Recently, electrospinning (ES) of fibers has been shown to be an attractive strategy for drug delivery. One of the main features of ES is that a wide variety of drugs can be loaded into the fibers to ...improve their bioavailability, to enhance dissolution, or to achieve controlled release. Besides, ES is a continuous technology with low energy consumption, which can make it a very economic production alternative to the widely used freeze drying and spray drying. However, the low production rate of laboratory‐scaled ES has limited the industrial application of the technology so far. This article covers the various ES technologies developed for scaled‐up fiber production with an emphasis on pharmaceutically relevant examples. The methods used for increasing the productivity are complied, which is followed by a review of specific examples from literature where these technologies are utilized to produce oral drug delivery systems. The different technologies are compared in terms of their basic principles, advantages, and limitations. Finally, the different downstream processing options to prepare tablets or capsules containing the electrospun drug are covered as well.
This article is categorized under:
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Application of scaled‐up electrospinning in oral drug delivery.
In chronic intestinal diseases like inflammatory bowel disease, parenteral administration of biopharmaceuticals is associated with numerous disadvantages including immune reactions, infections, low ...patient compliance, and toxicity caused by high systemic bioavailability. One alternative that can potentially overcome these limitations is oral administration of biopharmaceuticals, where the local delivery will reduce the systemic exposure and furthermore the manufacturing costs will be lower. However, the development of oral dosage forms that deliver the biologically active form to the intestines is one of the greatest challenges for pharmaceutical technologists due to the sensitive nature of biopharmaceuticals.
The present article discusses the various drug delivery technologies used to produce orally administered solid dosage forms of biopharmaceuticals with an emphasis on colon-targeted delivery. Solid oral dosage compositions containing different types of colon-targeting biopharmaceuticals are compiled followed by a review of currently applied and emerging drying technologies for biopharmaceuticals. The different drying technologies are compared in terms of their advantages, limitations, costs and their effect on product stability.
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High speed electrospinning (HSES), compatible with pharmaceutical industry, was used to demonstrate the viability of the preparation of drug-loaded polymer nanofibers with radically ...higher productivity than the known single-needle electrospinning (SNES) setup. Poorly water-soluble itraconazole (ITRA) was formulated with PVPVA64 matrix polymer using four different solvent-based methods such as HSES, SNES, spray drying (SD) and film casting (FC). The formulations were assessed in terms of improvement in the dissolution rate of ITRA (using a “tapped basket” dissolution configuration) and analysed by SEM, DSC and XRPD. Despite the significantly increased productivity of HSES, the obtained morphology was very similar to the SNES nanofibrous material. ITRA transformed into an amorphous form, according to the DSC and XRPD results, in most cases except the FC samples. The limited dissolution of crystalline ITRA could be highly improved: fast dissolution occurred (>90% within 10min) in the cases of both (the scaled-up and the single-needle) types of electrospun fibers, while the improvement in the dissolution rate of the spray-dried microspheres was significantly lower. Production of amorphous solid dispersions (ASDs) with the HSES system proved to be flexibly scalable and easy to integrate into a continuous pharmaceutical manufacturing line, which opens new routes for the development of industrially relevant nanopharmaceuticals.
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Three solvent based methods: spray drying (SD), electrospinning (ES) and air-assisted electrospinning (electroblowing; EB) were used to prepare solid dispersions of itraconazole and ...Eudragit E. Samples with the same API/polymer ratios were prepared in order to make the three technologies comparable. The structure and morphology of solid dispersions were identified by scanning electron microscopy and solid phase analytical methods such as, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Raman chemical mapping. Moreover, the residual organic solvents of the solid products were determined by static headspace-gas chromatography/mass spectroscopy measurements and the wettability of samples was characterized by contact angle measurement. The pharmaceutical performance of the three dispersion type, evaluated by dissolution tests, proved to be very similar. According to XRPD and DSC analyses, made after the production, all the solid dispersions were free of any API crystal clusters but about 10wt% drug crystallinity was observed after three months of storage in the case of the SD samples in contrast to the samples produced by ES and EB in which the polymer matrix preserved the API in amorphous state.
The reuse of by-products and residue streams is an important topic due to environmental and financial aspects. Manganese clay is a residue of manganese ore processing and is generated in huge ...amounts. This residue may contain some radionuclides with elevated concentrations. In this study, the radon emanation features and the massic exhalation rate of the heat-treated manganese clay were determined with regard to brick production. From the manganese mud depository, 20 samples were collected and after homogenization radon exhalation characteristics were determined as a function of firing temperatures from 100 to 750 °C. The major naturally occurring radionuclides 40K, 226Ra and 232Th concentrations were 607 ± 34, 52 ± 6 and 40 ± 5 Bq kg−1, respectively, comparable with normal clay samples. Similar to our previous studies a strong correlation was found between the internal structure and the radon emanation. The radon emanation coefficient decreased by ∼96% from 0.23 at 100 °C to 0.01 at 750 °C. The massic radon exhalation rate of samples fired at 750 °C reduced by 3% compared to samples fired at 100 °C. In light of the results, reusing of manganese clay as a brick additive is possible without any constraints.
•Firing temperatures affect radon emanation and exhalation rate of manganese clay.•The radon exhalation was determined using accumulation chamber technique.•Investigation of naturally occurring radionuclides in manganese clay samples.•Reusing of manganese clay as an additive material in brick was surveyed.
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•Solid formulation of infliximab was prepared with high productivity using HSES.•HP-β-CD aqueous solution was a suitable matrix system to form electrospun fibers.•HSES technology ...induced no aggregate formation of infliximab.•The formulation was fully dissolved within 2 min resulting in a clear solution.
Solid formulations of monoclonal antibodies present several advantages, such as improved stability and increased shelf-life as well as simpler storage and transportation. In this study, we present a gentle drying technology for monoclonal antibodies, applying the water soluble 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) as matrix, to prepare a solid reconstitution dosage form. High-speed electrospinning of an aqueous infliximab-containing HP-β-CD solution was carried out at 25 °C resulting in fibers with an average diameter of 2.5 μm. The mAb-loaded electrospun fibers were successful to preserve the stability of infliximab in solid form. The results of size exclusion chromatography and gel electrophoresis indicated no significant increase in aggregate formation during the electrospinning process compared to the initial matrix solution. The binding activity of infliximab was preserved during electrospinning compared to the reference liquid formulation. Due to the enhanced surface area, excellent reconstitution capability, i.e. clear solution within 2 min without any vigorous mixing, could be achieved in a small-scale reconstitution test. The results of this work demonstrate that high-speed electrospinning is a very promising technique to manufacture the solid formulation of monoclonal antibodies for applications such as fast reconstitutable powders.
Toarcian black shale that hosts Mn-carbonate microbialites at Úrkút, Hungary was investigated by mineralogical, inorganic, and organic geochemical methods for characterization and comparison with ...other European black shales representative of the Toarcian Oceanic Anoxic Event. Based on the authigenic mineral composition, calculations were made to estimate environmental conditions during sediment accumulation and early diagenesis. Geochemical and petrographic results of organic, carbonate, and REE multiple-proxy analyses revealed a strong congruence between the host black shale and the Mn-carbonate ore beds. The Úrkút black shale is really a gray shale with moderate to low TOC contents that accumulated in a starved basin. The organic matter and anoxic characteristics resulted from rapid accumulation of organic matter from microbial booms, accompanied by a geothermally generated hydrothermal circulation system, and a high rate of authigenic mineral formation (clay minerals and proto-ore minerals). The inferred enzymatic Mn and Fe oxidation blocked carbonate formation by decreasing the pH. The system remained suboxic via syngenetic mineral accumulation (Fe-rich biomats), and became anoxic during diagenesis in conjunction with pyrite generation. The separation of black shale beds and Mn-ore beds is not distinct through the section. Instead, a distal hydrothermally induced clay-rich authigenic assemblage (marlstone) best describes the black shale, in which Mn-oxide proto-ore beds (Mn-rich laminae) formed from the beginning of black shale deposition, when the oxygen supply in the sedimentary basin was insufficient for enzymatic Mn(II) oxidation. Mn-oxide proto-ore was transformed to Mn-carbonate ore during microbially mediated processes during early diagenesis. The drivers for Mn-bearing organic matter-rich marlstones were most probably a combination of regional and local processes, with generation of a tectonic rift system that promoted geothermally generated hydrothermal fluids, which initiated microbial blooms. Black shale mineralogy, geochemistry, and organic matter at Úrkút differ from those of the epicontinental shelf black shales of the Tethyan Ocean.
•Multi-proxy study of the Alpine–Mediterranean black shale•Mineralogy and geochemistry of the ore and the black shale are very similar.•Ore was formed via microbial blooms governed by hydrothermal activity.•Mineralogical and geochemical data reflect an ancient failed rift system.•Úrkút proxies differ from those of the Tethyan epicontinental shelf occurrences.
•Physically stable amorphous IR formulations of spironolactone were melt-extruded.•Degree of drug degradation was determined non-invasively by Raman spectrometry.•Transmission and confocal Raman ...spectrometry were compared for the measurement of residual drug crystallinity.•Raman spectrometry could well estimate the glass-transition temperature of solid dispersions.•Dependence of drug degradation and residual crystallinity on extrusion parameters was statistically described.
Raman spectrometry was utilized to estimate degraded drug percentage, residual drug crystallinity and glass-transition temperature in the case of melt-extruded pharmaceutical products. Tight correlation was shown between the results obtained by confocal Raman mapping and transmission Raman spectrometry, a PAT-compatible potential in-line analytical tool. Immediate-release spironolactone–Eudragit E solid dispersions were the model system, owing to the achievable amorphization and the heat-sensitivity of the drug compound. The deep investigation of the relationship between process parameters, residual drug crystallinity and degradation was performed using statistical tools and a factorial experimental design defining 54 different circumstances for the preparation of solid dispersions. From the examined factors, drug content (10, 20 and 30%), temperature (110, 130 and 150°C) and residence time (2.75, 11.00 and 24.75min) were found to have significant and considerable effect. By forming physically stable homogeneous dispersions, the originally very slow dissolution of the lipophilic and poorly water-soluble spironolactone was reasonably improved, making 3minute release possible in acidic medium.
The goals of this work were to evaluate if high-speed electrospinning can be used as a gentle and continuous drying technology to produce protein-containing cyclodextrin-based fibers from an aqueous ...solution and to convert the produced protein-cyclodextrin fibers into a directly compressible powder. A 400 mL/h feeding rate was used during the electrospinning experiments, corresponding to a ~270 g/h production rate of the dried material. The produced fibers were collected in a cyclone. The fibers were found grindable without secondary drying, and the ground powder was mixed with tableting excipients and was successfully tableted by direct compression. The model protein-type drug (β-galactosidase) remained stable during each of the processing steps (electrospinning, grinding, tableting) and after 6 months of storage at room temperature in the tablets. The obtained results demonstrate that high speed electrospinning can be a gentle alternative to traditional drying methods used for protein-type drugs, and that tablet formulation is achievable from the electrospun material prepared this way.
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Investigation of downstream processing of nanofibrous amorphous solid dispersions to generate tablet formulation is in a quite early phase. Development of high speed electrospinning opened up the ...possibility to study tableting of electrospun solid dispersions (containing polyvinylpyrrolidone-vinyl acetate and itraconazole ITR in this case). This work was conducted to investigate the influence of excipients on dissolution properties and the feasibility of scaled-up rotary press tableting. The dissolution rates from tablets proved to be mainly composition dependent. Magnesium stearate acted as a nucleation promoting agent (providing an active hydrophobic environment for crystallization of ITR) hindering the total dissolution of ITR. This crystallization process proved to be temperature dependent as well. However, the extent of dissolution of more than 95% was realizable when a less hydrophobic lubricant, sodium stearyl fumarate (soluble in the medium), was applied. Magnesium stearate induced crystallization even if it was put in the dissolution medium next to proper tablets. After optimization of the composition, scaled-up tableting on a rotary press was carried out. Appropriate dissolution of ITR from tablets was maintained for 3 months at 25°C/60% relative humidity. HPLC measurements confirmed that ITR was chemically stable both in the course of downstream processing and storage.
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