Colon-specific devices based on methacrylic functionalized Tween monomer networks: Swelling studies and in vitro drug release

Colon-targeted delivery devices based on methacrylic functionalized Tween monomer networks, useful for 5-FU or Ferulic acid site-specific release, were synthesized. The basic design consists of methacrylic functionalized Tween monomer-based networks prepared with or without acrylic acid as co-monomer. The swelling behaviour and loaded drugs release from these gels was studied as a function of pH. The devices showed a strong pH-dependent swelling behaviour, allowing a maximum release at pH 7.4. The acrylic acid introduction increased the polymeric gels pores size, as evidenced by the loading efficiency increase, but also reduced the amount of released drug in basic media compared to analogous network not containing the co-monomer. This behaviour, already found in the matrix swelling, could be attributed to a slower hydrolysis kinetics of the ester bond in functionalized Tween monomers, which implies a reduced ability to absorb water from a basic medium, resulting in a lower capacity to release the loaded drug.Since our device possesses a maximum drug release in the media at pH 7.4, it could be used for colon-targeted drug delivery of both 5-FU and Ferulic acid.     

Effect of bases with different solubility on the release behavior of risperidone loaded PLGA microspheres

Poly (D, L-lactide-co-glycolide) (PLGA) microspheres are attractive delivery vehicles due to their excellent sustained release capabilities. One major problem with PLGA microspheres is that the hydrophobic properties of PLGA generally cause a lag period in the process of drug release, leading to fluctuation of drug concentration in the blood and various resulting adverse reactions. Herein, Mg(OH)?, an inorganic base, and arginine, an organic base, were separately co-encapsulated into risperidone-loaded PLGA microspheres at varying concentration using the solvent evaporation method to improve release profiles from the microspheres. High encapsulation efficiencies were obtained in all formulations. The surface of base-free microspheres was smooth, whereas a few pores formed in base co-encapsulated microspheres. After 7-days degradation, many inter-connecting pores were formed in the interior of the microspheres containing 10 mg Mg(OH)?. The final pH in the microspheres with Mg(OH)? was higher than in those with arginine after 28-days degradation. The initial release of risperidone from microspheres containing Mg(OH)? was higher than from those containing arginine, and the latter release exhibited a more uniform pattern. Microspheres with 5mg and 10mg arginine exhibited zero-order release kinetics. However, both bases eliminated the lag phase of release. These results indicate that the incorporation of bases has potential in addressing the problem of the lag period in drug release from PLGA microspheres, and improving release behavior toward an ideal model.     

Stimuli‐responsive zein‐based nanoparticles as a potential carrier for ellipticine: Synthesis,release, and in vitro delivery

In the present research, we have investigated a drug delivery system based on the pH‐responsive behaviors of zein colloidal nanoparticles coated with sodium caseinate (SC) and poly ethylene imine (PEI). These systematically designed nanoparticles were used as nanocarriers for encapsulation of ellipticine (EPT), as an anticancer drug. SC and PEI coatings were applied through electrostatic adsorption, leading to the increased size and improved polydispersity index of nanoparticles as well as sustained release of drug. Physicochemical characteristics such as hydrodynamic diameter, size distribution, zeta potential and morphology of nanoparticles prepared using different formulations and conditions were also determined. Based on the results, EPT was encapsulated into the prepared nanoparticles with a high drug loading capacity (5.06%) and encapsulation efficiency (94.8%) under optimal conditions. in vitro experiments demonstrated that the release of EPT from zein‐based nanoparticles was pH sensitive. When the pH level decreased from 7.4 to 5.5, the rate of drug release was considerably enhanced. The mechanism of pH‐responsive complexation in the drug encapsulation and release processes was extensively investigated. The pH‐dependent electrostatic interactions and drug state were hypothesized to affect the release profiles. Compared to the EPT‐loaded zein/PEI nanoparticles, the EPT‐loaded zein/SC nanoparticles exhibited a better drug sustained‐release profile, with a smaller initial burst release and longer release period. According to the results of in vitro cytotoxicity experiments, drug‐free nanoparticles were associated with a negligible cytotoxicity, whereas the EPT‐loaded nanoparticles displayed a high toxicity for the cancer cell line, A549. Our findings indicate that these pH‐sensitive protein‐based nanoparticles can be used as novel nanotherapeutic tools and potential antineoplastic drug carriers for cancer chemotherapy with controlled release.     

The drug release profile from calcium-induced alginate gel beads coated with an alginate hydrolysate

Calcium-induced alginate gel bead (Alg-Ca) coated with an alginate hydrolysate (Alg), e.g. the guluronic acid block (GB) was prepared and the model drug, hydrocortisone release profiles were investigated under simulated gastrointestinal conditions. Their molecular weights were one sixth or one tenth that of Alg and the diffraction patterns of the hydrolysates resembled that of Alg. The drug release rate from Alg-Ca coated with GB apparently lowered than that of Alg-Ca (coating-free) in the gastric juice (pH1.2). And the coating did not resist the disintegration of Alg-Ca in the intestinal juice (pH 6.8) and the gel erosion accelerated the drug release. On the other hand, for the coated Alg-Ca containing chitosan, the drug release showed zero-order kinetics without rapid erosion of Alg-Ca. The drug release rate from Alg-Ca was able to be controlled by the coating and modifying the composition of the gel matrix.     

Rapid and precise release from nano-tracted poly(N-isopropylacrylamide) hydrogels containing linear poly(acrylic acid)

We investigated the rapid and precise molecular release from hydrogels in response to dual stimuli. To achieve precise on/off drug release using thermoresponsive poly(N-isopropylacrylamide) hydrogels, we prepared nano-structured semi-IPNs, which consisted of thermosensitive PNIPAAm networks penetrated by pH-responsive poly(acrylic acid) (PAAc) linear chains and perforated to create nano-tracts as a molecular pathway. The present nano-tracted semi-IPNs show a rapid deswelling response to both temperature and pH. Model drug releases were investigated when simultaneous changes in temperature and pH were applied. We observed that the cationic drug was rapidly released and then abruptly discontinued from the nano-tracted semi-IPNs in response to the dual stimuli, and clear release and stopping cycles were repeatedly observed on successive steps. Moreover, the release rates and amount of drug released were controllable by the deswelling speed of the gels and the PAAc content inside the gels. This novel release system using the nano-tracted semi-IPNs may be useful for the high performance, pulsed release of molecules.     

Drug release by pH‐responsive molecular tweezers: Atomistic details from molecular modeling

pH‐responsive molecular tweezers have been proposed as an approach for targeting drug‐delivery to tumors, which tend to have a lower pH than normal cells. We performed a computational study of a pH‐responsive molecular tweezer using ab initio quantum chemistry in the gas‐phase and molecular dynamics (MD) simulations in solution. The binding free energy in solution was calculated using steered MD. We observe, in atomistic detail, the pH‐induced conformational switch of the tweezer and the resulting release of the drug molecule. Even when the tweezer opens, the drug molecule remains near a hydrophobic arm of the molecular tweezer. Drug release cannot occur, it seems, unless the tweezer is in a hydrophobic environment with low pH. © 2014 Wiley Periodicals, Inc.     

A novel biocompatible drug carrier for oral delivery and controlled release of antibiotic drug: loading and release of clarithromycin as an antibiotic drug model

In this work, a novel biocompatible carrier was designed by modification of nanoporous carbon material and synthesized by hydrothermal condensation of d-Fructose, as the carbon source, in the presence of Pluronic^® F127, as the surfactant. The prepared material is completely biocompatible and suitable for oral drug delivery. As this nanoporous carbon has surface decorated hydroxyl groups, they are able to react with 3-aminopropyltriethoxysilane agent and produce amino-functionalized nanoporous carbon. The synthesis of amine-modified carbon nanoporous material was confirmed by X-ray powder diffraction, IR spectroscopy, elemental analysis, thermal analysis and nitrogen adsorption analysis. Clarithromycin as an active drug molecule with carbonyl and hydroxyl functional groups in chemical structure was chosen as the drug model and stored in pores of the amine-modified nanoporous carbon. Release of clarithromycin from modified nanoporous carbon was investigated in mouth and stomach pH values. The results showed that this drug carrier can transfer the drug up to stomach without any leak or release. The release time was investigated, and the results showed that the carrier is also successful for the controlled-release delivery.     

Hybrid alginate beads with thermal‐responsive gates for smart drug delivery

Polysaccharide‐based thermo‐responsive material was prepared by grafting PNIPAAm onto hybrid alginate beads, in which a biomineralized polyelectrolyte layer was constructed aiming to enhance the mechanical strength and ensure higher graft efficiency. XPS results demonstrated that the incorporation of PNIPAAm to the hybrid beads was successful, and the PNIPAAm‐grafted beads were more hydrophilic than the ungrafted ones as indicated by their swelling behavior. The drug release behaviors revealed that the grafted beads were both thermo‐ and pH‐sensitive, and the PNIPAAm existed in the pores of the alginate beads acted as the “on–off” gates: the pores of the beads were covered by the stretched PNIPAAm to delay the drug release at 25°C and opened to accelerate the drug release at 37°C because of the shrinking of PNIPAAm molecules. This paper would be a useful example of grafting thermo‐responsive polymers onto biodegradable natural polymer substrate. The obtained beads provide a new mode of behavior for thermo‐responsive “smart” polysaccharide materials, which is highly attractive for targeting drug delivery system and chemical separation. Copyright © 2010 John Wiley & Sons, Ltd.     

Ultrasound-Triggered Release of Ibuprofen from a Chitosan-Mesoporous Silica Composite- a Novel Approach for Controlled Drug Release

Summary: In this work, an attempt was made to synthesize a novel Chitosan-Mesoporous silica (CS-MS) hybrid composite to design a drug delivery system based on ultrasound triggered stimuli-responsive smart release. The in-vitro drug release properties of both the Mesoporous Silica (MS) and Chitosan (CS) hybrids were investigated. Ibuprofen (Ibu) was used as a model drug. The results from powder X-Ray diffraction (XRD) patterns, and BET N₂ adsorption isotherms exhibited that MS can accommodate drug molecules into the lumen of the channels and pores. Drug release, stimulated by temperature and pH of the release media was also investigated. We studied the Ultrasound (US) triggered release of Ibu in a simulated body fluid (pH 7.4). The results exhibited that US can be used as a non-invasive technique for drug release from polymeric materials. The enhancing effect of ultrasound on drug release is due to the Cavitation effect, without causing any significant destruction on the polymer morphology.     

Synthesis and characterization of a pH responsive and mucoadhesive drug delivery system for the controlled release application of anti-cancerous drug

In this work a novel pH sensitive composite, polyacrylamide grafted succinyl chitosan intercalated bentonite (AAm-g-NB/SC) was prepared as a drug carrier system for the controlled delivery of paclitaxel. Characterization of the drug delivery system was carried out using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), thermal analysis etc. The equilibrium swelling behaviour of the composite was studied and the result showed a maximum at pH 7.4. The in vitro drug release study of paclitaxel indicated that about 15.6% of drug release was found to be occurred at pH 1.2 within 16 h, whereas about 82.5% of drug release was occurred at the intestinal pH condition of 7.4. In vitro biocompatibility study was performed and the result showed good biocompatibility of the composite in the concentration range 6.25–100 µg/mL. The cytotoxicity assay was carried out in cancerous cell line of Human colorectal Adenocarcinoma. Mucous glycoprotein assay study showed that the drug delivery system having good apparent adhering property towards mucin. The investigation indicated that paclitaxel, an anticancer drug can be successfully entrapped in the AAm-g-NB/SC composite for the controlled and targeted delivery for colorectal cancer therapy.     

In Vitro Release of Local Anaesthetic and Anti-Inflammatory Drugs from Crosslinked Collagen Based Device

The drug delivery systems that are the object of this article take the form of a hydrophilic matrix (collagen or crosslinked collagen) containing a drug. These devices can be used as The model active agents, were chosen from the range of local anaesthetics (lidocaine hydrochloride), anti-inflammatory (diclofenac sodium salt) and antioxydant (caffeic acid). Whatever the drug affinity for water, in the first time of the experiments, the release appears to be systematically delayed when the matrix is crosslinked. For lidocaine hydrochloride based systems, as the amount of drug increases in the matrix, the high gap concentration between the matrix and the buffer solution promote the diffusion and a Fickian behavior is observed on the release curves. Depending on the chemical nature of the drug and its solubility, several interactions between the drug and the collagen matrix can be considered. A new drug delivery system containing caffeic acid as the anti-inflammatory and antioxydant molecule could be tested. This new system was able to release 95% of the drug in 5 h and the global release rate depends on the initial drug concentration in the device.     

载药脂质体复合缺钙磷灰石骨水泥支架的研究

采用食盐颗粒浸出法制备了缺钙磷灰石水泥(CPC)多孔支架;用脂质体包裹盐酸万古霉素制备了载药脂质体。将它们两者结合,制备了脂质体载药复合缺钙磷灰石水泥(dl-CPC)支架。结果表明:缺钙CPC多孔支架能够将载药脂质体吸附在其大孔表面或微孔里;dl-CPC支架对MC3T3-E1细胞的生长没有负面影响,显示出良好的细胞相容性。此外,dl-CPC支架具有很好的抗菌性能,能够抑制大肠杆菌生长,抗菌率达99%(12 h)。dl-CPC支架浸泡在磷酸缓冲溶液中,释放药物的速度比较缓慢(前4周);而直接吸附药物的CPC支架,在1周内大部分药物释放出来,出现暴释现象。另结果表明:dl-CPC支架具有缓释药物和骨再生的双重功能,可用于骨缺损的修复及治疗慢性骨髓炎。     

The controlled release of a drug from biodegradable chitosan gel beads

Chitosan (CS) forms a gel in solutions with a pH above 12, and the gelation occurs at pH of about 9 in 10% amino acid solutions. In this paper, we investigated the enzymatic degradation and the drug release profile of this novel CS gel beads. The degradability of the CS gel beads was affected by the CS properties, e.g. the degree of deacetylation. The release of prednisolone (PS), as a model drug, from the CS gel beads was sustained significantly compared with the gel prepared with NaOH only. However, the release was not able to be sustained by the increment of NaOH concentration in the solution employed for the preparation of CS gel beads. We also investigated the control of drug release from CS gel beads by application of a complex formed between chondroitin sulfate (Cho) and CS. The release of PS from the CS gel beads treated with Cho was prolonged, and the release pattern was not affected by the treatment time. The time to 50% drug release was about 5 min with PS powder, about 200 min in CS gel beads with 10% glycine (Gly) (pH 9.0), and about 330 min in the CS gel beads with 10% Gly (pH 9.0) treated with Cho. Thus CS gel beads appear promising as a vehicle for sustained drug delivery, and the degradation of CS gel beads may be controlled by the degree of deacetylation of CS.     

Core‐shell structure microcapsules with dual pH‐responsive drug release function

We report dual pH‐responsive microcapsules manufactured by combining electrostatic droplets (ESD) and microfluidic droplets (MFD) techniques to produce monodisperse core (alginate)‐shell (chitosan) structure with dual pH‐responsive drug release function. The fabricated core‐shell microcapsules were size controllable by tuning the synthesis parameters of the ESD and MFD systems, and were responsive in both acidic and alkaline environment, We used two model drugs (ampicillin loaded in the chitosan shell and diclofenac loaded in the alginate core) for drug delivery study. The results show that core‐shell structure microcapsules have better drug release efficiency than respective core or shell particles. A biocompatibility test showed that the core‐shell structure microcapsules presented positive cell viability (above 80%) when evaluated by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The results indicate that the synthesized core‐shell microcapsules were a potential candidate of dual‐drug carriers.     

Design of controlled release system with multi-layers of powder

Pellets containing active ingredients were coated with water-insoluble powders, i.e. hydrogenated caster oil (Lubliwax (WAX)) and magnesium stearate (Mg-St). The influences of the structural difference of the sustained release layer and curing conditions on the drug release rate were investigated. Sodium valproate (VP-Na) was used as a highly water-soluble model drug. Drug release profiles were influenced by the combination of the WAX layer and the Mg-St layer. Even if the formula of sustained release layers were the same, drug release rate could be affected by the structural difference of the controlled release layer. The Mg-St layer was more effective in prolonging drug release than the WAX layer. Compared with single and double layer types, the triple layer (sandwich) type was most effective in obtaining a long sustained drug release. Heat-treatment retarded drug release mainly by increasing the density of the sustained release layer of the WAX. The Mg-St was effective in protecting the agglomeration between particles during heat-treatment. Optimal heat-treatment conditions were found to exist. Scanning electron microscopy (SEM) analysis indicated that heat-treatment caused the WAX to melt, formed a film-like structure and made the release layer dense. Furthermore, heat-treatment changed the release pattern of VP-Na from sustained release pellets with a multi-layer of powder, leading to zero-order release.     

Characterization of factors affecting the release of low-solubility drug from prolonged release tablets

Diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid monosodium salt) was investigated as a low-solubility drug and Naklofen^® retard prolonged release tablets, containing 100 mg of diclofenac sodium as a prolonged release lipophilic matrix system using factorial design approach. First, the solubility characteristics of diclofenac sodium in aqueous media with various ionic strengths, ionic compositions and pH in the range of 1-8 were determined. The obtained results showed that the solubility of diclofenac sodium depends mainly on pH of the aqueous medium and less on the composition and ionic strength of the medium. Next, the estimation of the effects of six different factors (type of the dissolution apparatus, rotation speeds of the stirring elements, pH, ionic strengths of dissolution medium, the applied salt, and the producer of the on-line connected dissolution apparatus and UV spectrophotometer) on the release of diclofenac sodium, using the two-level six-factorial design was investigated. It was found that rotation speeds of the stirring elements, pH, and ionic strengths of the dissolution medium have a significant impact on the drug release and should be further followed in future drug release analyses. The advantages of the factorial design approach are obvious in this work. It is a very economic way of obtaining the maximum amount of information in a short period of time, especially in the case of prolonged release formulations where each experiment requires at least 24 h.     

Reduction and pH dual‐responsive block copolymers containing pendent p‐nitrobenzyl carbamate functionalities: Synthesis and self‐assembly behavior

We report on the preparation of reduction‐responsive amphiphilic block copolymers containing pendent p‐nitrobenzyl carbamate (pNBC)‐caged primary amine moieties by reversible addition–fragmentation chain transfer (RAFT) radical polymerization using a poly(ethylene glycol)‐based macro‐RAFT agent. The block copolymers self‐assembled to form micelles or vesicles in water, depending on the length of hydrophobic block. Triggered by a chemical reductant, sodium dithionite, the pNBC moieties decomposed through a cascade 1,6‐elimination and decarboxylation reactions to liberate primary amine groups of the linkages, resulting in the disruption of the assemblies. The reduction sensitivity of assemblies was affected by the length of hydrophobic block and the structure of amino acid‐derived linkers. Using hydrophobic dye Nile red (NR) as a model drug, the polymeric assemblies were used as nanocarriers to evaluate the potential for drug delivery. The NR‐loaded nanoparticles demonstrated a reduction‐triggered release profile. Moreover, the liberation of amine groups converted the reduction‐responsive polymer into a pH‐sensitive polymer with which an accelerated release of NR was observed by simultaneous application of reduction and pH triggers. It is expected that these reduction‐responsive block copolymers can offer a new platform for intracellular drug delivery. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1333–1343     

Magnetic‐targeted pH‐responsive drug delivery system via layer‐by‐layer self‐assembly of polyelectrolytes onto drug‐containing emulsion droplets and its controlled release

Novel magnetic‐targeted pH‐responsive drug delivery system have been designed by the layer‐by‐layer self‐ assembly of the polyelectrolytes (oligochitosan as the polycation and sodium alginate as the polyanion) via the electrostatic interaction with the oil‐in‐water type hybrid emulsion droplets containing the superparamagnetic ferroferric oxide nanoparticles and drug molecules [dipyridamole (DIP)] as cores. Here the drug molecules were directly encapsulated into the interior of droplets without etching the templates and refilling with the desired guest molecules. The drug‐delivery system showed high encapsulation efficiency of drugs and drug‐loading capacity. The cumulative release ratio of dipyridamole from the oligochitosan/sodium alginate multilayer‐encapsulated magnetic hybrid emulsion droplets (DIP/Fe₃O₄‐OA/OA)@(OCS/SAL)₄ was up to almost 100% after 31 h at pH 1.8. However, the cumulative release ratio was only 3.3% at pH 7.4 even after 48 h. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Effect of an oscillating magnetic field on the release properties of magnetic collagen gels

The paper describes the effect of an oscillating magnetic field (OMF) on the morphology and release properties of collagen gels containing magnetic nanoparticles and microparticles and fluorescent drug analogues. Collagen gels were prepared through fibrillogenesis of collagen in the presence of iron oxide magnetic particles averaging 10 nm or 3 mum in diameter and rhodamine-labeled dextran (Dex-R) of molecular weights between 3000-70 000 g/mol. Dextran molecules effectively simulate protein-based drugs, since they have similar molecular weights and dimensions. The paper discusses the effect of an OMF on the release properties of the gels and proposes an empirical model to predict the release rate. It also demonstrates the self-repair capability of collagen gels following the structural damage caused by an OMF.     

Adsorption and controlled release of Chlortetracycline HCl by using multifunctional polymeric hydrogels

Adsorption and controlled release of Chlortetracycline HCl to and from multifunctional polymeric materials (HEMA/MAA) hydrogels were investigated. P(HEMA/MAA) hydrogels were synthesized by gamma radiation-induced copolymerization of 2-hydroxyethylmethacrylate (HEMA) and methacrylic acid (MAA) in aqueous solution. The influence of copolymer composition and pH value of the surrounding medium on the type of water diffusion into the glassy polymer were discussed. Drug, Chlortetracycline HCl containing hydrogels, with different drug concentration to polymer ratios, was loaded by direct adsorption method. The influence of MAA content in the gel on the adsorption capacities of hydrogel was studied. Chlortetracycline HCl adsorption capacity of hydrogels was found to increase from 8 to 138 mg Chlortetracycline HCl per gram dry gel with increasing amount of MAA in the gel system and drug concentration. The effect of pH on the releasing behavior of Chlortetracycline HCl from gel matrix was investigated. In vitro drug release studies in different buffer solutions show that the basic parameters affecting the drug release behavior of hydrogel are the pH of the solution and MAA content of hydrogel.