Experiment on formulation and drug release behavior of porosity asymmetric membrane capsules in vitro

Porosity asymmetric membrane capsules were prepared to study the relationship between the capsule formulation and drug release. Cellulose acetate (CA) and pore formers were used in the capsule shell formulation as the main semipermeable membrane material. The capsules were permeable to both water and dissolved solutes. Using sparingly soluble drug acetaminophen as a model, cumulative release was calculated. The slope of the release profile from the distilled water had good relationship with the concentration of the pore formers F68. The release of acetaminophen was independent to the pH, osmotic pressure of dissolution medium, but influenced by intensity of agitation. When the concentration of pore former was low, zero-order release behavior was observed within 24?h which was consistent with Fickian diffusion model. When the concentration of pore former was high, however, Higuchi model release was found which is caused by Fickian diffusion and osmotic pressure release. With scanning electron microscope (SEM), the surface structure and cross-section of the capsule shell were also studied before and after drug delivery. With simple preparation and broad scope of drug application, porosity asymmetric membrane capsules can give desired drug extended release and show more convenience than controlled tablets with laser drilling.     

Experiment on formulation and drug release behavior of porosity asymmetric membrane capsules in vitro

Porosity asymmetric membrane capsules were prepared to study the relationship between the capsule formulation and drug release. Cellulose acetate (CA) and pore formers were used in the capsule shell formulation as the main semipermeable membrane material. The capsules were permeable to both water and dissolved solutes. Using sparingly soluble drug acetaminophen as a model, cumulative release was calculated. The slope of the release profile from the distilled water had good relationship with the concentration of the pore formers F68. The release of acetaminophen was independent to the pH, osmotic pressure of dissolution medium, but influenced by intensity of agitation. When the concentration of pore former was low, zero-order release behavior was observed within 24?h which was consistent with Fickian diffusion model. When the concentration of pore former was high, however, Higuchi model release was found which is caused by Fickian diffusion and osmotic pressure release. With scanning electron microscope (SEM), the surface structure and cross-section of the capsule shell were also studied before and after drug delivery. With simple preparation and broad scope of drug application, porosity asymmetric membrane capsules can give desired drug extended release and show more convenience than controlled tablets with laser drilling.     

Deformed shapes of axisymmetric capsules enclosed by elastic membranes

A boundary-value problem is formulated describing the shapes of inflated and deflated axisymmetric capsules enclosed by elastic membranes. When the membrane tension is isotropic and the principal bending moments obey constitutive equations involving the principal curvatures in the reference and deformed state but not the stretch ratios, the capsule shape is governed by a third-order ordinary differential equation for the meridional curvature involving the difference between the internal and external pressure. Numerical solutions of the boundary-value problem illustrate the shape of deflated spherical capsules enclosed by incompressible membranes and the shape of inflated and deflated biconcave capsules resembling red blood cells. The results demonstrate that the solution space of deformed spherical capsules consists of bifurcating branches arising at a sequence of transmural pressures, and illustrate the pressure developing inside spherical and biconcave capsules when a certain amount of fluid has been injected into, or withdrawn from, the interior.     

Liposome-based nanocapsules

Here we present three different types of mechanically stable nanometer-sized hollow capsules. The common point of the currently developed systems in our laboratory is that they are liposome based. Biomolecules can be used to functionalize lipid vesicles to create a new type of intelligent material. For example, insertion of membrane channels into the capsule wall can modify the permeability. Covalent binding of antibodies allows targeting of the capsule to specific sites. Liposomes loaded with enzymes may provide an optimal environment for them with respect to the maximal turnover and may stabilize the enzyme. However, the main drawback of liposomes is their instability in biological media as well as their sensitivity to many external parameters such as temperature or osmotic pressure. To increase their stability we follow different strategies: 1) polymerize a two-dimensional network in the hydrophobic core of the membrane; 2) coat the liposome with a polyelectrolyte shell; or 3) add surface active polymers to form mixed vesicular structures.     

Microfluidic Production of Biodegradable Microcapsules for Sustained Release of Hydrophilic Actives

Biodegradable microcapsules with a large aqueous lumen and ultrathin membrane are microfluidically designed for sustained release of hydrophilic bioactives using water‐in‐oil‐in‐water double‐emulsion drops as a template. As a shell phase, an organic solution of poly(lactic‐co‐glycolic acid) is used, which is consolidated to form a biodegradable membrane. The encapsulants stored in the lumen are released over a long period of time as the membranes degrade. The period can be controlled in a range of —three to five months at neutral pH condition by adjusting membrane thickness, providing highly sustained release and potentially enabling the programed release of multiple drugs. At acidic or basic condition, the degradation is accelerated, leading to the release in the period of approximately two months. As the membrane is semipermeable, the microcapsules respond to the osmotic pressure difference across the membrane. The microcapsules are inflated in hypotonic condition and deflated in hypertonic condition. Both conditions cause cracks on the membrane, resulting in the fast release of encapsulants in a day. The microcapsules implanted in mice also show sustained release, despite the period is decreased to a month. It is believed that the microcapsules are promising for the in vivo sustained release of drugs for high and long‐term efficacy.     

Charged Layered Boron Nitride‐Nanoflake Membranes for Efficient Ion Separation and Water Purification

2D layered nanomaterials have attracted considerable attention for their potential for highly efficient separations, among other applications. Here, a 2D lamellar membrane synthesized using hexagonal boron nitride nanoflakes (h‐BNF) for highly efficient ion separation is reported. The ion‐rejection performance and the water permeance of the membrane as a function of the ionic radius, ion valance, and solution pH are investigated. The nonfunctionalized h‐BNF membranes show excellent ion rejection for small sized salt ions as well as for anionic dyes (>97%) while maintaining a high water permeability, ≈1.0 × 10^?3 L m m^?2 h^?1 bar^?1). Experiments show that the ion‐rejection performance of the membrane can be tuned by changing the solution pH. The results also suggest that the rejection is influenced by the ionic size and the electrostatic repulsion between fixed negative charges on the BN surface and the mobile ions, and is consistent with the Donnan equilibrium model. These simple‐to‐fabricate h‐BNF membranes show a unique combination of excellent ion selectivity and high permeability compared to other 2D membranes.     

“Smart” Surface Capsules for Delivery Devices

This review describes emerging trends, basic principles, applications, and future challenges for designing next generation responsive “smart” surface capsules. Advances and importance of “surface” capsules which are not deposited onto the surface but are built into the surface are highlighted for selective applications with specific examples of surface sponge structures formed by high intensity ultrasonic surface treatment (HIUS). Surface capsules can be adapted for biomedical applications, membrane materials, lab‐on‐chip, organ‐on‐chip, and for template synthesis. They provide attractive self‐healing anticorrosion and antifouling prospects. Nowadays delivery systems are built from inorganic, organic, hybrid, biological materials to deliver various drugs from low molecular weight substances to large protein molecules and even live cells. It is important that capsules are designed to have time prolonged release features. Available stimuli to control capsule opening are physical, chemical and biological ones. Understanding the underlying mechanisms of capsule opening by different stimuli is essential for developing new methods of encapsulation, release, and targeting. Development of “smart” surface capsules is preferable to respond to multiple stimuli. More and more often a new generation of “smart” capsules is designed by a bio‐inspired approach.     

Self‐Assembly of Thiourea‐Crosslinked Graphene Oxide Framework Membranes toward Separation of Small Molecules

The poor mechanical strength of graphene oxide (GO) membranes, caused by the weak interlamellar interactions, poses a critical challenge for any practical application. In addition, intrinsic but large‐sized 2D channels of stacked GO membranes lead to low selectivity for small molecules. To address the mechanical strength and 2D channel size control, thiourea covalent‐linked graphene oxide framework (TU‐GOF) membranes on porous ceramics are developed through a facile hydrothermal self‐assembly synthesis. With this strategy, thiourea‐bridged GO laminates periodically through the dehydration condensation reactions via ? NH₂ and/or ? SH with ? O?C? OH as well as the nucleophilic addition reactions of ? NH₂ to C? O? C, leading to narrowed and structurally well‐defined 2D channels due to the small dimension of the covalent TU‐link and the deoxygenated processes. The resultant TU‐GOF/ceramic composite membranes feature excellent sieving capabilities for small species, leading to high hydrogen permselectivities and nearly complete rejections for methanol and small ions in gas, solvent, and saline water separations. Moreover, the covalent bonding formed at the GO/support and GO/GO interfaces endows the composite membrane with significantly enhanced stability.     

Neue Kapseltechnik für Diamantverbundwerkstoffe mittels PVD‐Verfahren

Novel encapsulation technique for diamond composites using PVD‐process For machining of mineral materials diamond tools consisting of a steel body combined with diamond impregnated segments are used. Frequently, these segments are hot pressed. Other process routes are pressureless sintering of green compacts partly combined with hot isostatic pressing and hot isostatic pressing of encapsulated powder mixtures. The compaction effect of hot isostatic pressing require a low porosity of sintered components realized by using ultra‐fine metal powder or an impermeable capsule made of metal or glass. The Institute of Materials Engineering pursues a novel process route by physical vapor deposition of a coating on pressureless sintered composites. The thin coating acts as a capsule and guarantees the pressure transfer in the following hot isostatic pressing process. Although bronze powders with particle sizes up to 90 μm are used, the manufacturing of diamond composites with low porosities is possible. In comparison to conventional encapsulation‐techniques the main advantages of this novel process route are the use of comparatively coarse metal powders and a larger geometric flexibility.     

Membrane Tension–Mediated Growth of Liposomes

Recent years have seen a tremendous interest in the bottom‐up reconstitution of minimal biomolecular systems, with the ultimate aim of creating an autonomous synthetic cell. One of the universal features of living systems is cell growth, where the cell membrane expands through the incorporation of newly synthesized lipid molecules. Here, the gradual tension‐mediated growth of cell‐sized (≈10 µm) giant unilamellar vesicles (GUVs) is demonstrated, to which nanometer‐sized (≈30 nm) small unilamellar vesicles (SUVs) are provided, that act as a lipid source. By putting tension on the GUV membranes through a transmembrane osmotic pressure, SUV–GUV fusion events are promoted and substantial growth of the GUV is caused, even up to doubling its volume. Thus, experimental evidence is provided that membrane tension alone is sufficient to bring about membrane fusion and growth is demonstrated for both pure phospholipid liposomes and for hybrid vesicles with a mixture of phospholipids and fatty acids. The results show that growth of liposomes can be realized in a protein‐free minimal system, which may find useful applications in achieving autonomous synthetic cells that are capable of undergoing a continuous growth–division cycle.     

Thermal bonding of polymeric capillary electrophoresis microdevices in water

A new method for thermally bonding poly(methyl methacrylate) (PMMA) substrates to form microfluidic systems has been demonstrated. A PMMA substrate is first imprinted with a Si template using applied pressure and elevated temperature to form microchannel structures. This embossing method has been used to successfully pattern over 65 PMMA pieces using a single Si template. Thermal bonding for channel enclosure is accomplished by clamping together an imprinted and a blank substrate and placing the assembly in boiling water for 1 h. The functionality of these water-bonded microfluidic substrates was demonstrated by performing high-resolution electrophoretic separations of fluorescently labeled amino acids. Testing of bond strength in four microdevices showed an average failure pressure of 130 kPa, which was comparable to the bond strength for devices sealed in air. Subsequent profilometry of separated substrates revealed that the dimensions of the channels were well preserved during the bonding process. This new methodology for generation of microfluidic constructs should facilitate the permanent incorporation of hydrated, molecular size-selective membranes in microdevices, thus circumventing problems associated with membrane swelling in microfluidic systems upon exposure to water.     

Ultra‐Light and Scalable Composite Lattice Materials

Architected lattice materials are some of the stiffest and strongest materials at ultra‐light density (<10 mg cm^?3), but scalable manufacturing with high‐performance constituent materials remains a challenge that limits their widespread adoption in load‐bearing applications. We show mesoscale, ultra‐light (5.8 mg cm^?3) fiber‐reinforced polymer composite lattice structures that are reversibly assembled from building blocks manufactured with a best‐practice high‐precision, high‐repeatability, and high‐throughput process: injection molding. Chopped glass fiber‐reinforced polymer (polyetherimide) lattice materials produced with this method display absolute stiffness (8.41 MPa) and strength (19 kPa) typically associated with metallic hollow strut microlattices at similar mass density. Additional benefits such as strain recovery, discrete damage repair with recovery of original stiffness and strength, and ease of modeling are demonstrated.

     

Smart Microcapsules with Molecular Polarity‐ and Temperature‐Dependent Permeability

Microcapsules with molecule‐selective permeation are appealing as microreactors, capsule‐type sensors, drug and cell carriers, and artificial cells. To accomplish molecular size‐ and charge‐selective permeation, regular size of pores and surface charges have been formed in the membranes. However, it remains an important challenge to provide advanced regulation of transmembrane transport. Here, smart microcapsules are designed that provide molecular polarity‐ and temperature‐dependent permeability. With capillary microfluidic devices, water‐in‐oil‐in‐water (W/O/W) double‐emulsion drops are prepared, which serve as templates to produce microcapsules. The oil shell is composed of two monomers and dodecanol, which turns to a polymeric framework whose continuous voids are filled with dodecanol upon photopolymerization. One of the monomers provides mechanical stability of the framework, whereas the other serves as a compatibilizer between growing polymer and dodecanol, preventing macrophase separation. Above melting point of dodecanol, molecules that are soluble in the molten dodecanol are selectively allowed to diffuse across the shell, where the rate of transmembrane transport is strongly influenced by partition coefficient. The rate is drastically lowered for temperatures below the melting point. This molecular polarity‐ and temperature‐dependent permeability renders the microcapsules potentially useful as drug carriers for triggered release and contamination‐free microreactors and microsensors.     

Vibration of a single microcapsule with a hard plastic shell in an acoustic standing wave field

Observation techniques for measuring the small vibration of a single microcapsule of tens of nanometers in an acoustic standing wave field are discussed. First, simultaneous optical observation of a microbubble vibration by two methods is investigated, using a high-speed video camera, which permits two-dimensional observation of the bubble vibration, and a laser Doppler vibrometer (LDV), which can observe small bubble vibration amplitudes at high frequency. Bubbles of tens of micrometers size were trapped at the antinode of an acoustic standing wave generated in an observational cell. Bubble vibration at 27 kHz could be observed and the experimental results for the two methods showed good agreement. The radial vibration of microcapsules with a hard plastic shell was observed using the LDV and the measurement of the capsule vibration with radial oscillation amplitude of tens of nanometers was successful. The acoustic radiation force acting on microcapsules in the acoustic standing wave was measured from the trapped position of the standing wave and the radial oscillation amplitude of the capsules was estimated from the theoretical equation of the acoustic radiation force, giving results in good agreement with the LDV measurements. The radial oscillation amplitude of a capsule was found to be proportional to the amplitude of the driving sound pressure. A larger expansion ratio was observed for capsules closer to the resonance condition under the same driving sound pressure and frequency.     

Time domain 1H NMR as a new method to monitor softening of gelatin and HPMC capsule shells

Defined mechanical properties are an essential requirement for any pharmaceutical dosage form and this is particularly important in the case of liquid-filled capsules. Changes in the mechanical properties may be induced by exposure of the capsules to humidity or by a shift of the water equilibrium that typically occurs when hydrophilic or amphiphilic fill masses are used, for example, in self-emulsifying drug delivery systems. This study aims to characterize the softening of empty hard gelatin and hydroxypropyl methylcellulose (HPMC) capsules by means of mechanical tests, a Bareiss hardness test, and a stiffness test using a texture analysis method. A benchtop time domain NMR method is applied in addition to characterize the physico-chemical state of water in the capsule shells and to correlate this with the results of the mechanical tests. Hardness and stiffness measurements resulted in corresponding values, showing a softening for both capsule materials in a humid environment, which was most pronounced beyond 60% relative humidity. The capsules made of gelatin exhibited in general higher stiffness and hardness values compared to the HPMC capsules. The physico-chemical state of water in the capsule shells, as probed by a time domain NMR method, was interpreted in terms of a population balance model. Three different water populations were identified that differ in their molecular mobility, as indicated by their characteristic spin-lattice relaxation times, T1. The most loosely bound water fraction dominated in the capsule shells in the range beyond 60% relative humidity. Numerical correlation of the data led to a heuristic equation between the NMR-derived fraction of loosely bound water in the capsule shells and their mechanical stiffness and hardness. Adequate models were obtained for both capsule types, gelatin, and HPMC. Mechanical measurements of pharmaceutical capsules are generally destructive and time consuming. Testing is usually performed in an analytical laboratory, off-line from the manufacturing process, and involves only a small number of samples. Based on the here presented correlation between mechanical stiffness measurements and benchtop time domain NMR data, the latter method may be used as a nondestructive alternative for mechanical testing. This study also opens the possibility to investigate liquid-filled capsules and to establish a process analytical technology (PAT) during manufacturing.     

Experimental Evidence of Rapid Water Transport through Carbon Nanotubes Embedded in Polymeric Desalination Membranes

As water molecules permeate ultrafast through carbon nanotubes (CNTs), many studies have prepared CNTs‐based membranes for water purification as well as desalination, particularly focusing on high flux membranes. Among them, vertically aligned CNTs membranes with ultrahigh water flux have been successfully demonstrated for fundamental studies, but they lack scalability for bulk production and sufficiently high salt rejection. CNTs embedded in polymeric desalination membranes, i.e., polyamide thin‐film composite (TFC) membranes, can improve water flux without any loss of salt rejection. This improved flux is achieved by enhancing the dispersion properties of CNTs in diamine aqueous solution and also by using cap‐opened CNTs. Hydrophilic CNTs were prepared by wrapping CNT walls via bio‐inspired surface modification using dopamine solution. Cap‐opening of pristine CNTs is performed by using a thermo‐oxidative process. As a result, hydrophilic, cap‐opened CNTs‐embedded polyamide TFC membranes are successfully prepared, which show much higher water flux than pristine polyamide TFC membrane. On the other hand, less‐disperse, less cap‐opened CNTs‐embedded TFC membranes do not show any flux improvement and rather lead to lower salt rejection properties.     

Time Domain 1H NMR as a New Method to Monitor Softening of Gelatin and HPMC Capsule Shells

ABSTRACT

Defined mechanical properties are an essential requirement for any pharmaceutical dosage form and this is particularly important in the case of liquid-filled capsules. Changes in the mechanical properties may be induced by exposure of the capsules to humidity or by a shift of the water equilibrium that typically occurs when hydrophilic or amphiphilic fill masses are used, for example, in self-emulsifying drug delivery systems. This study aims to characterize the softening of empty hard gelatin and hydroxypropyl methylcellulose (HPMC) capsules by means of mechanical tests, a Bareiss hardness test, and a stiffness test using a texture analysis method. A benchtop time domain NMR method is applied in addition to characterize the physico-chemical state of water in the capsule shells and to correlate this with the results of the mechanical tests. Hardness and stiffness measurements resulted in corresponding values, showing a softening for both capsule materials in a humid environment, which was most pronounced beyond 60% relative humidity. The capsules made of gelatin exhibited in general higher stiffness and hardness values compared to the HPMC capsules. The physico-chemical state of water in the capsule shells, as probed by a time domain NMR method, was interpreted in terms of a population balance model. Three different water populations were identified that differ in their molecular mobility, as indicated by their characteristic spin-lattice relaxation times, T1. The most loosely bound water fraction dominated in the capsule shells in the range beyond 60% relative humidity. Numerical correlation of the data led to a heuristic equation between the NMR-derived fraction of loosely bound water in the capsule shells and their mechanical stiffness and hardness. Adequate models were obtained for both capsule types, gelatin, and HPMC. Mechanical measurements of pharmaceutical capsules are generally destructive and time consuming. Testing is usually performed in an analytical laboratory, off-line from the manufacturing process, and involves only a small number of samples. Based on the here presented correlation between mechanical stiffness measurements and benchtop time domain NMR data, the latter method may be used as a nondestructive alternative for mechanical testing. This study also opens the possibility to investigate liquid-filled capsules and to establish a process analytical technology (PAT) during manufacturing.     

Capacitive micromachined ultrasonic transducer design for high power transmission

Capacitive micromachined ultrasonic transducers (cMUTs) were developed to meet the demands of the ultrasonic industry. To achieve maximum efficiency, the conventional operation of the cMUT requires a bias voltage close to the collapse voltage. Total acoustic output pressure is limited by the efficiency of the cMUT and the maximum-allowed pulse voltage on the membrane. In this paper, we propose the collapse-snapback operation of the cMUT: the membrane is collapsed onto the substrate in the collapsing cycle, and released in the snapback cycle. The collapse-snapback operation overcomes the above-mentioned limitations of the conventional operation. The collapse-snapback operation utilizes a larger range of membrane deflection profiles (both collapsed and released profiles) and generates higher acoustic output pressures. The static finite element calculations were performed to design cMUTs with specific collapse and snapback voltages by changing the electrode parameters (radius (re), position (de), and thickness (te)). These designs were refined for optimum average displacement per cycle. An electrode radius greater than 60% of the membrane radius significantly improved the displacement per volt. Moderately thick membranes (te approximately 0.2 microm) were preferred, as thicker membranes reduced the displacement per volt. Under proper bias conditions, the collapse-snapback operation, designed for high-power transmission, allowed the application of pulse voltages larger than the difference of collapse and snapback voltages. Dynamic finite element calculations of an infinite cMUT array on the substrate loaded with acoustic fluid medium were performed to determine the dynamic response of the cMUT. Commercially available FEM packages ANSYS and LS-DYNA were used for static and dynamic calculations, respectively. The cMUTs were fabricated for optimal performance in the collapse-snapback operation. The transmit experiments were performed on a 2-D cMUT array using a calibrated hydrophone. Taking into account the attenuation and diffraction losses, the pressure on the cMUT surface was extracted. The cMUT generated 0.47 MPa (6 kPa/V) and 1.04 MPa (11 kPa/V) in the conventional and collapse-snapback operations, respectively. Therefore, collapse-snapback operation of the cMUTs was superior for high-power transmission.     

Fast mass transport through carbon nanotube membranes

The May 19, 2006 issue of Science included a paper by Holt et al. on "Fast Mass Transport Through Sub-2-Nanometer Carbon Nanotubes". The paper was also featured on the cover, showing methane molecules translating inside a carbon nanotube (CNT). The authors explained how they prepared 2-6-mum thin membranes consisting of double-walled carbon nanotubes (DWNTs) all aligned perpendicular to the apparent membrane surface. These tubes are open at both ends and the space between the tubes is filled with dense Si(3)N(4). Pure gas and water fluxes were measured at room temperature with the application of a small pressure difference. Interpretation of the results led to the conclusion that the membranes showed much higher fluxes than what was estimated from Knudsen gas diffusion and Poiseuille viscous flow models. The membranes have a straight-channel morphology with a narrow pore-size distribution and exceptionally smooth pore walls. The unusual geometry and surface properties make it difficult to compare the membrane's properties with common membranes but there is no question that the mass transport in the aligned DWNTs is fast indeed. To appreciate how fast, we will consider their transport properties starting from the perspective of "conventional" porous membrane technology. Recent molecular dynamics simulations suggest that none of the classic models for gas (Knudsen) and water (Poiseuille) permeation work in a meaningful way for these nanotube membranes, and new models are needed.     

Delivery Systems for Low Molecular Weight Payloads: Core/Shell Capsules with Composite Coacervate/Polyurea Membranes

Composite polyurea/coacervate core/shell capsules are formed by coupling associative biopolymer phase separation with interfacial polymerization. They combine the excellent chemical stability of synthetic polymer barriers with the strong adhesive properties of protein‐based complex coacervates, inspired by biological underwater glues. To encapsulate volatile oil droplets, a primary coacervate hydrogel capsule is formed by a protein and weak polyanion and is reinforced with a polyurea membrane synthesized in situ at the interface between the coacervate and the oil core. The polyurea layer provides an excellent permeability barrier against diffusion of small volatile molecules while the coacervate portion of the shell enhances adhesion on the targeted substrate.