their electron densities and their laplacians. Also, the natural bond orbital (NBO) calculations were performed to derive natural atomic orbital occupancies, and partial charges of the interacting atoms in the equilibrium tube-molecule distance.

RETRACTED: Biomedical microelectromechanical systems (BioMEMS): Revolution in drug delivery and analytical techniques

Advancement in microelectromechanical system has facilitated the microfabrication of polymeric substrates and the development of the novel class of controlled drug delivery devices. These vehicles have specifically tailored three dimensional physical and chemical features which together, provide the capacity to target cell, stimulate unidirectional controlled release of therapeutics and augment permeation across the barriers. Apart from drug delivery devices microfabrication technology’s offer exciting prospects to generate biomimetic gastrointestinal tract models. BioMEMS are capable of analysing biochemical liquid sample like solution of metabolites, macromolecules, proteins, nucleic acid, cells and viruses. This review summarized multidisciplinary application of biomedical microelectromechanical systems in drug delivery and its potential in analytical procedures.

Cast Natural Rubber Films Comprising Triethyl Citrate

The various triethyl citrate-loaded natural rubber (NR) films were prepared by casting technique employing dichloromethane (DCM) as solvent. The wettability, mechanical properties and topology of prepared dry films were determined. The contact angle of distilled water onto the cast films was measured using the goniometer. Triethyl citrate-loaded NR films exhibited the continuous porous structure. The presence of triethyl citrate in NR films promoted wettability and surface free energy whereas the tensile strength decreased. The unique porous topography of triethyl citrate-loaded NR film exhibited the potential for applying this material as the scaffold or controlled drug delivery devices in the future.

Colonic Drug Delivery Systems Based on Natural Polysaccharides and their Evaluation

Natural polysaccharides are found in abundance, are inexpensive, safe and available in a variety of structures which can easily be modified chemically and biochemically. A number of natural gums and mucilages along with their chemically modified forms have been evaluated as controlled drug delivery devices. They are reported to be capable of providing the desired drug release profiles and in some cases, have shown comparable drug release properties with currently available sustained release products in the market. Colon specific drug delivery based on natural polysaccharides has highly been acclaimed in recent years. A colon specific drug delivery system should prevent drug release in the stomach as well as the small intestine. Several polysaccharides have been reported to be capable of preventing drug release in the upper GI tract while being susceptible to enzymatic degradation by colonic bacterial enzymes. A wide range of natural or modified polysaccharides has been investigated for peroral delivery of drugs to the colon. As the release of drug from these polysaccharides based systems is independent of pH and gastric emptying time these polysaccharides based systems are considered the most effective and preferable means for colonic drug delivery in terms of target specificity.

English

Two demineralized bovine bone membranes after cleaning and cutting into appropriated size, incorporated with doxycycline (DOX) and tetracycline (TET)were evaluated as controlled drug delivery devices and. The complete release time was 96 h (15 days) with a quick release in the first 12 h, decreasing exponentially to zero when it reaches 96 h. The release system fits in a pseudo second order kinetic model allowing the calculation of relevant parameters such as the initial release kinetics of the drug (h) with values ​​of 0.228 µg g-1 h-1 for DOX  and 0.625 µg g-1h-1 for TET, and a release rate constant (k) 37.66 g mg-1 h-1 for DOX and 43.03 g mg-1h-1for TET. The amount released by TET is higher than for the DOX in all the periods analyzed, but with the same desorption profile although any additional treatment on the membranes surface has been made. Both systems can be characterized as a controlled release device, due to  their effective retention even  long time after the start of experiment. Its use incorporated with antimicrobials agents is an important tool as physical barrier in periodontal regeneration to help combat periodontal pathogens and modulate the inflammatory response of the host, limiting tissue destruction.   Key words: Desorption kinetic, doxycycline, tetracycline, membranes, collagen and drug delivery.

Wet microcontact printing (µCP) for micro-reservoir drug delivery systems

When micro-reservoir-type drug delivery systems are fabricated, loading solid drugs in drug reservoirs at microscale is often a non-trivial task. This paper presents a simple and effective solution to load a small amount of drug solution at microscale using ‘wet’ microcontact printing (µCP). In this wet µCP, a liquid solution containing drug molecules (methylene blue and tetracycline HCl) dissolved in a carrier solvent was transferred to a target surface (drug reservoir) by contact printing process. In particular, we have investigated the dependence of the quantity and morphology of transferred drug molecules on the stamp size, concentration, printing times, solvent types and surfactant concentration. It was also found that the repetition of printing using a non-volatile solvent such as polyethylene glycol (PEG) as a drug carrier material actually increased the transferred amount of drug molecules in proportion to the printing times based on asymmetric liquid bridge formation. Utilizing this wet µCP, drug delivery devices containing different quantity of drugs in micro-reservoirs were fabricated and their performance as controlled drug delivery devices was demonstrated.

Entering the era of nanoscience: time to be so small.

The field of nanoscience has produced more hype than probably any other branch of materials science and engineering in its history. Still, the potentials of this new field largely lay undiscovered ahead of us; what we have learnt so far with respect to the peculiarity of physical processes on the nanoscale is only the tip of an iceberg. Elaborated in this critical review is the idea that the surge of interest in physical chemistry of phenomena at the nanoscale presents a natural consequence of the spatial refinement of the human ability to controllably manipulate the substratum of our physical reality. Examples are given to illustrate the sensitivity of material properties to grain size on the nanoscale, a phenomenon that directly contributed to the rise of nanoscience as a special field of scientific inquiry. Main systemic challenges faced by the present and future scientists in this field are also mentioned. In part, this perspective article resembles standing on the constantly expanding seashore of the coast of nanoscience and nanoengineering and envisioning the parts of the island where the most significant advances may be expected to occur and where, therefore, most of the attention of scientist in this field is to be directed: (a) crossing the gap between life science and materials science; (b) increasing experimentation sensitivity; (c) crisscrossing theory and experiments; and (d) conjoining top-down and bottom-up synthetic approaches. As for materials and the application areas discussed, a special emphasis is placed on calcium phosphate nanoparticles and their usage in controlled drug delivery devices and other applications of biomedical relevance. It is argued that the properties of nanoparticles as drug carriers often comprise the critical determinant for- the efficacy of the drug therapy. Therefore, the basic properties of nanoparticles to be optimized for the purpose of maximizing this efficacy are discussed: size, size distribution, morphology, polymorphic nature, crystallinity, biocompatibility, biodegradability, drug elution profiles, and aggregation propensity.

Water diffusion in poly(vinyl alcohol) membranes: A rigorous analysis of the pervaporation process

Abstract In the design of crosslinked polymer elements for separation and fuel cell technology, controlled drug delivery devices or micro-scale sensor-actuator systems, profound knowledge of mass transport in the polymer network is of substantial interest for a systematic ab initio evaluation of separation efficiency, drug release rates and response characteristics. The study of solvent transport in polymeric membranes is frequently based on the pervaporation process, analysing the flux of one or more permeants under well-defined boundary conditions. Yet, for quantitative analysis, assumptions such as concentration-independent diffusion coefficients and neglect of gas-phase boundary layer resistances and local mass transfer effects are common, but remain largely unverified as information on the solvent distribution in the membrane is not usually available. The present study therefore introduces an advanced experimental methodology and combines the routine permeation flux measurement with the determination of local concentration profiles in the membrane, allowing diffusion coefficients to be specified directly as a function of solvent content. For physically crosslinked poly(vinyl alcohol) membranes, it could thus be demonstrated that water transport is successfully described by pure Fickian diffusion with an exponential expression accounting for the concentration-dependent solvent diffusion coefficient.

An electric-field responsive microsystem for controllable miniaturised drug delivery applications

Abstract A novel MEMS based drug delivery device has been developed, consisting of an array of metallic contacts on silicon and Pyrex glass wafers. The meander structured device creates a uniform electric field which stimulates drug release. An electro-active hydrogel based polymer matrix has also been developed, which responds to an electrical stimulus and shrinks or de-swells on application of an electric field from the fabricated device. Different drug candidates can be encapsulated within the polymer matrix. The de-swelling of the polymer enables the encapsulated drug to be released from the matrix. The gel is able to recover its original size once electric stimulation is ceased. By controlling the applied voltage and its duration, the drug release rate and dose can be precisely controlled. Controlled drug delivery devices may be integrated with sensor technology in combined diagnostic/therapeutic point of care devices.

A New Methodology for Quantitative LSPR Biosensing

Localized surface plasmon resonance (LSPR) biosensing holds the promise of being able to map out the spatio-temporal nature of protein secretions of individual cells or controlled drug delivery devices in a label-free manner. Before these applications can be realized, however, it first must be shown that LSPR can be used for detecting protein concentrations on length and time scales that are applicable to such mass-transport limited processes, roughly 10 μm and 1 second, respectively. In this work a quantitative analysis methodology for LSPR biosensing is presented by which surface-receptor fractional occupancy as well as the local analyte concentration can be determined to within these specifications.

Prediction of the mutual diffusion coefficient for controlled drug delivery devices

Diffusion coefficients of drugs in polymers were predicted using models based on modified free volume theory of diffusion. The descriptors used were chosen to uniquely relate the structure with desired properties. Model parameters were obtained using quantitative structure property relationships (QSPRs) developed using multiple linear regression and artificial neural networks with Bayesian regularization. Viability of the approach was established by predicting solvent diffusion coefficient in polymer for four polymer–solvent systems (polystyrene–toluene, polyvinylacetate–toluene, polystyrene–ethylbenzene and polystyrene–tetrahydrofuran) and comparing with the experimental values. The model was subsequently used on three polymer–drug systems (paclitaxel–polycaprolactone, hydrocortisone–polyvinylacetate and procaine–polyvinylacetate). The predicted diffusion coefficient for Paclitaxel–Polycaprolactone was used to study the release of Paclitaxel from Polycaprolactone under perfect sink condition. It is envisaged that the proposed model could be used in a reverse engineering framework to select polymers for designing the optimally controlled drug release devices.

Morphological and degradation studies of sirolimus-containing poly(lactide-co-glycolide) discs

The effect of residual solvent and copolymer ratio on the in vitro degradation and drug release behavior of a bioabsorbable polymer/drug system was investigated in an effort to understand and develop the use of these excipients for controlled drug delivery devices. Sirolimus-containing poly(lactide-co-glycolide) (PLGA) discs were fabricated by a solution-casting method using dimethyl sulfoxide (DMSO) as the solvent. The residual DMSO was removed from a set of discs by supercritical carbon dioxide extraction, and reflections of crystalline sirolimus were observed in the wide-angle X-ray scattering profile observed after extraction. A correlation was not observed between the extent of drug crystallization and extraction conditions and copolymer ratio. Mass loss, molecular weight, and sirolimus release were monitored during an in vitro study of the oven-dried neat PLGA, sirolimus-containing PLGA, and extracted sirolimus-containing PLGA discs during 56 days. The sirolimus-containing PLGA discs with residual DMSO exhibited a faster sirolimus release rate compared to the extracted discs. The residual DMSO facilitated release of sirolimus. The discs that contained PLGA with higher glycolide content, particularly 50% glycolide, degraded faster and exhibited faster sirolimus release.

An Electric-Field Responsive Microsystem for Controllable Miniaturised Drug Delivery Applications

A novel MEMS based drug delivery device has been developed, consisting of an array of metallic contacts. The meander structured device created a uniform electric field which stimulates drug releases. An electro-active hydrogel based polymer matrix responds to an electrical stimulus and shrinks or de-swells on application of an electric field from the fabricated device. Different drug candidates can be encapsulated within the polymer matrix. The de-swelling of the polymer enables the encapsulated drug to be released from the matrix. The gel is able to recover its original size once electric stimulation has been stopped. By controlling the voltage and time, the drug release rate and dose can be precisely controlled. Controlled drug delivery devices may be integrated with sensor technology in combined diagnostic / therapeutic point of care devices.

Bioinspired conformational changes: an adaptable mechanism for bio-responsive protein delivery

Hydrogels that respond to their environment have been extensively used as controlled drug delivery devices. An emerging trend is to form these “dynamic” hydrogels from polymers that undergo conformational changes. Indeed, nanometer scale polymer conformational changes have translated to macroscopic changes in hydrogel properties and controlled the release of encapsulated drugs. This review will focus on the mechanisms that control protein release from dynamic hydrogels. Specifically, we will highlight emerging mechanisms to form dynamic hydrogels, whose functional nature is derived from nature-inspired polymer conformational changes. Pertinent results from the literature will be examined to illustrate how these nanometer scale polymer conformational changes influence therapeutic protein release from dynamic hydrogels.