Comparative Evaluation of Porous Versus Nonporous Mucoadhesive Films as Buccal Delivery System of Glibenclamide

The present research work focused on the comparative assessment of porous versus nonporous films in order to develop a suitable buccoadhesive device for the delivery of glibenclamide. Both films were prepared by solvent casting technique using the 3² full factorial design, developing nine formulations (F1–F9). The films were evaluated for ex vivo mucoadhesive force, ex vivo mucoadhesion time, in vitro drug release (using a modified flow-through drug release apparatus), and ex vivo drug permeation. The mucoadhesive force, mucoadhesion time, swelling index, and tensile strength were observed to be directly proportional to the content of HPMC K4M. The optimized porous film (F4) showed an in vitro drug release of 84.47 ± 0.98%, ex vivo mucoadhesive force of 0.24 ± 0.04 N, and ex vivo mucoadhesion time of 539.11 ± 3.05 min, while the nonporous film (NF4) with the same polymer composition showed a release of 62.66 ± 0.87%, mucoadhesive force of 0.20 ± 0.05 N, and mucoadhesive time of 510 ± 2.00 min. The porous film showed significant differences for drug release and mucoadhesion time (p < 0.05) versus the nonporous film. The mechanism of drug release was observed to follow non-Fickian diffusion (0.1 < n < 0.5) for both porous and nonporous films. Ex vivo permeation studies through chicken buccal mucosa indicated improved drug permeation in porous films versus nonporous films. The present investigation established porous films to be a cost-effective buccoadhesive delivery system of glibenclamide.KEY WORDS: buccoadhesive drug delivery, glibenclamide, in vitro release and ex vivo permeation, porous film     

Porosity and pore size regulate the degradation product profile of polylactide

Porosity and pore size regulated the degradation rate and the release of low molar mass degradation products from porous polylactide (PLA) scaffolds. PLA scaffolds with porosities above 90% and different pore size ranges were subjected to hydrolytic degradation and compared to their solid analog. The solid film degraded fastest and the degradation rate of the porous structures decreased with decreasing pore size. Degradation products were detected earlier from the solid films compared to the porous structures as a result of the additional migration path within the porous structures. An intermediate degradation rate profile was observed when the pore size range was broadened. The morphology of the scaffolds changed during hydrolysis where the larger pore size scaffolds showed sharp pore edges and cavities on the scaffold surface. In the scaffolds with smaller pores, the pore size decreased during degradation and a solid surface was formed on the top of the scaffold. Porosity and pore size, thus, influenced the degradation and the release of degradation products that should be taken into consideration when designing porous scaffolds for tissue engineering.     

Superhydrophobic Properties of Nanostructured–Microstructured Porous Silicon for Improved Surface-Based Bioanalysis

Wettability is a fundamental property of a solid surface, which plays important roles in many industrial applications. The possibility to create well-controlled nonwetting states on silicon surfaces without photolithography-based processing can bring many advantages in the biotechnology and microfluidics areas. In this paper, superhydrophobic properties of macroporous–nanoporous structured silicon are reported. The superhydrophobic porous silicon layers are prepared by electrochemical etching of bulk crystalline silicon wafers. Altered anodization conditions provide surfaces with varying pore morphologies, yielding different wetting properties, ranging from highly wetting (nanoporous morphologies) to water-repellent surfaces (macroporous morphologies). Subsequent surface modification with a fluorocarbon coupling agent can further improve nonwetting properties and stabilize the surface for a long term. Contact angles as high as 176° were achieved on macroporous silicon and superhydrophobicity was maintained for several months without degradation. The porous surfaces have proven to be a very attractive substrate for protein microarrays. Fluorescence-based assay of immunoglobulin G in plasma is reported with a limit of detection of 1 pM, a spot size of 50 μm, and an array density of 15,625 spots per square centimeter. Macroporous surfaces have also been developed for matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) applications, where the intrinsic hydrophobic surface properties confine the deposited sample to MALDI spots of less than 200 μm with well-defined MALDI crystals, providing a high-sensitivity readout. Furthermore, a superhydrophobic MALDI-TOF MS target anchor chip composed of nonporous anchor points surrounded by superhydrophobic porous areas for sample deposition and on anchor point confinement is reported. Such anchor chips allowed localized crystallization of large sample volumes (5 μL) improving the hydrophobic spot confinement strategy in terms of final MALDI crystal localization and readout sensitivity.     

Enabling multienzyme biocatalysis using nanoporous materials

Multistep reactions catalyzed by a covalently immobilized enzyme-cofactor-enzyme system were achieved. Lactate dehydrogenase (LDH), glucose dehydrogenase (GDH), and cofactor NADH were incorporated into two porous silica glass supports. One of the glass supports had pores of 30 nm in diameter, while the other was of 100-nm pore size. Effective shuttling of the covalently bound NADH between LDH and GDH was achieved, such that regeneration cycles of NADH/NAD(+) were observed. The glass of 30-nm pore size afforded enzyme activities that were about twice those observed for the glass of 100-nm pore size, indicating the former provided better enzyme-cofactor integration. The effect of the size of spacers was also examined. The use of longer spacers increased the reaction rates by approximately 18 times as compared to those achieved with glutaraldehyde linkage. It appeared that the concave configuration of the nanopores played an important role in enabling the multistep reactions. The same multienzyme system immobilized on nonporous polystyrene particles of 500-nm diameter was only approximately 2% active as the glass-supported system. It is believed that the nanoporous structure of the glass supports enhances the molecular interactions among the immobilized enzymes and cofactor, thus improving the catalytic efficiency of the system.     

Porous devices derived from co-continuous polymer blends as a route for controlled drug release

In this study we examine the release profile of bovine serum albumin (BSA) from a porous polymer matrix derived from a co-continuous polymer blend. The porosity is generated through the selective extraction of one of the continuous phases. This is the first study to examine the approach of using morphologically tailored co-continuous polymer blends as a template for generating porous polymer materials for use in controlled release. A method for the preparation of polymeric capsules is introduced, and the effect of matrix pore size and surface area on the BSA release profile is investigated. Furthermore, the effect of surface charge on release is examined by surface modification of the porous substrate using layer-by-layer deposition techniques. Synthetic, nonerodible polymer, high-density polyethylene (HDPE), was used as a model substrate prepared by melt blending with two different styrene-ethylene-butylene copolymers. Blends with HDPE allow for the preparation of porous substrates with small pore sizes (300 and 600 nm). A blend of polylactide (PLA) and polystyrene was also used to prepare porous PLA with a larger pore size (1.5 microm). The extents of interconnectivity, surface area, and pore dimension of the prepared porous substrates were examined via gravimetric solvent extraction, BET nitrogen adsorption, mercury porosimetry, and image analysis of scanning electron microscopy micrographs. With a loading protocol into the porous HDPE and PLA involving the alternate application of pressure and vacuum, it is shown that virtually the entire porous network was accessible to BSA loading, and loading efficiencies of between 80% and 96% were obtained depending on the pore size of the carrier and the applied pressure. The release profile of BSA from the microporous structure was monitored by UV spectrophotometry. The influence of pore size, surface area, surface charge, and number of deposited layers is demonstrated. It is shown that an effective closed-cell structure in porous PLA can be prepared, effectively eliminating all short-term BSA release.     

Protamine assembled in multilayers on colloidal particles can be exchanged and released

Biocomposite thin films assembled on colloidal particles by means of layer-by-layer adsorption have been suggested as drug carriers and diagnostic devices. Protamine (PRM)/dextransulfate (DXS) and protamine/bovine serum albumine (BSA) multilayers were fabricated on colloidal silica and subsequently investigated by means of fluorescence activated cell sorting (FACS) and microelectrophoresis. Fluorescein labeled polyelectrolytes were embedded at different positions in the multilayers as a marker for layer growth. FACS showed that PRM and DXS formed regular growing stable multilayers, yet adsorbed PRM can be nevertheless exchanged with PRM in solution during layer formation and also after the multilayer formation has been completed. Up to 90% of the PRM pool was available for exchange. PRM together with BSA as demonstrated by SFM did not form multilayers under the applied conditions although the zeta-potential, commonly used as an indicator for stepwise adsorption, observed characteristic alternations. The capability of bound PRM to exchange with PRM in solution is attributed to its relatively small size. The demonstrated exchange may have importance in designing multilayers with smart release features. Furthermore, FACS proved to be a rather suitable means to quantify the aggregation behavior during coating and washing. Singulets, doublets, triplets, and aggregates of higher order could be clearly resolved. The aggregation of particles coated with PRM/DXS layers was higher than that of silica particles coated with PAH/PSS layers. In the first case about 50% of all recorded events are attributed to aggregats, while the PAH/PSS coating produced only about 10% aggregates.     

Evaluation of cellular adhesion and organization in different microporous polymeric scaffolds

The lack of prediction accuracy during drug development and screening risks complications during human trials, such as drug‐induced liver injury (DILI), and has led to a demand for robust, human cell‐based, in vitro assays for drug discovery. Microporous polymer‐based scaffolds offer an alternative to the gold standard flat tissue culture plastic (2D TCPS) and other 3D cell culture platforms as the porous material entraps cells, making it advantageous for automated liquid handlers and high‐throughput screening (HTS). In this study, we optimized the surface treatment, pore size, and choice of scaffold material with respect to cellular adhesion, tissue organization, and expression of complex physiologically relevant (CPR) outcomes such as the presence of bile canaliculi‐like structures. Poly‐l‐ lysine and fibronectin (FN) coatings have been shown to encourage cell attachment to the underlying substrate. Treatment of the scaffold surface with NaOH followed with a coating of FN improved cell attachment and penetration into pores. Of the two pore sizes we investigated (A: 104 ± 4 μm; B: 175 ± 6 μm), the larger pore size better promoted cell penetration while limiting tissue growth from reaching the hypoxia threshold. Finally, polystyrene (PS) proved to be conducive to cell growth, penetration into the scaffold, and yielded CPR outcomes while being a cost‐effective choice for HTS applications. These observations provide a foundation for optimizing microporous polymer‐based scaffolds suitable for drug discovery. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:505–514, 2018     

Ethylcellulose-Based Matrix-Type Microspheres: Influence of Plasticizer RATIO as Pore-Forming Agent

In this study, ethylcellulose (EC)-based microsphere formulations were prepared without and with triethyl citrate (TEC) content of 10% and 30% by water-in-oil emulsion-solvent evaporation technique. Diltiazem hydrochloride (DH) was chosen as a hydrophilic model drug and used at different drug/polymer ratios in the microspheres. The aim of the work was to evaluate the influence of plasticizer ratio on the drug release rate and physicochemical characteristics of EC-based matrix-type microspheres. The resulting microspheres were evaluated for encapsulation efficiency, particle size and size distribution, surface morphology, total pore volume, thermal characteristics, drug release rates, and release mechanism. Results indicated that the physicochemical properties of microspheres were strongly affected by the drug/polymer ratio investigated and the concentration of TEC used in the production technique. The surface morphology and pore volume of microspheres significantly varied based on the plasticizer content in the formulation. DH release rate from EC-based matrix-type microspheres can be controlled by varying the DH to polymer and plasticizer ratios. Glass transition temperature values tended to decrease in conjunction with increasing amounts of TEC. Consequently, the various characteristics of the EC microspheres could be modified based on the plasticized ratio of TEC.     

Preparation and gas storage of high surface area microporous carbon derived from biomass source cornstalks

Microporous carbon (MC) with a high surface area has been prepared from cornstalks through carbonization and KOH activation. The surface area of the obtained product varies to some extent but the pore size of the material remains within the micropore region as the concentration of KOH activating agent is increased. The MC we prepared exhibits H2 adsorption capacities up to 4.4 wt% at 77K and this material is also able to adsorb considerable amounts of CH4 and CO2. The high adsorption capacities for gases are attributed to the relatively narrow pore size and the high surface area of the porous carbon material.     

Formulation and optimization of porous osmotic pump-based controlled release system of oxybutynin

The aim of the current study was to design a porous osmotic pump-based drug delivery system for controlled release of oxybutynin. The porous osmotic pump contains pore-forming water-soluble additives in the coating membrane, which after coming in contact with water, dissolve, resulting in an in situ formation of a microporous structure. The dosage regimen of oxybutynin is one 5-mg tablet 2 to 3 times a day. The plasma half-life ranges from ∼2 to 3 hours. Hence, oxybutynin was chosen as a model drug with an aim to develop a controlled release system for a period of 24 hours. Linear and reproducible release similar to that of Ditropan XL was achieved for optimized formulation (f2>50) independent of hydrodynamic conditions. The effect of different formulation variables, namely, ratio of drug to osmogent, membrane weight gain, and level of pore former on the in vitro release was studied. Cellulose acetate (CA) was used as the semipermeable membrane. It was found that drug release rate increased with the amount of osmogent because of the increased water uptake, and hence increased driving force for drug release. Oxybutynin release was inversely proportional to the membrane weight gain; however, directly related to the level of pore former, sorbitol, in the membrane. This system was found to deliver oxybutynin at a zero-order rate for 20 hours. The effect of pH on drug release was also studied. The optimized formulations were subjected to stability studies as per International Conference on Harmonisation (ICH) guidelines and formulations were stable after a 3 month study. Published: July 13, 2007     

Porous silicon biosensor for detection of viruses

There is a growing need for virus sensors with improved sensitivity and dynamic range, for applications including disease diagnosis, pharmaceutical research, agriculture and homeland security. We report here a new method for improving the sensitivity for detection of the bacteriophage virus MS2 using thin films of nanoporous silicon. Porous silicon is an easily fabricated material that has extremely high surface area to volume ratio, making it an ideal platform for surface based sensors. We have developed and evaluated two different methods for covalent bioconjugation of antibodies inside of porous silicon films, and we show that the pore penetration and binding efficiency depend on the wettability of the porous surface. The resulting films were used to selectively capture dye-labeled MS2 viruses from solution, and a viral concentration as low as 2 x 10(7) plaque-forming units per mL (pfu/mL) was detectable by measuring the fluorescence from the exposed porous silicon film. The system exhibits sensitivity and dynamic range similar to the Luminex liquid array-based assay while outperforming protein micro-array methods.     

Amino acid modified carbon nanotubes with optimal pore size for chiral separation

Precisely controlling pore size of porous materials is of great importance for chiral separation, but a great challenge in practical applications. In contrast, the molecular dynamics (MD) simulation can be quite a convenient way to determine the effect of the pore dimension on the chiral resolution performances and thus to define the optimal pore size. In this work, inner-wall functionalised carbon nanotubes (CNTs) were used as porous materials and D- and L-phenylalanine were selected as chiral probes. The enantioseparation behaviour was investigated via varying the pore diameter of CNTs, controlling the grafting amount of chiral selectors and tuning the spacer length. Results show that varying the pore size has a significant effect on the enantioselectivity. Additionally, the effect of the introduction of varying the grafting ratio and tuning the spacer length on the chiral separation performance was also examined in this work. It was found that varying the grafting ratio, especially the spacer length between substrates and selectors, could also be one of the most effective alternatives to improving enantioselectivity. Our findings can provide a guidance for the practical applications in the chiral separation.     

Polyelectrolyte multilayers for tunable release of antibiotics

Polyelectrolyte multilayers incorporating gentamicin were fabricated using layer-by-layer deposition. The multilayers could be precisely tuned with regard to dosage, and release rate under aqueous physiological conditions could be controlled. The films were demonstrated efficacious against Staphylococcus aureus and nontoxic toward murine osteoblasts MC3T3. The films were made in a layer-by-layer process with a heterostructural architecture that represents a general strategy for incorporating charged small molecular species into polyelectrolyte multilayers without the need for any physical or chemical premodification, expanding the range of active species that can be delivered from these films while maintaining the ease of layer-by-layer fabrication process.     

Entamoeba invadens: enhancement of excystation and metacystic development by cytochalasin D

Effects of three actin-modifying drugs, cytochalasin D, latrunculin A, and jasplakinolide, on the excystation and metacystic development in vitro of Entamoeba invadens were examined by transfer of the cysts to growth medium with the drugs. Cytochalasin D unexpectedly increased the number of metacystic amoebae of E. invadens strain IP-1 during incubation. Metacystic development, which was determined by the number of nuclei of metacystic amoebae, was faster in the culture with cytochalasin D than in the culture without the drug. These results suggest that cytochalasin D enhances the excystation and metacystic development. In contrast, latrunculin A and jasplakinolide inhibited these process. No excystation occurred in encystation medium even in the presence of cytochalasin D, suggesting that growth medium is essential for excystation. Excystation was further enhanced when the cysts were incubated with cytochalasin D before culture in growth medium with the drug. The enhancing effect of cytochalasin D on the excystation and metacystic development was abrogated by jasplakinolide. Thus, the results indicate that cytochalasin D, unlike latrunculin A and jasplakinolide, caused enhancement of the excystation and metacystic development of this parasite.     

Molecular simulation of permeation behaviour of ethanol/water molecules with single-layer graphene oxide membranes

Graphene oxide (GO)-based materials have shown promise as water-permeating membranes in pervaporation separation. However, the feed permeation and surface affinity of single-layer nanoporous GO sheet for liquid mixtures remain unresolved. Here, the pressure-driven molecular transport of pure ethanol and pure water, as well ethanol-water mixtures, crossing through single-layer nanoporous GO sheet was studied by non-equilibrium molecular dynamics simulations. We show that single-layer GO sheet with controlled pore sizes can effectively reject ethanol and allow water permeation with high permeability. This means that porous GO sheets could act as an effective dehydration membrane, therefore providing the initial barrier for ethanol passage in GO-based membrane. The pore size effect was considered as the separation mechanism. Both ethanol and water molecules in the mixture show comparable affinity with GO surfaces. The hydrogen-bonding coupling interaction between mixture and surface functional groups provide addition influence on the molecular transport through GO pores.     

Biomedical applications of electrostatic layer-by-layer nano-assembly of polymers,enzymes, and nanoparticles

The introduction of electrostatic layer-by-layer (LbL) self-assembly has shown broad biomedical applications in thin film coating, micropatterning, nanobioreactors, artificial cells, and drug delivery systems. Multiple assembly polyelectrolytes and proteins are based on electrostatic interaction between oppositely charged layers. The film architecture is precisely designed and can be controlled to 1-nm precision with a range from 5 to 1000 nm. Thin films can be deposited on any surface including many widely used biomaterials. Microencapsulation of micro/nanotemplates with multilayers enabled cell surface modification, controlled drug release, hollow shell formation, and nanobioreactors. Both in vitro and in vivo studies indicate potential applications in biology, pharmaceutics, medicine, and other biomedical areas.     

Sustained Release of Poorly Water-Soluble Drug from Hydrophilic Polymeric Film Sandwiched Between Hydrophobic Layers

This proof-of-concept study explores the feasibility of using a drug-loaded hydrophilic polymeric layer sandwiched between two hydrophobic layers for improving film drug load while achieving sustained release of poorly water-soluble drug. Such films having total thickness in range ~?146–250 μm were prepared by slurry-based casting using hydrophilic hydroxypropyl methylcellulose (HPMC) as matrix layer containing fenofibrate (FNB) as the model drug, encased between two very thin rate-limiting layers of 10 μm each of hydrophobic poly-?-caprolactone (PCL). Film precursor slurry consisted of HPMC with plasticizer and water along with micronized FNB powders, which were dry-coated with hydrophilic silica. Characterization techniques demonstrated the presence of homogeneously dispersed crystalline FNB in films. The films are very thin and hence two-dimensional; hence, average drug load per unit area in range ~?5 to ~?9 mg/cm² could be achieved by altering the thickness of the drug matrix layer. Drug amount and drug content uniformity were measured through assay of ten circular samples ~?0.712 cm² in area punched out using a circular-shaped punch tool. Drug release rate was investigated using USP IV flow-through cell and surface dissolution imaging system. Thinner films followed Fickian diffusion, and thicker films followed non-Fickian anomalous diffusion. Overall, the application of middle layer thickness could be used as a tool to manipulate drug load without the need for altering its formulation or precursor preparation by changing its thickness, hence achieving relatively high drug loading yet having sustained release of drug.     

Polypeptide multilayer film co-delivers oppositely-charged drug molecules in sustained manners

The current state-of-the-art for drug-carrying biomedical devices is mostly limited to those that release a single drug. Yet there are many situations in which more than one therapeutic agent is needed. Also, most polyelectrolyte multilayer films intended for drug delivery are loaded with active molecules only during multilayer film preparation. In this paper, we present the integration of capsules as vehicles within polypeptide multilayer films for sustained release of multiple oppositely charged drug molecules using layer-by-layer nanoassembly technology. Calcium carbonate (CaCO(3)) particles were impregnated with polyelectrolytes, shelled with polyelectrolyte multilayers, and then assembled onto polypeptide multilayer films using glutaraldehyde. Capsule-integrated polypeptide multilayer films were obtained after decomposition of CaCO(3) templates. Two oppositely charged drugs were loaded into capsules within polypeptide multilayer films postpreparation based on electrostatic interactions between the drugs and the polyelectrolytes impregnated within capsules. We determined that the developed innovative capsule-integrated polypeptide multilayer films could be used to load multiple drugs of very different properties (e.g., opposite charges) any time postpreparation (e.g., minutes before surgical implantation inside an operating room), and such capsule-integrated films allowed simultaneous delivery of two oppositely charged drug molecules and a sustained (up to two weeks or longer) and sequential release was achieved.     

Free‐Standing 3D Nanoporous Duct‐Like and Hierarchical Nanoporous Graphene Films for Micron‐Level Flexible Solid‐State Asymmetric Supercapacitors

High energy density and power density within a limited volume of flexible solid‐state supercapacitors are highly desirable for practical applications. Here, free‐standing high‐quality 3D nanoporous duct‐like graphene (3D‐DG) films are fabricated with high flexibility and robustness as the backbones to deposit flower‐like MnO₂ nanosheets (3D‐DG@MnO₂). The 3D‐DG is the ideal support for the deposition of large amount of active materials because of its large surface area, appropriate pore structure, and negligible volume compared with other kinds of carbon backbones. Moreover, the 3D‐DG preserve the distinctive 2D coherent electronic properties of graphene, in which charge carriers move rapidly with a small resistance through the high‐quality and continuous chemical vapor deposition‐grown graphene building blocks, which results in a high rate performance. Marvelously, ultrathin (≈50 μm) flexible solid‐state asymmetric supercapacitors (ASCs) using 3D‐DG@MnO₂ as the positive electrode and 3D hierarchical nanoporous graphene films as the negative electrode display ultrahigh volumetric energy density (28.2 mW h cm^?3) and power density (55.7 W cm^?3) at 2.0 V. Furthermore, as‐prepared ASCs show high cycle stability clearly demonstrating their broad applications as power supplies in wearable electronic devices.     

Porous polystyrene beads as carriers for self-emulsifying system containing loratadine

The aim of this study was to formulate a self-emulsifying system (SES) containing a lipophilic drug, loratadine, and to explore the potential of preformed porous polystyrene beads (PPB) to act as carriers for such SES. Isotropic SES was formulated, which comprised Captex 200 (63% wt/wt), Cremophore EL (16% wt/wt), Capmul MCM (16% wt/wt), and loratadine (5% wt/wt). SES was evaluated for droplet size, drug content, and in vitro drug release. SES was loaded into preformed and characterized PPB using solvent evaporation method. SES-loaded PPB were evaluated using scanning electron microscopy (SEM) for density, specific surface area (S_BET), loading efficiency, drug content, and in vitro drug release. After SES loading, specific surface area reduced drastically, indicating filling of PPB micropores with SES. Loading efficiency was least for small size (SS) and comparable for medium size (MS) and large size (LS) PPB fractions. In vitro drug release was rapid in case of SS beads due to the presence of SES near to surface. LS fraction showed inadequate drug release owing to presence of deeper micropores that resisted outward diffusion of entrapped SES. Leaching of SES from micropores was the rate-limiting step for drug release. Geometrical features such as bead size and pore architecture of PPB were found to govern the loading efficiency and in vitro drug release from SES-loaded PPB. Published: March 24, 2006