Advancing fibrous delivery systems for pharmaceutics

Recently published research articles

Continuous end-to-end production of solid drug dosage forms: Coupling flow synthesis and formulation by electrospinning

Based on the concept of continuous manufacturing an end-to-end benchtop device was developed unprecedented for the production of solid drug dosage forms by connecting flow synthesis and formulation via electrospinning (ES). Together with the optimized two-step continuous-flow synthesis of acetylsalicylic acid (ASA) a water-soluble polymeric excipient (polyvinylpyrrolidone K30, PVPK30) was introduced. The resulting polymeric solution could be readily electrospun into solid nanofibers with high purity in one single step due to the excellent yet gentle drying effect of ES. The ASA-loaded fibers were electrostatically deposited onto a water-soluble pullulan sheet and the obtained double-layered films were continuously cut into orally dissolving webs (ODWs) as final dosage formulation. The synthesis as well as the dosing of the fibrous films were monitored by Process Analytical Technology (PAT) tools (IR and Raman spectroscopy) with active feedback on product quality. The successful coupling of flow synthesis and fiber formation confirms that ES enables versatile formulation of pharmaceuticals in future continuous production systems.

Controlled-release solid dispersions of Eudragit® FS 100 and poorly soluble spironolactone prepared by electrospinning and melt extrusion

Eudragit® FS (EudFS), a novel anionic metachrylate terpolymer with pH dependent solubility was processed using electrospinning (ES) for the first time and melt extrusion (EX) for controlled delivery of a poorly water-soluble model drug, spironolactone (SPIR). Optimization of ES showed good spinnability of EudFS. Nanofibrous products could be obtained using fairly polar solvents (acetone, dichloromethane-ethanol (1:1), dimethylformamide). Drug-loaded nanofibers were prepared using novel alternating current electrospinning at multiple times higher throughput than direct current electrospinning. Melt extrusion proved to be also a feasible technique to prepare EudFS-based solid dispersions above 100°C. The viscoelasticity of EudFS melts was characterized in terms of temperature, frequency and heating time dependence. Solid state analyses revealed amorphous SPIR content in the electrospun fibers, however, signs of residual crystallinity could be detected in the extruded sample with 20% SPIR according to XRPD and EDS mapping. In vitro dissolution of the EudFS-based solid dispersions showed superior control of drug release compared to the physical mixture of crystalline SPIR and EudFS. At gastric pH where the polymer is insoluble the drug was more restrained in the ground extrudates than in the electrospun fibers. This state was followed by a quick burst as the pH rose to 7.4. EudFS, well-processed by electrospinning or melt extrusion, proved to be a promising matrix for oral drug delivery applications especially targeting the colon.

Novel alternating current electrospinning of hydroxypropylmethylcellulose acetate succinate (HPMCAS) nanofibers for dissolution enhancement: the importance of solution conductivity

Novel high-yield alternating current electrospinning (ACES) as well as direct current (DCES) methods were investigated to prepare high quality hydroxypropylmethylcellulose acetate succinate (HPMCAS) fibers for the dissolution enhancement of poorly soluble spironolactone (SPIR). Although HPMCAS is of great pharmaceutical importance as a carrier of marketed solid dispersion-based products, it was found to be unprocessable using electrospinning. Addition of small amounts of polyethylene oxide as aid polymer provided smooth fibers with DCES but strongly beaded products with ACES. Solution characteristics were thus modified by introducing further excipients. In the presence of sodium dodecyl sulfate (SDS) high quality HPMCAS-based fibers were obtained even at higher throughput rates of ACES owing to the change in conductivity (rather than surface tension). Replacement of SDS to non-surface-active salts (CaCl2 and NH4Ac) maintained the fine quality of nanofibers confirming the importance of conductivity in ACES process. The HPMCAS-based fibers contained SPIR in an amorphous form according to DSC and XRPD. In vitro dissolution tests revealed fast drug release rates depending on the salt used to adjust conductivity. The presented results signify that ACES can be a prospective process for high scale production of fibrous solid dispersions in which conductivity of solution has a fundamental role.

AC and DC electrospinning of hydroxypropylmethylcellulose with polyethylene oxides as secondary polymer for improved drug dissolution

Alternating current electrospinning (ACES) capable to reach multiple times higher specific productivities than widely used direct current electrospinning (DCES) was investigated and compared with DCES to prepare drug-loaded formulations based on one of the most widespread polymeric matrix used for commercialized pharmaceutical solid dispersions, hydroxypropylmethylcellulose 2910 (HPMC). In order to improve the insufficient spinnability of HPMC (both with ACES and DCES) polyethylene oxide (PEO) as secondary polymer with intense ACES activity was introduced into the electrospinning solution. Different grades of this polymer used at as low concentrations in the fibers as 0.1% or less enabled the production of high quality HPMC-based fibrous mats without altering its physicochemical properties remarkably. Increasing concentrations of higher molecular weight PEOs led to the thickening of fibers from submicronic diameters to several microns of thickness. ACES fibers loaded with the poorly water-soluble model drug spironolactone were several times thinner than drug-loaded fibers prepared with DCES in spite of the higher feeding rates applied. The amorphous HPMC-based fibers with large surface area enhanced the dissolution of spironolactone significantly, the presence of small amounts of PEO did not affect the dissolution rate. The presented results confirm the diverse applicability of ACES, a novel technique to prepare fibrous drug delivery systems.

Alternating current electrospinning for preparation of fibrous drug delivery systems

Alternating current electrospinning (ACES) was compared to direct current electrospinning (DCES) for the preparation of drug-loaded nanofibrous mats. It is generally considered that DCES is the solely technique to produce nanofibers using the electrostatic force from polymer solutions, however, less studied and also capable ACES provides further advantages such as increased specific productivities. A poorly water-soluble drug (carvedilol) was incorporated into the fibers based on three different polymeric matrices (an acid-soluble terpolymer (Eudragit® E), a base-soluble copolymer (Eudragit® L 100-55) and a nonionic homopolymer (Polyvinylpyrrolidone K90)) to improve the dissolution of the weak base drug under different pH conditions. Morphology and fiber diameter evaluation showed similar electrospun fibers regardless the type of the high voltage and the major differences in feeding rates. The amorphous ACES and DCES fibers provided fast and total drug dissolutions in all cases. The presented results show that ACES can be a more feasible novel alternative to formulate fibers for drug delivery purposes.

Melt-blown and electrospun drug-loaded polymer fiber mats for dissolution enhancement: A comparative study

Melt blowing (MB) was investigated to prepare a fast dissolving fibrous drug-loaded solid dispersion and compared with solvent-based electrospinning (SES) and melt electrospinning (MES). As a conventional solvent-free technique coupled with melt extrusion (EX) and using a high speed gas stream, MB can provide high quality micro- and nanofibers at industrial throughput levels. Carvedilol, a weak-base model drug with poor water solubility, was processed using a common composition optimized for the fiber spinning and blowing methods based on a hydrophilic vinylpyrrolidone-vinyl acetate copolymer (PVPVA64) and PEG 3000 plasticizer. Scanning electron microscopy combined with fiber diameter analysis showed diameter distributions characteristic to each prepared fibrous fabrics (the mean value increased towards SES<MB<MES). Differential scanning calorimetry and X-ray diffraction studies revealed that the incorporated drug was in amorphous form regardless the preparation method. The HPLC studies demonstrated that all of the materials produced by the different techniques passed the regulatory purity requirements. The fibers exhibited ultrafast drug release tested under neutral pH conditions, the melt blown sample dissolved within 2 minutes owing to its large specific surface area. The presented results confirm the applicability of MB as a novel formulation technique for polymer-based drug delivery systems.

Electroblowing and electrospinning of fibrous diclofenac sodium-cyclodextrin complex-based reconstitution injection

Electrospinning, electroblowing and freeze-drying were investigated to prepare fast dissolving cyclodextrin-based drug-loaded solid complexes. Combining the huge surface area of fibrous mats with the capabilities of cyclodextrins to prepare a reconstitution injection was tested to overcome the instability of liquid-based products. Diclofenac sodium was used as drug with limited water solubility and 2-hydroxypropyl-β-cyclodextrin (HPβCD) as carrier and solubilizer. The applied composition of the complex was determined based on phase solubility measurements. In order to resolve the frequent unavoidable interruption of the fiber formation during electrospinning from the HPβCD solution, high-speed blowing air was coupled with the electrostatic force (electroblowing) to draw polymer-free HPβCD fibers steadily, moreover, at increased flow rates. According to the scanning electron microscopic images, X-ray diffraction, differential scanning calorimetry no traces of crystallinity of the drug were detectable in the fibers as opposed to the freeze-dried product. Reconstitution tests of the fibers showed fast dissolution obtaining clear solutions equivalent to a marketed liquid-based bolus injection. The results demonstrate the first time the viability of electroblowing for preparing drug delivery systems.

High speed electrospinning for scaled-up production of amorphous solid dispersion of itraconazole

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 10 min) 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.

Plasticized drug-loaded melt electrospun polymer mats: characterization, thermal degradation, and release kinetics

Melt electrospinning (MES) was used to prepare fast dissolving fibrous drug delivery systems in the presence of plasticizers. This new method was found promising in the field of pharmaceutical formulation because it combines the advantages of melt extrusion and solvent-based electrospinning. Lowering of the process temperature was performed using plasticizers in order to avoid undesired thermal degradation. Carvedilol (CAR), a poorly water-soluble and thermal-sensitive model drug, was introduced into an amorphous methacrylate terpolymer matrix, Eudragit® E, suitable for fiber formation. Three plasticizers (triacetin, Tween® 80, and polyethylene glycol 1500) were tested, all of which lowered the process temperature effectively. Scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Raman microspectrometry investigations showed that crystalline CAR turned into an amorphous form during processing and preserved it for longer time. In vitro dissolution studies revealed ultrafast drug dissolution of the fibrous samples. According to the HPLC impurity tests, the reduced stability of CAR under conditions applied without plasticizer could be avoided using plasticizers, whereas storage tests also indicated the importance of optimizing the process parameters during MES.

Solvent-free melt electrospinning for preparation of fast dissolving drug delivery system and comparison with solvent-based electrospun and melt extruded systems

The solvent-free melt electrospinning (MES) method was developed to prepare a drug delivery system with fast release of carvedilol (CAR), a drug with poor water solubility. To the authors knowledge, this is the first report for preparing drug-loaded melt electrospun fibers. Cationic methacrylate copolymer of Eudragit® E type was used as a fiber forming polymer matrix. For comparison, ethanol-based electrospinning and melt extrusion (EX) methods were used to produce samples that had the same composition as the melt electrospun system. According to the results of scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Fourier transformed infrared spectrometry investigations, amorphous solid nanodispersions/solutions of CAR in Eudragit® E matrix were obtained in all cases with 20 m/m % drug content. In vitro drug release in acidic media from the extrudates was significantly faster (5 min) than that from crystalline CAR. Moreover, ultrafast drug release was achieved from the solvent-free melt and ethanol-based electrospun samples because of their huge surface area and the soluble polymer matrix in the acidic media. These results demonstrate that solvent-free MES is a promising, novel technique for the production of drug delivery systems with enhanced dissolution because it can combine the advantages of EX (e.g., solvent-free, continuous process, and effective amorphization) and solvent-based electrospinning (huge product surface area).