Influence of process variables and formulation composition on sphericity and diameter of Ca-alginate-chitosan liquid core capsule prepared by extrusion dripping method

ABSTRACT

The influence of process variables and formulation composition on the sphericity and diameter of the alginate capsules which contained dual cations (Ca-and-chitosan) are characterized in this study. Capsule sphericty was not influenced by needle diameter but instead, capsule diameter increased proportionally with the needle diameter. The combined effects of the liquid core solution and alginate solution on the sphericity of the capsules are tabulated. Spherical capsules can be produced when the following criteria were fulfilled: stirring speed is in the range of 240–300 rpm; calcium chloride concentration is >5 g/L; viscosity of liquid core solution is >203 mPa.s; as well as viscosity of alginate solution is in between 47 and 386 mPa.s. The capsule diameter was predicted using a modified Tate’s law equation and an error analysis was conducted to evaluate the equation. The predicted diameter was well correlated with the experimental data with an average absolute deviation <3.6%.     

Dual Growth Factor Delivery Using Biocompatible Core–Shell Microcapsules for Angiogenesis

An optimized electrodropping system produces homogeneous core–shell microcapsules (C‐S MCs) by using poly(L ‐lactic‐co‐glycolic acid) (PLGA) and alginate. Fluorescence imaging clearly shows the C‐S domain in the MC. For release control, the use of high‐molecular‐weight PLGA (HMW 270 000) restrains the initial burst release of protein compared to that of low‐MW PLGA (LMW 40 000). Layer‐by‐layer (LBL) assembly of chitosan and alginate on MCs is also useful in controlling the release profile of biomolecules. LBL (7‐layer) treatment is effective in suppressing the initial burst release of protein compared to no LBL (0‐layer). The difference of cumulative albumin release between HMW (7‐layer LBL) and LMW (0‐layer LBL) PLGA is determined to be more than 40% on day 5. When dual angiogenic growth factors (GFs), such as platelet‐derived GF (PDGF) and vascular endothelial GF (VEGF), are encapsulated separately in the core and shell domains, respectively, the VEGF release rate is much greater than that of PDGF, and the difference of the cumulative release percentage between the two GFs is about 30% on day 7 with LMW core PLGA and more than 45% with HMW core PLGA. As for the angiogenic potential of MC GFs with human umbilical vein endothelial cells (HUVECs), the fluorescence signal of CD31+ suggests that the angiogenic sprout of ECs is more active in MC‐mediated GF delivery than conventional GF delivery, and this difference is significant, based on the number of capillary branches in the unit area. This study demonstrates that the fabrication of biocompatible C‐S MCs is possible, and that the release control of biomolecules is adjustable. Furthermore, MC‐mediated GFs remain in an active form and can upregulate the angiogenic activity of ECs.     

Preparation of alginate-gelatin capsules and its properties

Capsules based on alginate and gelatin prepared by extrusion method could increase the cell numbers of Lactobacillus casei ATCC 393 to be 10⁸ CFU·g⁻¹ in the wet state of the capsules. The capsules were spherical, smooth-surfaced and non-aggregated with a diameter of (4.0 ± 0.3) mm. The behavior of the samples were quite similar at low relative humidity (33%, 52%) and the ratio of weight change reached 93%. Four kinds of capsules in simulated gastric fluid (SGF) exhibited shrinkage while the beads eroded accompanied with slight swelling in simulated intestinal fluid (SIF). The pH values affected the stability of the capsules and with the increase in pH, the capsules changed from shrank then swelled and finally, broke into pieces. The capsules behaved differently under different ion intensities and the introduction of gelatin weakened the stability of capsules compared with the alginate ones. Cells of L. casei ATCC 393 could be continuously released from the capsules in the simulated gastrointestinal tract (GIT) and the release amounts and speeds in SIF were much higher and faster than those in SGF.     

Bioinspired Superhydrophobic Fe3O4@Polydopamine@Ag Hybrid Nanoparticles for Liquid Marble and Oil Spill

Fe₃O₄ nanoparticles (NPs) with Ag NPs evenly distributed on the surface are fabricated by using polydopamine (PDA) as the intermediate layer. Silanization and thiol chemistry are used to firmly combine the Fe₃O₄@ PDA core and outer surface Ag NPs. The spherical and hybrid nanoparticles are termed Fe₃O₄@PDA@Ag NPs, which possess a core–shell and hierarchical structure. After surface modification with 1H,1H,2H,2H‐perfluorodecanethiol, the hybrid Fe₃O₄@PDA@Ag NPs become highly hydrophobic. Slight rolling of a water droplet on the as‐prepared NPs causes the formation of a “liquid marble”, which is capable of performing remote actuation on various solid surfaces, such as glass sheet, paper, plastic, textile, and ceramic, and at the liquid–air interface using a permanent magnet. Liquid marbles with self‐assembled NPs on the liquid surface have potential to act as a miniaturized reactor for manipulation of inner liquid droplet with high positioning precision. In addition, the Fe₃O₄@PDA@Ag NPs are multifunctional and can be applied for oil/water separation and antibacterial purpose.     

S‐layer Coated Emulsomes as Potential Nanocarriers

The present study introduces a novel nanocarrier system comprising lipidic emulsomes and S‐layer (fusion) proteins as functionalizing tools coating the surface. Emulsomes composed of a solid tripalmitin core and a phospholipid shell are created reproducibly with an average diameter of approximately 300 nm using temperature‐controlled extrusion steps. Both wildtype (wt) and recombinant (r) S‐layer protein SbsB of Geobacillus stearothermophilus PV72/p2 are capable of forming coherent crystalline envelope structures with oblique (p1) lattice symmetry, as evidenced by transmission electron microscopy. Upon coating with wtSbsB, positive charge of emulsomes shifts to a highly negative zeta potential, whereas those coated with rSbsB become charge neutral. This observation is attributed to the presence of a negatively charged glycan, the secondary cell wall polymer (SCWP), which is associated only with wtSbsB. The present study shows for the first time the ability of recombinant and wildtype S‐layer proteins to cover the entire surface of emulsomes with its characteristic crystalline lattice. Furthermore, in vitro cell culture studies reveal that S‐layer coated emulsomes can be uptaken by human liver carcinoma cells (HepG2) without showing any significant cytotoxicity over a wide range of concentrations. The utilization of S‐layer fusion proteins equipped in a nanopatterned fashion by identical or diverse functions may lead to further development of emulsomes in nanomedicine, especially for drug delivery and targeting.     

Improving covalent cell encapsulation with temporarily reactive polyelectrolytes

Calcium alginate/poly-l-lysine beads were coated with either 50% hydrolyzed poly(methyl vinyl ether–alt–maleic anhydride) (PMM₅₀), or with poly(vinyl dimethyl azlactone-co-methacrylic acid) (50:50, PMV₅₀), to form covalently shell-crosslinked capsules, and compared with analogous capsules coated with sodium alginate. All capsule types were prepared with and without C2C12 murine myoblast cells, and implanted into mice for up to 6 weeks. Cell viability, capsule integrity, fibrotic overgrowth, and mechanical strength of the capsules were assessed, and correlated with inflammatory cytokine marker levels in tail vein blood samples taken at different time points. AP-PMM₅₀ capsules displayed the least amount of fibrotic overgrowth, were found to be the strongest, and showed the lowest levels of TNF-α in tail vein serum samples taken at 4 h, 24 h, 1 and 6 weeks post transplantation. The results for APA and AP-PMV₅₀ capsules were more variable and depended on the presence or absence of encapsulated cells.     

Hollow spherical nucleic acids for intracellular gene regulation based upon biocompatible silica shells

Cellular transfection of nucleic acids is necessary for regulating gene expression through antisense or RNAi pathways. The development of spherical nucleic acids (SNAs, originally gold nanoparticles functionalized with synthetic oligonucleotides) has resulted in a powerful set of constructs that are able to efficiently transfect cells and regulate gene expression without the use of auxiliary cationic cocarriers. The gold core in such structures is primarily used as a template to arrange the nucleic acids into a densely packed and highly oriented form. In this work, we have developed methodology for coating the gold particle with a shell of silica, modifying the silica with a layer of oligonucleotides, and subsequently oxidatively dissolving the gold core with I(2). The resulting hollow silica-based SNAs exhibit cooperative binding behavior with respect to complementary oligonucleotides and cellular uptake properties comparable to their gold-core SNA counterparts. Importantly, they exhibit no cytotoxicity and have been used to effectively silence the eGFP gene in mouse endothelial cells through an antisense approach.     

Modified-release capsules containing sodium riboflavin 5′-phosphate

Introduction: The focus of this work was to produce delayed-release capsules containing riboflavin (vitamin B₂, as API) layered pellets. Riboflavin therapy is indicated in patients with a riboflavin deficiency, which usually occurs in conjunction with malabsorption, alcoholism or a protein-calorie deficiency and rarely as the sole vitamin deficiency. Riboflavin is readily absorbed from the upper gastrointestinal tract by a specific transport mechanism. The dissolution rate of coated capsules was controlled through the coating of the capsules and the thickness of the coating layer.

Methods: The core pellets (Cellet 300) were loaded with a 10% aqueous solution of sodium riboflavin 5′-phosphate by a layering technique in a coating pan. Hard capsules were filled with riboflavin layered pellets and coated with Eudragit NE polymer with different coating layer thicknesses. The dissolution was tested in gastric and intestinal fluids with the half-change method. The dissolution profiles were analyzed with the use of different mathematical models and an attempt was made to predict the optimum coating film thickness that ensures the required degree and rate of dissolution.

Results: A new solid dosage form was developed which can enhance the bioavailability of riboflavin. RRSBW distribution and the Chapman–Richards growth function were used to fit the dissolution profiles. Statistical analysis indicated that the best products were described by the Chapman–Richards equation. The results were utilized to create a theoretical model suitable for prediction of the optimum film thickness that ensures the required release of riboflavin.     

Atomic‐Layer‐Deposition‐Assisted Formation of Carbon Nanoflakes on Metal Oxides and Energy Storage Application

Nanostructured carbon is widely used in energy storage devices (e.g., Li‐ion and Li‐air batteries and supercapacitors). A new method is developed for the generation of carbon nanoflakes on various metal oxide nanostructures by combining atomic layer deposition (ALD) and glucose carbonization. Various metal oxide@nanoflake carbon (MO@f‐C) core‐branch nanostructures are obtained. For the mechanism, it is proposed that the ALD Al₂O₃ and glucose form a composite layer. Upon thermal annealing, the composite layer becomes fragmented and moves outward, accompanied by carbon deposition on the alumina skeleton. When tested as electrochemical supercapacitor electrode, the hierarchical MO@f‐C nanostructures exhibit better properties compared with the pristine metal oxides or the carbon coating without ALD. The enhancement can be ascribed to increased specific surface areas and electric conductivity due to the carbon flake coating. This peculiar carbon coating method with the unique hierarchical nanostructure may provide a new insight into the preparation of ‘oxides + carbon’ hybrid electrode materials for energy storage applications.     

Feasibility studies of concomitant administration of optimized formulation of probiotic-loaded Vancomycin hydrochloride pellets for colon delivery

Objective of this study was to develop Vancomycin HCl pellets loaded with Saccharomyces boulardii (S.b.) for pH-dependent system and CODES? for augmenting the efficacy of Vancomycin HCl in the treatment of colitis. Pellets were prepared by extrusion–spheronization. In the pH-dependent system, the pellets were coated with Eudragit FS 30D. These pellets exhibited spherical form and a uniform surface coating. The CODES? system consisted of three components: core containing mannitol, drug and probiotic, an inner acid-soluble coating layer, and an outer layer of enteric coating material. Statistical factorial design was used to optimize both formulations. Scanning electron micrographs of coated pellets revealed uniform coating. In vitro drug release of these coated pellets was studied sequentially in various buffers with (2%) and without rat cecal content for a period of 12?h. From the optimized pH-dependent formulation, F6 (20% w/w coating level and 15% w/v concentration of polymer), higher amount of probiotic was released in earlier time phase (first 5?h) as compared to the CODES? and so R5 [containing acid-soluble inner coating layer (15% w/w coating level and 12% w/v concentration of Eudragit E100), and an outer layer of enteric coating material (12% w/w coating level and 10% w/v concentration of Eudragit L100)] was considered as the best formulation after confirming in vivo X-ray studies conducted on rabbits, suggesting that Vancomycin HCl and S.b. may be co-administered as pellets [CODES?] to enhance the effectiveness of Vancomycin HCl in the treatment of colitis without its associated side effects, which can only be confirmed after clinical trials.     

Bridging Systemic Immunity with Gastrointestinal Immune Responses via Oil‐in‐Polymer Capsules

As peripheral lymphocytes are typically excluded from the gastrointestinal lymph tissues, current parenteral vaccinations fail to simultaneously induce systemic and mucosal responses. To break the natural barrier, “immunoticket” capsules are developed and heralded, which are designed with positive charged shells and oily core to spatiotemporally deliver antigens and all‐trans retinoic acid (RA). After intramuscular vaccinations, these capsules function as an immunoticket to cultivate peripheral dendritic cells (DCs) with gut‐homing receptors (CCR9). By hitchhiking on the concentration gradient of the CC‐motif chemokine ligand 25 (CCL25), the primed DCs would home to the gut associated lymphoid tissues (GALTs) and induce antigen‐specific IgA secretion and T cell engagements. Compared with the currently employed RA‐involving formulations, the immunoticket capsules stimulate enhanced RA‐mediated gut‐tropism by mounting the inflammatory innate immunity. Through controlling the RA payload, the potential regulatory T cell engagement is circumvented. In ovalbumin (OVA) and EV71 vaccinations, the immunoticket capsules induce potent serum IgG titer and antigen‐specific cytotoxic T cells in the peripheral lymph tissues, as well as robust IgA secretion and T cell engagements on gastrointestinal sites. The data suggest the potential of the immunotickets to serve as a facile, effective, and safe strategy to provide comprehensive immune responses against gastrointestinal infections and diseases     

Process and formulation variables affecting the performance of a rupturable capsule-based drug delivery system with pulsatile drug release

The objective of this study was to optimize several process and formulation parameters, which influence the performance of a rupturable, pulsatile drug delivery system. The system consisted of a drug-containing hard gelatin capsule, a swelling layer of croscarmellose (Ac-Di-Sol®) and a binder, and an outer ethylcellulose coating. Polyvinyl pyrrolidone (Kollidon 90F) was superior to HPMC and HPC as a binder for the swelling layer with regard to binding (adherence to capsule) and disintegration properties of the swelling layer. The capsule-to-capsule uniformity in the amount of swelling layer and outer ethylcellulose coating, which significantly affected the lag time prior to rupture of the capsule, was optimized by decreasing the batch size, and by increasing the rotational pan speed and the distance between the spray nozzle and the product bed. The type of baffles used in the coating pan also affected the layering uniformity. Fully-filled hard gelatin capsules had a shorter lag time with a higher reproducibility compared to only half-filled capsules, because the swelling pressure was directed primarily to the outer ethylcellulose coating and not to the inner capsule core. Stability studies revealed that the lag time of the capsules was stable over a 240-day period when the moisture content was kept unchanged.     

Preparation and incorporation of microcapsules in functional coatings for self‐healing of packaging board

The replacement of flexible polyolefin barrier layers with novel, thin, functional polymer coatings in the production of paperboard packaging involves the risk of deteriorated barrier and mechanical properties during the converting process. Local defects or cracks in the protective barrier layer can arise because of the stress induced in creasing and folding operations. In this study, the incorporation of microencapsulated self‐healing agents in coating formulations applied both by spot‐ and uniform‐coating techniques was studied. The preparation process of microcapsules with a hydrophobic core surrounded by a hydrophobically modified polysaccharide membrane in aqueous suspension was developed to obtain capsules fulfilling both the criteria of small capsule size and reasonably high solids content to match the requirements set on surface treatment of paperboard for enhancement of packaging functionality. The survival of the microcapsules during application and their effectiveness as self‐healing agents were investigated. The results showed a reduced tendency for deteriorated barrier properties and local termination of cracks formed upon creasing. The self‐healing mechanism involves the rupture of microcapsules local to the applied stress, with subsequent release of the core material. Crack propagation is hindered by plasticization of the underlying coating layer, while the increased hydrophobicity helps to maintain the barrier properties. Copyright © 2009 John Wiley & Sons, Ltd.     

Evaluation of recent advances in continuous film coating processes

Background: Continuous film coating processes are recognized for their high production rates but have had slow acceptance for pharmaceutical production because of perceived high product losses during start-up and shut-down. In this article, the recent improvements in continuous coater designs were evaluated with respect to coating uniformity and reduction in product losses. Two separate studies represent trials conducted in newly redesigned continuous coating pans from two different coating pan manufacturers. Method: Multivitamin tablets were coated with Opadry® II, high performance film coating system, in both batch and continuous modes in the continuous coater. Tablet samples collected throughout all phases of the process were tested for color development and uniformity. Soft gelatin capsules were coated with a delayed release coating formulation, Nutrateric®, nutritional enteric coating system. Samples of the soft gelatin capsules were taken throughout the process and tested for resistance to simulated gastric fluid as a measure of coating uniformity and delayed release functionality performance. Conclusions: The results from both the immediate release and delayed release case studies support the assertion that continuous coating processes are capable of applying aqueous film coatings with significant improvements in coating uniformity and reduction in product loss.     

Delayed release film coating applications on oral solid dosage forms of proton pump inhibitors: case studies

Background: Formulation of proton pump inhibitors (PPIs) into oral solid dosage forms is challenging because the drug molecules are acid-labile. The aim of this study is to evaluate different formulation strategies (monolithic and multiparticulates) for three PPI drugs, that is, rabeprazole sodium, lansoprazole, and esomeprazole magnesium, using delayed release film coating applications. Method: The core tablets of rabeprazole sodium were prepared using organic wet granulation method. Multiparticulates of lansoprazole and esomeprazole magnesium were prepared through drug layering of sugar spheres, using powder layering and suspension layering methods, respectively. Tablets and drug-layered multiparticulates were seal-coated, followed by delayed release film coating application, using Acryl-EZE®, aqueous acrylic enteric system. Multiparticulates were then filled into capsules. The final dosage forms were evaluated for physical properties, as well as in vitro dissolution testing in both compendial acid phase, 0.1N HCl (pH 1.2), and intermediate pH, acetate buffer (pH 4.5), followed by phosphate buffer, pH 6.8. The stability of the delayed release dosage forms was evaluated upon storage in accelerated conditions [40°C/75% relative humidity] for 3 months. Results: All dosage forms demonstrated excellent enteric protection in the acid phase, followed by rapid release in their respective buffer media. Moreover, the delayed release dosage forms remained stable under accelerated stability conditions for 3 months. Conclusions: Results showed that Acryl-EZE enteric coating systems provide excellent performance in both media (0.1N HCl and acetate buffer pH 4.5) for monolithic and multiparticulate dosage forms.     

Core‐Cone Structured Monodispersed Mesoporous Silica Nanoparticles with Ultra‐large Cavity for Protein Delivery

A new type of monodispersed mesoporous silica nanoparticles with a core–cone structure (MSN‐CC) has been synthesized. The large cone‐shaped pores are formed by silica lamellae closely packed encircling a spherical core, showing a structure similar to the flower dahlia. MSN‐CC has a large pore size of 45 nm and a high pore volume of 2.59 cm³ g⁻¹. MSN‐CC demonstrates a high loading capacity of large proteins and successfully delivers active β‐galactosidase into cells, showing their potential as efficient nanocarriers for the cellular delivery of proteins with large molecular weights.     

The "music" of core-shell spheres and hollow capsules: influence of the architecture on the mechanical properties at the nanoscale

We report on the first measurement of elastic vibrational modes in core-shell spheres (silica-poly(methyl methacrylate), SiO2-PMMA) and corresponding spherical hollow capsules (PMMA) with different particle size and shell thickness using Brillouin light scattering, supported by numerical calculations. These localized modes allow access to the mechanical moduli down to a few tens of nanometers. We observe reduced mechanical strength of the porous silica core, and for the core-shell spheres a striking increase of the moduli in both the SiO2 core and the PMMA shell. The peculiar behavior of the vibrational modes in the hollow capsules is attributed to antagonistic dependence on overall size and layer thickness in agreement with theoretical predictions.     

Systematic study of alginate-based microcapsules by micropipette aspiration and confocal fluorescence microscopy

Micropipette aspiration and confocal fluorescence microscopy were used to study the structure and mechanical properties of calcium alginate hydrogel beads (A beads), as well as A beads that were additionally coated with poly-l-lysine (P) and sodium alginate (A) to form, respectively, AP and APA hydrogels. A beads were found to continue curing for up to 500 h during storage in saline, due to residual calcium chloride carried over from the gelling bath. In subsequent saline washes, micropipette aspiration proved to be a sensitive indicator of gel weakening and calcium loss. Aspiration tests were used to compare capsule stiffness before and after citrate extraction of calcium. They showed that the initial gel strength is largely due to the calcium alginate gel cores, while the long term strength is solely due to the poly-l-lysine–alginate polyelectrolyte complex (PEC) shells. Confocal fluorescence microscopy showed that calcium chloride exposure after PLL deposition led to PLL redistribution into the hydrogel bead, resulting in thicker but more diffuse and weaker PEC shells. Adding a final alginate coating to form APA capsules did not significantly change the PEC membrane thickness and stiffness, but did speed the loss of calcium from the bead core.     

Kinetics and Mechanism of Drug Release From Calcium Alginate Membrane Coated Tablets

Compressed tablets containing guaifenesin (model drug), calcium acetate (reactant) and pharmaceutical excipients were prepared. The tablets were coated with calcium alginate hydrogel using a novel, self-correcting membrane coating technique. Effects of coating time, the type of alginate polymer and pH of the dissolution medium on the rate of drug release were evaluated. In distilled water, zero order drug release profiles were obtained from the coated tablets. The release rate decreased with an increase in the coating time (increased coat thickness) and molecular weight of alginate polymer. The release rate constants correlated with model for spherical reservoir system and, were used to calculate permeability of guaifenesin in the calcium alginate coatings. Alginate polymer with higher guluronic acid content provided acid stable coating and higher molecular weight polymer produced membrane with lower permeability for guaifenesin.     

Bead Coating Process Via an Excess of Crosslinking Agent

Abstract

Coated beads were prepared by soaking in sodium alginate solutions spherical matrices (beads) of carboxymethylcellulose crosslinked with aluminum chloride (AlCl3) and loaded with ambroxol hydrochloride as a model drug. The residual amount of the crosslinker induced an interfacial crosslinking reaction of the sodium alginate. Therefore, an insoluble, smooth and uniform in thickness coat was formed around the beads. As the coating time increased, the coat thickness increased until1 AlCl3 was present inside the beads. The rate of drug release from the coated beads was slower than that from the uncoated beads and decreased with the increase in coating time. Moreover, a constant rate phase, subsequent a burst period for the samples obtained with the highest coating times, was achieved. The dynamic swelling analysis allowed to exclude the influence of the polymer relaxation on the release process which appeared to be controlled by the alginate coat.