Controlled Drug Release System Research Articles

Biological evaluation of degradable, stimuli-sensitive multiblock copolymers having polydepsipeptide- and poly(ε-caprolactone) segments in vitro

Polydepsipeptides, alternating copolymers consisting of α-amino acids and α-hydroxy acids, are degradable polymers. Depsipeptide-based polymers of varied architectures can be synthesized via ring-opening polymerization of various morpholine-2,5-dione derivatives. Thermoplastic phase-segregated multiblock copolymers with poly(ε-caprolactone) (PCL) and poly(iso-butyl-morpholinedione) segments have been synthesized from the macrodiols and an aliphatic diisocyanate as a coupling agent. The respective multiblock copolymers showed shape-memory capabilities and good elastic properties, making them attractive candidates for potential application as biomaterials for controlled drug release systems, scaffolds to be applied in tissue engineering or biofunctional implants. Thus, these abilities cumulate to form multifunctional materials, combining degradability with shape-memory capability. The advantages of depsipeptide-based multiblock copolymers compared to previously reported poly(ether)ester-derived biomaterials having shape-memory property may result from their different degradation products, as the resulting α-amino acids may act as a buffer for the hydroxy acids, thereby stabilizing pH values. In this context, we report on the biological evaluation of material samples in accordance with international standards (EN DIN ISO 10993-5 and 10993-12). Here, extracts of the substrates were exposed to a continuous fibroblast like cell line (L929) to study cytocompatibility of extractable substrates. Cell viability, morphology, LDH-release (as a parameter for the functional integrity of the cell membrane), activity of the mitochondrial dehydrogenases (as a parameter of the cell activity) and assembly of the actin- and vinculin cytoskeleton indicated no incompatibilities between the extracts and L929 cells. These results suggest that depsipeptide-based multiblock copolymers are promising candidates for soft, multifunctional implant materials.

How to change a shrimp into an intelligent drug carrier?

Design of hybrid systems (structures composed of a carrier and pharmacological agent) for controlled release inside the body is a major direction in creation of new forms of drugs. These novel drug carriers should possess better accessibility and effectiveness with limited side-effects. The main purpose of this study was to construct a new form of chitosan carrier with the ability to transform from sol to gel at the physiological temperature of human body. Controlled drug release systems were formed by mixing b-sodium glycerophosphate with the solutions of chitosan glutaminate.

A Novel Controlled Release Drug Delivery System for Multiple Drugs Based on Electrospun Nanofibers Containing Nanoparticles

This study describes development of a novel controlled drug release system for multiple drugs, it consisted of Chitosan nanoparticles/PCL composite electrospun nanofibers with core-sheath structures. Two model agents' rhodamine B and naproxen were successfully loaded in the core and sheath region respectively. The behavior of these two agents demonstrated a good controlled release and temporality, providing a new way to obtain program or temporality release for multiple agents. Particularly, this is potential applications in the field of tissue engineering, sutures and wound dressings.

Soluble Hyperbranched Poly(glycolide) Copolymers

A series of (hyper)branched poly(glycolide) copolymers has been prepared by copolymerization of glycolide (GA) with 2,2-bis(hydroxymethyl)butyric acid (BHB) via combined ROP/AB2-polycondensation. Polymerization was conducted in bulk and catalyzed by stanneous-2-ethyl hexanoate (Sn(Oct)2). The branched topology of the resulting polyesters was studied in detail by 1D- and 2D-NMR spectroscopy and confirmed by the synthesis and characterization of model compounds. The AB2 monomer BHB was incorporated either as a dendritic or focal unit, but hardly in linear or terminal mode. As expected for multifunctional polycondensation, SEC measurements showed polydisperse products with polydispersity index in the range of 1.88 to 3.40. Mn of the copolymers varied from 1100 to 4000 g/mol. MALDI−TOF MS analysis allowed to verify the main polymeric species. Furthermore, MALDI−TOF evidenced incorporation of several BHB units per macromolecule, confirming a successful condensation reaction and the formation of branched copolymers. Detailed 1H NMR characterization (1D and 2D methods) permitted calculation of the molar composition, the conversion and the degree of branching (DB), which ranged between 0.12 and 0.44. Differential scanning calorimetry (DSC) measurements showed that in contrast to linear PGA (Tm > 220 °C) the melting behavior and the glass-transition temperature of the branched poly(glycolide) copolymers changed drastically. The presence of dendritic units in the polymer backbone resulted in a depression of the melting point and amorphous materials at amounts of BHB exceeding 15%. The amorphous hyperbranched poly(glycolide) copolymers show enhanced solubility in common solvents (e.g., acetone, ethyl acetate, THF) and improved processability in contrast to linear PGA and possess potential for use in slow or controlled drug release systems.

Temperature‐Responsive Controlled Drug Delivery System Based on Titanium Nanotubes

AbstractIn this study, we reported a smart temperature‐sensitive drug release system based on titanium nanotubes. Titanium nanotubes were fabricated with an electrochemical approach. The 3‐trimethoxysilyl propylmethacrylate (MPS) was initially coupling to the surfaces of titanium nanotubes, and then polymerizing with N‐isopropylacrylamide (NIPAAm) and acrylamide (AAm) to form a hydrogel covering layer. Scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) were employed to characterize the titanium nanotubes drug delivery systems. SEM images revealed that titanium nanotubes had relatively uniform distribution in diameters (52 ± 9 nm) and around 410 nm in length. FTIR spectra suggested that MPS was immobilized and in turn triggering the formation of PNIPAAm/PAAm network onto the surfaces of titanium nanotubes. Drug release profiles indicated that a temperature‐responsive controlled drug release system based on titanium nanotubes was achieved. This study provides alternative for developing novel implantable controlled drug delivery systems from titanium nanotubes.

Polymers in Biomedicine and Electronics

The versatility of polymeric materials originates from the broad variety in their chemical structure and in their hierarchical organization as well as from the possibility to realize a wide spectrum of functions. Often such functions result from a combination ofamoleculararchitecture/morphology with a physical process and therefore require integration in a suitable system (e.g. medical device, electric circuit) or environment (e.g. physiological environment). Frequently, research in the area of functional polymers is motivated by applications. This special issue focuses on two application areas, in which polymer research as well as product development are progressing rapidly: Biomedicine and Electronics. Here (multi)functional polymers are an enabling technology and in this way create substantial and sustainable value. The significance of this topic is also highlighted at the conference ‘‘Polymers in Biomedicine and Electronics’’, which takes place from Oct 3 to 5, 2010 in Berlin combining the biannual meetings of the Gesellschaft Deutscher Chemiker (GDCh) Division ‘‘Macromolecular Chemistry’’ and of the Berlin-Brandenburgischer Verband fur Polymerforschung (BVP). Topics of the conference cover the design and the synthesis of functional polymers, physical principles underlying the function, the characterization of such functionswithin a system as well as product-oriented industrial research. Smart biomaterials, biocompatible coatings and their applications in controlled drug delivery systems or in regenerative therapies will be discussed in the biomedicine-oriented sessions of the conference. Photovoltaic, charge transport, light emission aswell as sensors andactuatorswill be subjects in the area of electronics.

Tramadol hydrochloride/montmorillonite composite: Preparation and controlled drug release

The adsorption of tramadol hydrochloride (TH) by montmorillonite (MMT) was investigated, to obtain a controlled drug release system. The adsorption isotherm was fitted by the Langmuir model and followed the pseudo-second-order kinetics. The composite was characterized by XRD, FTIR and TG-DTA. TH was intercalated into MMT in vertical orientation giving a basal spacing of 1.99 nm. Release of the intercalated TH was studied in simulated gastric fluid (SGF, pH = 1.2) and simulated intestinal fluid (SIF, pH = 7.4) at 37 °C. Controlled release of TH from TH/MMT was observed.

Synthesis, characterization and controlled release of cephalexin drug from smart poly(2-hydroxyethyl methacrylate/poly(alkylene glycol)(meth)acrylates hydrogels

In this work, novel hydrogels based on 2-hydroxyethyl methacrylate (HEMA) and different poly(alkylene glycol)(meth)acrylates (BIS) were prepared by radiation-induced copolymerization. The influence of different BIS types with variation in chain length, based on ethylene glycol (EG) and/or propylene glycol (PG) pendant units, on the nature and inherent properties of P(HEMA/BIS) copolymeric hydrogels was the main idea of this paper. Swelling studies were conducted for all types of P(HEMA/BIS) copolymeric hydrogels in a wide pH and temperature range. Additional characterization of structure, morphology and thermal behaviour of the obtained hydrogels was conducted by Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and thermogravimetric (TG) analysis. The modelling of drug release and diffusion characteristics was tested using cephalexin (CEX). The results indicate that P(HEMA/BIS) hydrogels’ properties are significantly dependent on the type of BIS. The hydrogels with ethylene glycol (EG) pendant chains show a noticeable pH and/or temperature sensitivity and can be considered smart hydrogels. The introduction of propylene glycol (PG) units, pure and mixed with ethylene glycol (EG) pendant chains, can additionally tune the characteristics of such gels. Furthermore, drug release studies indicate that these types of P(HEMA/BIS) copolymeric hydrogels are suitable candidates for controlled drug release systems.

Mechanical and geometric property characterization of dry-coated tablets with contact ultrasonic techniques

A dry-coated tablet is a solid dosage form with a controlled drug-release system, which consists of a core and an outer layer. The accuracy of its geometric (e.g. the outer layer wall and core thicknesses) and mechanical properties (e.g. Young's moduli and mass densities of associated materials) could be crucial to its therapeutic and structural functions. The objective of current study is to develop a non-destructive technique for determining the geometric and mechanical properties of dry-coated tablets. Two contact ultrasonic techniques (i.e. pitch-catch and pulse-echo measurement modes) are employed and the properties of all the structural components of a set of experimental tablets are measured and reported. The thicknesses of the outer layers of the sample tablets are used to obtain the eccentricity of the core tablets. The two approaches are compared for their effectiveness in obtaining these properties of the sample dry-coated tablets. The thicknesses of the outer layers obtained with the proposed approach and with the direct (destructive) measurements are also compared. A good agreement is found; there is an approximately 2% difference. The eccentricity and concentricity of a set of tablets are determined and it is concluded that the observed consistent anomaly in eccentricity can be attributed to the same root cause and its correction can be achieved by control input based on monitoring data. Potential of the approach for in-die real-time monitoring of compaction presses and its PAT (Process Analytical Technology) applications for the pharmaceutical manufacturing are also discussed.

Controlling the drug release rate from biocompatible polymers with micro-patterned diamond-like carbon (DLC) coating

During the past year, we have witnessed the evolution of an intense public controversy regarding late thrombosis following implantation of drug eluting stent (DES) in patients with obstructive coronary artery disease. To overcome the problem, DES should possess sufficient biocompatibility and non-thrombogenicity with a controlled drug release system. A new DES composed of biocompatible polymers coated with antithrombogenic diamond-like carbon (DLC) coating was proposed. In this study, the drug release profile of the newly proposed drug eluting system was thoroughly investigated. Three polymers were selected as base drug-reservoir materials: hydrophilic 2-methacryloyloxyethyl phosphorylcholine (MPC), hydrophobic poly (ethylene-co-vinyl acetate) (EVA) and less hydrophobic polyurethane (PU). The three polymers are currently used or studied for biomedical materials, while MPC and DLC were already confirmed as excellent biocompatible materials with antithrombogenicity. After coating the lattice-like patterned DLC on both polymers containing drug, samples were soaked in 2 ml of medium of phosphate-buffered saline with 10% ethanol. The drug release rate was measured by a spectrophotometer. The percentile cover area of patterned DLC on polymers was varied from 0% (without DLC) to 100% (fully covered). The sample without DLC coating presented an initial burst of the drug release from the polymer matrix, whereas the DLC-coated samples inhibited the initial burst release from polymers within the first five days of the experiments. It was found that the drug eluting profiles could be effectively controlled by changing the cover area of micro-patterned DLC coatings on polymers, which may be applicable to the next-generation DES system that eventually prevents late thrombosis.

Surface deformation of gold nanorod-loaded poly(dl-lactide-co-glycolide) nanoparticles after near infrared irradiation: an active and controllable drug release system

A novel drug release method for poly(DL-lactide-co-glycolide) (PLGA) nanoparticles is reported. NIR laser irradiation (808 ± 3 nm) on gold nanorods (GNRs) co-encapsulated in PLGA nanoparticles triggered surface protuberances (as studied by AFM) and induced rapid drug release. The NIR thus acts as a non-invasive external light source for active and controllable drug release from the PLGA/GNR composite nanoparticles. This type of drug delivery system may be of value in in vivo target delivery in the future.

Single and Multi-Layered Nanofibers for Rapid and Controlled Drug Delivery

This paper introduces a new delivery system for rapid and controlled drug release. Mixture of hydrophilic, (poly vinyl alcohol, PVA, and randomly methylated beta-cyclodextrin, RM beta-CD), and hydrophobic (poly D,L-lactide, PLA, and poly D,L-lactide-co-glycoside, PLGA) polymers were electrospun to make a multi-layered/multicomponent nanofiber mat. The release characteristics of the drug were modified using the layer by layer approach to help compensate the limitation of the individual materials. Incorporation of RM beta-CD to the PVA solution was able to significantly decrease the degradation rate of the resulting fiber mat from a few weeks to a few seconds. Hydrophilic polymer mat (PVA-RM beta-CD) can dissolve in the release media instantly and provide rapid release of the drug. This characteristic makes such carriers suitable as sublingual delivery systems in the treatment of acute disorders. Polyesters, PLA and PLGA, can control drug release via hydrolysis of the polymer and provide sustained and controlled release of the drug. Blends of these hydrophilic and hydrophobic polymers can effectively prolong drug release and decrease physiological toxicity resulting from fast release of drugs. These carriers may be suitable for the treatment of chronic disease where sustained release of the drug is required.

A Promising Drug Controlled-Release System Based on Diacetylene/Phospholipid Polymerized Vesicles

A novel polymerized vesicular carrier loaded with paclitaxel was developed by introducing the ultraviolet (UV) cross-linkable 10,12-pentacosadiynoic acid (PCDA) into bilayered phospholipid vesicles with the purpose of improving the physicochemical stability as well as the controlled-release property of liposomes. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results revealed the enhanced stability of PCDA-polymerized vesicles against Triton X-100. In particular, alteration in PCDA/phospholipids ratios and UV-irradiation time can modulate the cumulative paclitaxel released. For instance, vesicles composed of phospholipids only released 98.0 +/- 2.1% of paclitaxel within 24 h. Over the same time period, 72.0 +/- 5.8%, 43.9 +/- 6.5%, and 20.1 +/- 5.4% of paclitaxel was released from polymerized PCDA/phospholipid vesicles at molar ratios of 1:3, 1:1, and 3:1, respectively. Likewise, by increasing the UV-irradiation time from 20 to 40 min, the cumulative release of paclitaxel from polymerized PCDA/phospholipid vesicles at molar ratio of 1:1 decreased from 90.5 +/- 3.7% to 37.6 +/- 2.3% over a time period of experimental observation of 24 h. The influences of vesicle composition (i.e., PCDA/phospholipids ratio) and UV-irradiation time on the release rates of paclitaxel were further examined by finite element (FE) analyzed using Abaqus. Our results demonstrate that novel polymerized vesicles capable of regulating the release of anticancer drugs such as paclitaxel have been developed.

PH-sensitive hydrogels based on bovine serum albumin for anticancer drug delivery

Protein conjugates consisting of hydroxyethyl methacrylate and acrylic acid monomers in the presence of bovine serum albumin (BSA) were prepared by gamma irradiation to examine the potential use of these hydrogels in the controlled drug release systems. The study parameter was the BSA content in the as-prepared conjugates. Polymers were characterized with FTIR, scanning electron microscopy (SEM), and swelling studies. The polymerization reaction caused the rearrangement of the BSA carbonyl hydrogen bonding and finally led to the modification of the BSA secondary structure as proved by FTIR. SEM proved that the prepared conjugates matrices are porous, with a three-dimensional interconnected microstructure. The swelling kinetics of the hydrogels and the release dynamics of an anticancer model drug (flutamide) have been studied. High equilibrium swelling values, up to 1550%, could be observed and were correlated with the increase in pH, temperature, and BSA content. The mechanism of swelling changed from Fickian to non-Fickian by reducing the acidity of the medium. This study proved that there is a direct relationship between the protein content in the conjugates and both the loaded and the released drug. These pH responsive conjugates may be exploited for the delivery of flutamide. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

Dielectric behaviour and relaxation processes of montmorillonite clay nano‐platelet colloidal suspensions in poly(vinyl pyrrolidone)–ethylene glycol oligomer blends

AbstractBACKGROUND: Intercalated and exfoliated montmorillonite (MMT) clay structures in polymer matrices improve the thermal, mechanical, electrical and pharmaceutical properties of organic–inorganic materials. Poly(vinyl pyrrolidone) (PVP)–ethylene glycol oligomer (EGO) blends are biocompatible and non‐toxic materials. The dielectric characterization of MMT clay nano‐platelet colloidal suspensions in PVP–EGO blends is important in understanding the ionic conduction behaviour in many complex phenomena occurring in biological systems, and in selective membranes and their use in controlled drug release systems and in liquid electrolytes.RESULTS: An investigation using dielectric spectroscopy in the 20 Hz to 1 MHz frequency range of MMT clay nano‐platelet colloidal suspensions in PVP–EGO blends confirmed that the PVP segmental motion, ionic conduction relaxation time, electric double layer relaxation time and direct current electrical conductivity are significantly influenced by the clay concentration and EGO chain length. In these materials, ionic motion and PVP segmental dynamics are strongly coupled. Intercalation of EGO structures in clay galleries and exfoliation of clay platelets by adsorption of PVP–EGO structures on clay surfaces are governed by hydrogen bonding interactions between the carbonyl groups of PVP monomer units, the hydroxyl groups of EGOs and the hydroxylated aluminate surfaces of the MMT clay.CONCLUSION: The dielectric behaviour of intercalated and exfoliated structures of MMT clay nano‐platelet colloidal suspensions in PVP–EGO blends provides a convenient way to obtain liquid organic‐inorganic polymeric nanocomposite electrolytes with tailored ionic conduction properties. Copyright © 2009 Society of Chemical Industry

Preparation and Characterization of Quantum Dots Coated Magnetic Hollow Spheres for Magnetic Fluorescent Multimodal Imaging and Drug Delivery

Innovative nanocomposites of magnetic and fluorescent multifunctional hollow spheres were developed, which combined magnetic resonance imaging (MRI), magnetic targeting, fluorescent imaging (FI) and drug delivery into one system. Fe3O4 hollow spheres were used as templates for the deposition of polyelectrolyte (PE) multilayers and CdTe quantum dots (QDs) via layer-by-layer (LBL) method. The PE multilayers/QDs coated Fe3O4 hollow spheres showed high magnetization and fluorescence, which can be used as magnetic and fluorescent multimodal imaging agent in vivo. The multifunctional nanomaterials of polyelectrolyte multilayers/QDs coated Fe3O4 hollow spheres were used as controlled drug release system, which showed pH-sensitive drug release over a long time. By combining the multiplexing imaging capability, the magnetic and fluorescent nanocomposites are potential candidates for simultaneous disease diagnosis and therapy.

Preparation of Uniformly Sized Chitosan Nanospheres by a Premix Membrane Emulsification Technique

Chitosan nanospheres have great potential in drug controlled release systems, because they show excellent degradability, biocompatibility, and nontoxicity. The particle size control and size distribution of nanospheres are necessary in order to improve reproducibility, bioavailability, and repeatable release behavior. In order to prepare uniformly sized and size-controllable chitosan nanospheres, in this study, a premix membrane emulsification technique was developed on the basis of direct membrane emulsification, and the uniformly sized chitosan nanospheres were successfully prepared by optimizing preparation conditions. The detail preparation process is as follows: The chitosan aqueous solution was used as a dispersed phase, and the mixture of liquid paraffin and petroleum ether containing emulsifier was used as a continuous phase. The coarse emulsions were first prepared by low-speed stator homogenization and then poured into the premix reservoir. Nanodroplets were achieved by extruding the coarse emulsions through the SPG (Shirasu porous glass) membrane with a high pressure. The nanodroplets were further cross-linked to obtain chitosan nanospheres. In this process, several factors played key roles in obtaining chitosan nanoparticles with narrow size distribution, including the amounts of emulsifier in oil phase, the composition of oil phase, the concentration of chitosan, the ratio of water to oil phase, the transmembrane pressure and number of passes, and so on. The results showed that the chitosan nanospheres from 300 nm to 1.85 mu m were successfully prepared by premix membrane emulsification by changing the pore size of the membrane and the polydispersity index could be as low as 0.027 under optimized conditions, and it is a potential technique to prepare size-controllable uniform chitosan nanospheres with fast production.

One Step Preparation of Controlled Drug Release Systems in Supercritical Carbon Dioxide

AbstractDrug delivery systems based on copolymers of N‐isopropylacrylamide were first prepared by a one step method, in which supercritical carbon dioxide was simultaneously used as a polymerization medium and an impregnation agent. The obtained microspheres were characterized by scanning electronic microscopy (SEM), differential scanning calorimetry (DSC), transmission electron microscopy (TEM) and X‐ray diffraction (XRD). The release effect of the in situ prepared microgels impregnated with ibuprofen was presented through in vitro release simulation.

Preparation and characterization of poly(N‐tert‐butylacrylamide‐co‐acrylamide) ferrogel

AbstractMagnetic‐field‐sensitive gel, called ferrogel, was prepared by a two‐step procedure in which first step requires synthesis of the poly(N‐tert‐butylacrylamide‐co‐acrylamide) [P(NTBA‐co‐AAm)] hydrogel and during second step magnetite (Fe3O4) particles were formed in the hydrogel via coprecipitation of Fe(II) and Fe(III) ions in alkaline medium at 70°C. The obtained ferrogel was characterized by attenuated total reflectance Fourier transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy combined with energy dispersive spectroscopy, and electron spin resonance measurements. The magnetic responsive of the ferrogel was also investigated by applying magnetic field to the ferrogel. The extent of a bending degree of the ferrogel depends on the applied magnetic field strength. In addition, the magnetic responsive studies also indicated that formed magnetite content in the hydrogel is high enough to achieve considerable magnetic response to external magnetic field. As a result, the P(NTBA‐co‐AAm) ferrogel may be useful for potential applications in magnetically controlled drug release systems, magnetic‐sensitive sensors, and pseudomuscular actuators. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009

An in vitro release study of 5-fluoro-uracil (5-FU) from swellable poly-(2-hydroxyethyl methacrylate) (PHEMA) nanoparticles

Nanomaterials are at the leading edge of the rapidly developing field of nanotechnology. The use of nanoparticles as drug delivery vehicles for anticancer therapeutics has great potential to revolutionize the future of cancer therapy. The present paper concerns both the optimizations of anticancer drug loading and its release from polymeric nanoparticles. The major aim of this study was to design poly (HEMA) nanoparticles as swelling controlled drug release system for anticancer drug. The prepared nanoparticles were characterized by Infra-Red (IR) Spectra, Particle size Analysis, and Scanning Electron Microscopy (SEM). The nanoparticles were loaded with widely used anticancer drug, 5-Fluorouracil, and controlled release of drug was investigated to observe the effects of various parameters such as percent loading of the drug, chemical architecture of the nanocarriers, pH, temperature, and nature of release media on the release profiles. The chemical stability of 5-Fluorouracil (5-FU) was also tested in phosphate buffer saline (PBS) (pH = 7.4) and release was studied in various simulated biological fluids. The prepared nanoparticles could provide a possible pathway for controlled and targeted delivery of anticancer drug, thus causing lower side effects and higher efficacy.