Azobenzene/Tetraethyl Ammonium Photochromic Potassium Channel Blockers: Scope and Limitations for Design of Para-Substituted Derivatives with Specific Absorption Band Maxima and Thermal Isomerization Rate

Azobenzene/tetraethyl ammonium photochromic ligands (ATPLs) are photoactive compounds with a large variety of photopharmacological applications such as nociception control or vision restoration. Absorption band maximum and lifetime of the less stable isomer are important characteristics that determine the applicability of ATPLs. Substituents allow to adjust these characteristics in a range limited by the azobenzene/tetraethyl ammonium scaffold. The aim of the current study is to find the scope and limitations for the design of ATPLs with specific spectral and kinetic properties by introducing para substituents with different electronic effects. To perform this task we synthesized ATPLs with various electron acceptor and electron donor functional groups and studied their spectral and kinetic properties using flash photolysis and conventional spectroscopy techniques as well as quantum chemical modeling. As a result, we obtained diagrams that describe correlations between spectral and kinetic properties of ATPLs (absorption maxima of E and Z isomers of ATPLs, the thermal lifetime of their Z form) and both the electronic effect of substituents described by Hammett constants and structural parameters obtained from quantum chemical calculations. The provided results can be used for the design of ATPLs with properties that are optimal for photopharmacological applications.     

Engineering a drug eluting ocular patch for delivery and sustained release of anti-inflammatory therapeutics

Ocular inflammation is commonly associated with eye disease or injury. Effective and sustained ocular delivery of therapeutics remains a challenge due to the eye physiology and structural barriers. Herein, we engineered a photocrosslinkable adhesive patch (GelPatch) incorporated with micelles (MCs) loaded with loteprednol etabonate (LE) for delivery and sustained release of drug. The engineered drug loaded adhesive hydrogel, with controlled physical properties, provided a matrix with high adhesion to the ocular surfaces. The incorporation of MCs within the GelPatch enabled solubilization of LE and its sustained release within 15 days. In vitro studies showed that MC loaded GelPatch supported cell viability and growth. In addition, subcutaneous implantation of the MC loaded GelPatch in rats confirmed its in vivo biocompatibility and stability within 28 days. This non-invasive, adhesive, and biocompatible drug eluting patch can be used as a matrix for the delivery and sustained release of hydrophobic drugs.     

A Novel of Biodegradable Implants Based on PLGA for Control Delivery of Cisplatin

A novel controlled drug delivery micro-device was successfully prepared with biodegradable implants based on PLGA by solvent evaporation method. The micro-chambers were fabricated using the UV-LIGA technology. The controlled release process resulted from the design of the micro-chambers and the characteristics of biodegradable polymers. Implant bioactivity was tested using in vitro and in vivo release. The implants kept good shape and cisplatin was homogeneous loaded in the PLGA implants. The precast implants appeared hexagon. With different proportion of PLA and PGA segment, the swelling behavior and the hydrolytic degradation rate of implants became lower due to the increase of PLA hydrophobic segment. In vitro and in vivo drug release behavior was studied using cisplatin as model drug, the implants could control the diffusion of cisplatin. The results demonstrated that this type of controlled drug delivery micro-device could be more potential application in tumor therapy.     

Parametric Drug Release Optimization of Anti-Inflammatory Drugs by Gold Nanoparticles for Topically Applied Ocular Therapy

Eye drops represent 90% of all currently used ophthalmic treatments. Only 0.02% of therapeutic molecules contained in eye drops reach the eye anterior chamber despite their high concentration. The tear film efficiently protects the cornea, reducing access to the target. Thereby, the increase in the drug bioavailability and efficiency must come from the mucoadhesion optimization of the drug delivery system. The gold nanoparticles, used as a drug delivery system in this study, already showcased ultrastable and mucoadhesive properties. The goal was to study the gold nanoparticles’ ability to release two specific ophthalmic drugs, flurbiprofen and ketorolac. The parameters of interest were those involving the loading conditions, the gold nanoparticles properties, and the release experimental conditions. The drug release was measured using an in vitro model based on dialysis bags coupled with UV–visible spectroscopy. Gold nanoparticles showed an ability to release different molecules, whether hydrophobic or hydrophilic, in passive or active drug release environments. Based on these preliminary results, gold nanoparticles could represent a promising drug delivery system for ketorolac and flurbiprofen when topically applied through eye drops.     

一种新型的负载蛋白质药物微球的制备和释药性能

为了制备具有蛋白药物结肠靶向释放性能的新型药物载体,采用了水相溶液滴定反应法,分别以牛血清白蛋白(BSA)和乳铁蛋白(LF)为模型蛋白质药物,制得壳聚糖/纤维素磷酸钠(NaCS)/三聚磷酸钠(TPP)载药微球。利用电镜SEM和显微镜观测拍照,对微球的表面和截面形貌进行了表征,发现微球球形规则且颗粒大小均一。同时进行了体外药物模拟释放试验,考察了载药微球先后经过模拟胃液、模拟小肠液和模拟结肠液时的释药性能,及不同的释放条件和制造条件对于微球释药性能的影响,尤其考察了不同蛋白药物和不同干燥方式的影响。结果表明由临界点干燥法制得的负载乳铁蛋白(LF)微球在模拟胃液和小肠液释放量中5 h内只释放出不到20%的蛋白药物,而后在结肠模拟液中4 h内释放出蛋白药物80%以上。这些结果表明,壳聚糖/NaCS/TPP体系具有一定的作为结肠靶向药物释放载体的应用潜力。     

Advances in Chitosan-Based Nanoparticles for Drug Delivery

Nanoparticles (NPs) have an outstanding position in pharmaceutical, biological, and medical disciplines. Polymeric NPs based on chitosan (CS) can act as excellent drug carriers because of some intrinsic beneficial properties including biocompatibility, biodegradability, non-toxicity, bioactivity, easy preparation, and targeting specificity. Drug transport and release from CS-based particulate systems depend on the extent of cross-linking, morphology, size, and density of the particulate system, as well as physicochemical properties of the drug. All these aspects have to be considered when developing new CS-based NPs as potential drug delivery systems. This comprehensive review is summarizing and discussing recent advances in CS-based NPs being developed and examined for drug delivery. From this point of view, an enhancement of CS properties by its modification is presented. An enhancement in drug delivery by CS NPs is discussed in detail focusing on (i) a brief summarization of basic characteristics of CS NPs, (ii) a categorization of preparation procedures used for CS NPs involving also recent improvements in production schemes of conventional as well as novel CS NPs, (iii) a categorization and evaluation of CS-based-nanocomposites involving their production schemes with organic polymers and inorganic material, and (iv) very recent implementations of CS NPs and nanocomposites in drug delivery.     

Isopropyl Amino Acid Esters Ionic Liquids as Vehicles for Non-Steroidal Anti-Inflammatory Drugs in Potential Topical Drug Delivery Systems with Antimicrobial Activity

New derivatives of non-steroidal anti-inflammatory drugs were synthesized via conjugation with L-amino acid isopropyl esters. The characteristics of the physicochemical properties of the obtained pharmaceutically active ionic liquids were determined. It has been shown how the incorporation of various L-amino acid esters as an ion pair affects the properties of the parent drug. Moreover, the antimicrobial activity of the obtained compounds was evaluated. The proposed structural modifications of commonly used drugs indicate great potential for use in topical and transdermal preparations.     

Trimethyl Lock: A Multifunctional Molecular Tool for Drug Delivery,Cellular Imaging,and Stimuli‐Responsive Materials

Trimethyl lock (TML) systems are based on ortho‐hydroxydihydrocinnamic acid derivatives displaying increased lactonization reactivity owing to unfavorable steric interactions of three pendant methyl groups, and this leads to the formation of hydrocoumarins. Protection of the phenolic hydroxy function or masking of the reactivity as benzoquinone derivatives prevents lactonization and provides a trigger for controlled release of molecules attached to the carboxylic acid function through amides, esters, or thioesters. Their easy synthesis and possible chemical adaption to several different triggers make TML a highly versatile module for the development of drug‐delivery systems, prodrug approaches, cell‐imaging tools, molecular tools for supramolecular chemistry, as well as smart stimuliresponsive materials.     

Kidney-Protector Lipidic Cilastatin Derivatives as Structure-Directing Agents for the Synthesis of Mesoporous Silica Nanoparticles for Drug Delivery

Mesoporous silica nanomaterials have emerged as promising vehicles in controlled drug delivery systems due to their ability to selectively transport, protect, and release pharmaceuticals in a controlled and sustained manner. One drawback of these drug delivery systems is their preparation procedure that usually requires several steps including the removal of the structure-directing agent (surfactant) and the later loading of the drug into the porous structure. Herein, we describe the preparation of mesoporous silica nanoparticles, as drug delivery systems from structure-directing agents based on the kidney-protector drug cilastatin in a simple, fast, and one-step process. The concept of drug-structure-directing agent (DSDA) allows the use of lipidic derivatives of cilastatin to direct the successful formation of mesoporous silica nanoparticles (MSNs). The inherent pharmacological activity of the surfactant DSDA cilastatin-based template permits that the MSNs can be directly employed as drug delivery nanocarriers, without the need of extra steps. MSNs thus synthesized have shown good sphericity and remarkable textural properties. The size of the nanoparticles can be adjusted by simply selecting the stirring speed, time, and aging temperature during the synthesis procedure. Moreover, the release experiments performed on these materials afforded a slow and sustained drug release over several days, which illustrates the MSNs potential utility as drug delivery system for the cilastatin cargo kidney protector. While most nanotechnology strategies focused on combating the different illnesses this methodology emphasizes on reducing the kidney toxicity associated to cancer chemotherapy.     

Synthesis and Characterization of Chitosan Based Multilayer and pH Sensitive Co-Polymeric System for the Targeted Delivery of 5-Fluorouracil,an In Vitro Study

The principle aspiration is to develop a core shell carrier system for 5-Fluorouracil. Trisodiumcitrate crosslinked chitosan containing 5-Fluorouracil coated with cellulose acetate acts as core and copolymer of N-vinyl-2-pyrrolidone, 2-hydroxyethylmethacrylate, and itaconic acid act as shell. SEM, FTIR, and XRD studies were undertaken to characterize the samples. Swelling experiments were performed as a function of time, temperature, pH, and in simulated gastric and intestinal pH. Swelling factor was calculated for three different ions. Drug loading efficiency and in vitro release studies was done and compared. Drug delivery mechanism was found out by using Peppa's equation.     

Biocompatible hydrogels for the controlled delivery of anti-hypertensive agent: development,characterization and in vitro evaluation

The aim of the present exploration was to develop novel pH-sensitive cross-linked Gelatin/Polyvinyl pyrrolidone hydrogels using different ratios of both the polymers and to investigate the effect of polymers and degree of crosslinking on dynamic, equilibrium swelling and invitro release pattern of the model drug (captopril). Grafting polymerization technique was used for the preparation of these hydrogels using glutaraldehyde as crosslinking agent. These polymeric materials were then used as model systems to envisage various important characterizations like FTIR (Fourier transform infrared spectroscopy), XRD (X-ray diffraction) and scanning electron microscopy (SEM). Phosphate buffers of pH 1.2, 6.5 and 7.5 were used for swelling and invitro drug release profile investigation. Different parameters like swelling analysis, porosity, sol-gel analysis, average molecular weight between crosslinks (Mc), solvent interaction parameter (χ), volume fraction of polymer (V_2,s) and diffusion coefficient that affects the drug release behavior were also determined. Higher swelling and release was observed at lower pH values. FTIR spectra showed interaction between gelatin and polyvinyl pyrrolidone and successful formation of cross-linked structure. Pulsatile drug release study showed the controlled delivery of model drug. The release of drug occurred through non-fickian diffusion or anomalous mechanism. Aforementioned characterizations reveal successful formation of copolymer. pH sensitive swelling ability and drug release behavior suggest that the rate of polymer chain relaxation and the rate of drug diffusion from these hydrogels are comparable which also predicts their possible use for site specific captopril delivery.     

A new method for the determination of a hydrosilanization inhibitor applied to measurements during curing of a silicone elastomer

A new method for the quantitative determination of the hydrosilylation inhibitor 1‐ethynyl‐1‐cyclohexanol in a poly(dimethyl siloxane) matrix is presented. The method is based on headspace gas chromatography directly from the semisolid sample without solvent addition. The method was found to be both selective and sensitive. The relative standard deviation of the method was estimated to be 6%. The semisolid silicone sample was weighed directly in a headspace autosampler vial. After sample equilibration at 90°C for 1 h, the gas phase was injected into a gas chromatography system with a nonpolar methyl silicone capillary column. The inhibitor was detected with a flame ionization detector. The standard addition procedure was used for quantification. Recovery data on the inhibitor from the silicone during curing suggests that the inhibitor reacts with the silicone hydride crosslinker in the presence of the platinum catalyst to become part of the polymer network. This implies that the inhibitor will not migrate out from the silicone elastomer, which is a great advantage particularly for silicone elastomers used for medical devices or controlled drug release applications. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 79: 2349–2353, 2001     

Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome

Selective inhibition of the immunoproteasome is a promising approach towards the development of immunomodulatory drugs. Recently, a class of substituted thiazole compounds that combine a nonpeptidic scaffold with the absence of an electrophile was reported in a patent. Here, we investigated the mode of action of the lead compound by using a sophisticated chimeric yeast model of the human immunoproteasome for structural studies. The inhibitor adopts a unique orientation perpendicular to the β5i substrate‐binding channel. Distinct interactions between the inhibitor and the subpockets of the human immunoproteasome account for its isotype selectivity.     

Novel thermo‐responsive semi‐interpenetrating network microspheres of gellan gum‐poly(N‐isopropylacrylamide) for controlled release of atenolol

Thermoresponsive microspheres of gellan gum‐poly(N‐isopropylacrylamide), i.e., GG‐P(NIPAAm) semi‐interpenetrating polymer networks (semi‐IPNs) have been prepared by ionic crosslinking and used to study the controlled release (CR) of atenolol (ATL), an antihypertensive drug. Interaction of the drug with polymers was studied by Fourier transform infrared (FTIR) spectroscopy. Differential scanning calorimetry (DSC) was used to confirm the polymorphism and molecular level dispersion of ATL. Scanning electron microscopy (SEM) indicated spherical nature and smooth surfaces of the microspheres with some debris attached on their surfaces. Mean particle size measured by laser light diffraction ranged between 34 and 76 μm. Equilibrium swelling performed at 25°C and 37°C in pH 7.4 phosphate buffer exhibited thermoresponsive nature of the polymers. In vitro drug release performed at 25°C and 37°C indicated temperature‐dependency of ATL release, which was extended up to 12 h. In vitro release profiles at both the temperatures confirmed thermoresponsive nature of the polymers giving pulsatile trends. The % cumulative release data have been fitted to an empirical equation to estimate transport parameters and to understand the nature of drug release. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Supercritical antisolvent coprecipitation in the pharmaceutical field: Different polymeric carriers for different drug releases

The supercritical antisolvent process (SAS) was employed to obtain polymer/drug coprecipitated powders. Indeed, processes based on the use of supercritical fluids allow us to obtain polymer/active drug coprecipitated microparticles with tunable bioavailability. In this work, two different biocompatible polymers were selected to be used as carriers for obtaining drug microparticles with different releases for different applications: polyvinylpyrrolidone (PVP) was coprecipitated with ketoprofen to obtain a rapid drug release and zein was coprecipitated with ampicillin to obtain a controlled drug release. The experiments were performed both on a bench-scale and a pilot-scale plant. Ketoprofen is one of the most prescribed non-steroidal anti-inflammatory drugs. It is poorly soluble in water and, to overcome this inconvenience, in this work, it was coprecipitated with PVP. In correspondence with the optimized polymer/drug ratio, the dissolution rate of the active principle in the coprecipitated particles was about three times higher than the one of the unprocessed ketoprofen. The second model drug under study in this paper is ampicillin, a semi-synthetic penicillin that is one of the most commonly prescribed broad-spectrum antibiotics. Prolonging the release of the drug would imply a reduction in the number of administrations and, therefore, of the side effects associated with too high dosages. For this purpose, in this work, ampicillin was coprecipitated with zein. Zein/ampicillin microparticles were produced up to a polymer/drug ratio of 5/1 w/w; in this case, the antibiotic coprecipitated with zein reaches 90% of its dissolution in about 14 hours, while the unprocessed antibiotic takes about 3 hours to dissolve.