Electrospun Hydrophilic Janus Nanocomposites for the Rapid Onset of

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Electrospun Hydrophilic Janus Nanocomposites for the Rapid Onset of Therapeutic Action of Helicid Ke Wang, Xin-Kuan Liu, Xiao-Hong Chen, Deng-Guang Yu, Yao-Yao Yang, and Ping Liu ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b17663 • Publication Date (Web): 22 Dec 2017 Downloaded from http://pubs.acs.org on December 26, 2017

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ACS Applied Materials & Interfaces

Electrospun Hydrophilic Janus Nanocomposites for the Rapid Onset of Therapeutic Action of Helicid Ke Wang,1,† Xin-Kuan Liu,1,† Xiao-Hong Chen,1,† Deng-Guang Yu,*,† Yao-Yao Yang,1,† Ping Liu*,† †

School of Materials Science & Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.

1

These authors contributed equally.

*Corresponding authors Prof. Deng-Guang Yu and Prof. Ping Liu School of Materials Science and Engineering, University of Shanghai for Science and Technology, 516 Jungong Road, Shanghai 200093, China Tel./Fax: +86 21-55270632 E-mail: [email protected] (DGY); [email protected] (PL)

KEYWORDS: Janus nanofibers; Hydrophilic composites; Side-by-side electrospinning; Water-insoluble drug; Fast onset of therapeutic action

1 ACS Paragon Plus Environment

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ABSTRACT: The oral delivery of active ingredients for the fast onset of therapeutic effects is a well-known method in patients. In this study, a new kind of hydrophilic Janus structural nanocomposites was designed for the rapid dissolution and transmembrane permeation of helicid, an herbal medicine with poor water solubility. A side-by-side electrospinning process characterized by an eccentric spinneret was developed to fabricate the Janus nanocomposites. The morphology, inner structure, incorporated components and their physical

states,

hydrophilicity,

and

functional

performances

of

the

Janus

nanocomposites were investigated. The experimental results demonstrated that an unspinnable fluid (polyvinylpyrrolidone K10-sodium dodecyl sulfate) could be simultaneously

treated

with

an

electrospinnable

fluid

(polyvinylpyrrolidone

K90–helicid) to create Janus structural nanocomposites. The prepared Janus nanofibers exhibited linear morphology and notable side-by-side inner structure with all the incorporated components present in an amorphous state. Both the control of monolithic nanocomposites and the Janus composites can provide more than 10-fold the transmembrane rates of crude helicid particles. Compared with monolithic nanocomposites, the Janus nanocomposites exhibited improved hydrophilicity and can further promote the dissolution and transmembrane permeation of helicid for a potentially faster onset of therapeutic actions. The generation mechanisms and functional performance of Janus nanocomposites were suggested. The preparation protocols reported here can provide a useful approach for designing and developing new functional nanocomposites in the form of Janus structures. Meanwhile, the medicated hydrophilic Janus nanocomposites represent a newly developed kind of nano drug delivery system for the fast onset of therapeutic action of orally administered water-insoluble drugs.


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INTRODUCTION Oral administration (such as buccal, sublabial, and sublingual deliveries) is the most popular route for the patients because of its convenience.1 The fast onset of therapeutic action of active pharmaceutical ingredients (APIs) are highly prescribed for numerous diseases, such as heart attacks, fever, and pain, as well as psychiatric disorders, such as epilepsy.2-5 However, more than half of the developed and already used APIs show delivery problems associated with solubility,6,7 fast dissolution, and permeation to enter the circulatory system. Thus, the fast dissolution and permeation of water-insoluble drugs through oral administration are some of the most difficult and long existing multidisciplinary challenges for researchers in the related fields. Polymers have functioned as a backbone in pharmaceutical development in the past 50 years. New methods and polymeric excipients are continuously being introduced into this multidisciplinary branch to resolve several important and difficult issues. Advanced nanotechnologies are one of the most popular research topics owing to the applicability of nanoproducts with large surfaces and complex nanostructures in the development of novel kinds of nano drug delivery systems.8-10 Based on the application of the nanotechnologies, certain polymers with a series of molecular weights, such as polyvinylpyrrolidone (PVP), poly(ethylene glycol)/poly(ethylene oxide), and other oligomer/polymers with a similar molecular formula, can present different applications in drug delivery through scientific integration.11 For example, PVP K10 can be electrosprayed into nanoparticles for fast drug dissolution, dual drug-controlled release, and molecular self-assembly manipulation of medicated nanoparticles. However, PVP



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K30, PVP K60, and K90 can be electrospun into nanofibers for certain biomedical applications. At present, new technologies with fine capability, flexibility, and utility act as key elements in expanding and deepening the applications of already existing polymers in applied scientific fields.12-14 Electrospinning has improved the commercial viability of nanofiber-based products in a wide variety of fields,15,16 with many publications directly reporting the production of these materials on a large scale.17-19 In biomedical applications, medicated nanofibers reportedly provide all kinds of drug-controlled release profiles, including sustained, biphasic-controlled, long-time circulation, and multiple-phase.20,21 For enhancing the dissolution rates of water-insoluble drugs for immediate or pulsatile release, nanofiber-based solid dispersions (essentially pharmaceutical polymer-based composites) were quickly developed from traditional binary composites (with a homogeneously distributed guest API within a host polymer) to ternary nanocomposites, composites with four or more components (API, polymer, surfactant, and/or sweetening agent), and complex structural nanocomposites (such as core–shell).22 However, to the best of our knowledge, no research on the potential applications of Janus nanostructures for the rapid onset of drug therapeutic action has been reported to date. The narrow spinnable window of filament-forming polymers, limited solvent selection for spinnable solution preparation, assurance of sufficient active ingredients, and the incorporation of other additives normally contribute to the failure of forming a composite nanofiber by using single-fluid

blending electrospinning.23-26 The


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simultaneous treatment in structural formats of different kinds of solutions can resolve certain issues and expand the capability of electrospinning in generating complex nanostructures.27,28 These structures, including tri-layer, core-sheath, Janus, and their combinations, are useful in designing novel polymer-based functional nanomaterials. 29,30

The electrospinning processes utilized in creating these complex nanostructures

typically include coaxial, side-by-side, tri-axial, tri-layer side-by-side, and even quadru-axial electrospinning.31-33 As one of the most fundamental structures, Janus structure offer its own unique properties compared with its counterpart, the core–sheath, with both sides in direct contact with the surrounding environments; this structure can be effectively exploited to develop new types of nanomaterials for improved or even new functional performances in numerous applications.34-36 Meanwhile, when side-by-side electrospinning is applied to create Janus nanostructures, the two working fluids similarly contact each other but not in a whole surrounding manner such as that in the coaxial process. Thus, the interfacial interaction between the two working fluids substantially decreased, favoring a

successful

double-fluid

treating

process.

Correspondingly,

new

kinds

of

double-compartment nanostructures may be easier to be fabricated through side-by-side electrospinning than coaxial process for certain working fluid systems. However, despite the numerous publications on coaxial electrospinning, core–sheath nanofibers, tri-axial

electrospinning,

and

related

tri-layer

nanofibers,37,38

side-by-side

electrospinning and related Janus nanofibers have rarely been reported. Thus, Janus nanofibers are difficult to manufacture and are not facilely produced from a spinneret



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comprising two parallel metal capillaries; the two parallel working fluids typically repel and separate from each other because of identical charges when led into electrical fields.39 In this proof-of-concept study, a Janus nanocomposite was fabricated using a side-by-side electrospinning process, in which the eccentric spinneret acted as a key element. One side of the Janus nanofibers comprised an oligomer polymer (PVP K10) and a transmembrane enhancer (SDS) solidified from an unspinnable solution (“unspinnable” means that the solution can’t be converted into solid fibers), whereas the other side contained a filament-forming polymer (PVP K90) and a helicid formed from a spinnable solution (“spinnable” means that the solution can be converted into solid fibers). For comparison, a hydrophilic binary nanocomposite with PVP K90 and helicid and without the additional side was prepared using the traditional blending electrospinning method. Helicid, an herbal medicine extracted from plant Helicid nilgrinica Bedd, has been utilized for thousands of years in western China to cure insomnia and headaches by acting as a sedative agent. Commercially, this drug is delivered through oral dispersible tablets. Rapid onset of therapeutic action after oral administration is highly required by patients.40

EXPERIMENTAL SECTION Materials. PVP K90 (Mw = 360,000) and PVP K10 (Mw = 8,000) were purchased from Sigma-Aldrich Corp. (Shanghai, China). Helicid (98% purity) was purchased from Shananxi Red-Pomelo Biotechnology Co. Ltd., (Xian, China). Sodium dodecyl sulfate


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(SDS), basic magenta, N,N-dimethylacetamide (DMAc), and anhydrous ethanol were obtained from Shanghai Linhong Chemical Co., Ltd., (Shanghai, China). Electrospinning. Helicid is a poorly soluble drug in water and is insoluble in a series of typical organic solvents, such as ethanol, acetone, and chloroform. However, this drug is soluble in DMAc. Thus, a co-dissolving solution of 8% (w/v) PVP K90 and 2% (w/v) helicid was added in a 2:8 (volume ratio) mixture of DMAc and ethanol. The unspinnable liquid was composed of 9.7% (w/v) PVP K10 and 0.3% (w/v) SDS in an 75% ethanol aqueous solution because SDS is soluble in water. A content of 5×10-3 mg/mL basic magenta was added into the unspinnable liquid for observing the working processes. An eccentric spinneret was used to carry out side-by-side and single-fluid electrospinning processes. The double working fluids were derived quantitatively using two syringe pumps (KDS100, Cole-Parmer, USA). High voltage was supplied using a power supply (Shanghai Sute Electrical Co., Ltd.). After optimization, the applied voltage and fiber-collected distance were fixed at 12 kV and 20 cm, respectively. Two composite nanofibers were prepared: the monolithic nanocomposite (denoted by F1), which was fabricated through a single-fluid blending process of the electrospinnable fluid with a fixed flow rate of 1.0 mL/h, and the Janus nanocomposite (denoted by F2), which was fabricated through side-by-side electrospinning. The spinnable and unspinnable flow rates were optimized at 0.8 and 0.2 mL/h, respectively. Morphology. The prepared nanofibers were evaluated by scanning electron microscopy (SEM; FEI Quanta450FEG, USA). Prior to microscopy, fiber mats were



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sputter coated with platinum for 2 min. The cross-section samples were prepared by manually breaking fiber mats, which were inserted into liquid nitrogen for more than 15 min. The inner structure of nanofibers was evaluated using a H-800 transmission electron microscope (TEM; Hitachi, Japan). Physical status of the components and their interactions. X-ray diffraction (XRD) experiments were conducted using a Bruker X-ray powder diffractometer (Bruker-AXS, Karlsruhe, Germany). Raw drug, polymer powders, and nanofiber samples were detected within a 2θ angle range of 5° to 60°. A polarizing microscope (PM, 59XA-2, Shanghai Optical Instrument Factory, China) was utilized to observe the particles of raw materials. An MDSC 2910 differential scanning calorimeter (TA Instruments Co., USA) was exploited to conduct all differential scanning calorimetry (DSC) analyses. The samples were sealed and heated at a rate of 10 °C/min from the ambient temperature to 270 °C under nitrogen protection (40 mL/min). Hydrophilic property and drug-loading capability. The hydrophilicity of the nanocomposites was evaluated using a drop-shape analysis instrument (DSA100, Krüss GmbH, Hamburg, Germany) by measuring surface water contact angle (WCA). Approximately 3 µL of phosphate buffer solutions (PBS, pH 7.0, 0.1 M) was deposited onto the surface of a sample, and the receded processes of the droplet were recorded. In vitro dissolution and permeation tests. A RCZ-8A dissolution apparatus (Tian-Jin University Radio Factory, China) was exploited to carry out in vitro dissolution tests. Samples containing an equivalent of 32 mg of helicid (namely, 0.16 g


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of F1 and 0.20 g of F2) were placed in dissolution cells containing 900 mL of PBS at a constant temperature of 37 °C ± 1 °C, a rotation rate of 50 rpm and a sink condition of C < 0.2 Cs. Approximately 5.0 mL of aliquots were withdrawn from the dissolution media to measure drug concentrations at pre-determined time points. The withdrawn volume was replaced with 5.0 mL of fresh medium to maintain the bulk dissolution media at a constant volume. All experiments were repeated for six times. Ex vivo permeation tests. A diffusion test apparatus (RYJ-6A, Shanghai Huang-Hai Drug Control Instrument Co., Ltd., China) was used to conduct the ex vivo permeation experiments. A diagram of a diffusion cell is shown in Figure S1 in SI. The diffusion area of each cell was 2.60 cm2. Each donor and receptor compartment was filled with 1.0 and 7.2 mL of PBS, respectively. A magnetic stirrer in the receptor compartment was rotated at 50 rpm. The porcine sublingual mucosae were obtained from a local slaughterhouse and were utilized within 2 h of butchery. The mucosae were covered in the receptor compartments and equilibrated for 30 min at 37 °C before permeation experiments. The helicid particles (1.6 mg), nanofibers F1 (8.0 mg), or Janus nanofibers F2 (10.0 mg) were placed on the mucosal surfaces. At a pre-determined time point, 1.0 mL of aliquot was withdrawn from the receptor compartment, and 1.0 mL of fresh PBS was compensated. The aliquots were filtered through a 0.22-μm film before UV detection. All measurements were conducted in triplicate.



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RESULTS AND DISCUSSION Side-by-side electrospinning method. A schematic of the side-by-side electrospinning system is shown in Figure 1a. Similar with a typical single-fluid blending or a coaxial electrospinning system, side-by-side electrospinning is composed of a high-voltage generator that provides electrostatic energy, two syringe pumps that drive and meter the working fluids, a fiber collector, and a structural spinneret. As the most important component in the system, the spinneret not only determines the kind of electrospinning process (such as concentric spinneret for coaxial electrospinning and tri-axial spinneret for tri-axial electrospinning)

39

but also acts as a regulator to

manipulate the initial behaviors of the treated working fluids when led into electrical fields. Based on the report on coaxial and tri-axial electrospinning, the fabrication of Janus nanofibersby by using a spinneret comprising two parallel metal capillaries is supposedly easy.34,39 However, integrated Janus nanostructures through this kind of parallel spinneret are extremely difficult to achieve, particularly when one of the working fluids is unspinnable. Thus, an eccentric spinneret was developed here to fabricate Janus nanofibers. A digital picture of the home-made spinneret is shown in Figure 1b, with one metal capillary nested into another metal capillary and deviating on one side. This novel spinneret innovation was more suitable than the parallel spinneret for ensuring a matched behavior under the electrical field and a simultaneous solidification of two working fluids in a side-by-side manner.


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Figure 1. A schematic of side-by-side electrospinning (a) and a digital picture of a side-by-side nozzle of the eccentric spinneret (b). In the implementation of side-by-side electrospinning (Figure 2a), one pump is connected with the eccentric spinneret through direct insertion of fluid-contained syringe into the groove of the spinneret. Another pump drives the working fluid to the spinneret through a silica tubing. The inset of Figure 2a shows the pass routes of the double working fluids within the metal capillaries. High voltage can be transferred into the working fluid through an alligator clip. The collector under the spinneret must be grounded to the electrostatic energy away and thus eliminate the repulsion forces in continuous deposition and assembly of the final solid nanoproducts.

Figure 2. Observations of the working processes. (a) The connections of spinneret with the power supply and double working fluids; its inset shows the pass route of working fluids within the metal capillaries. (b) Blending electrospinning of the electrospinnable side for preparing the monolithic nanofibers F1; its inset is the corresponding Taylor cone. (c) A typical side-by-side electrospinning process for preparing Janus nanofibers F2; its inset is the compound Taylor cone. (d) A side-by-side electrospinning process with excess unspinnable fluid. 11 ACS Paragon Plus Environment


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When the electrospinning system was employed to prepare the monolithic nanocomposites F1, the pump for driving the unspinnable fluid was stopped. Under the experimental conditions, a digital picture of the single-fluid electrospinning process was shown in Figure 2b, with the inset showing the enlarged Taylor cone image. A typical fluid working process involves a Taylor cone formed under an electrical field, an intermediate straight fluid jet, and a followed bending and whipping region with gradually enlarged loops. When both pumps were turned on at flow rates of 0.8 and 0.2 mL/h for the electrospinnable and unspinnable working fluids, respectively, a digital picture of the side-by-side working process can be obtained and observed using a camera with 11× magnification (Figure 2c). The compound Taylor cone was exhibited in its inset with a red unspinnable side owing to the color marker basic magenta. Similarly in a typical single-fluid blending-electrospinning process, two working fluids were simultaneously emitted from the compound Taylor cone and passed through the straight fluid jet and the unstable region together to the fiber collector. However, when the flow rate of the unspinnable fluid increased to 0.4 mL/h, occasional dispatches were observed, which is exhibited in Figure 2d. Apparently, the side-by-side electrospinning process failed to accommodate two separate processes, namely, blending electrospinning of the spinnable fluid and typical electrospraying of the unspinnable fluid. These observations suggested that side-by-side electrospinning can be carried out with only one electrospinnable fluid between the double working fluids and one unspinnable fluid. However, the fluid flow rate ratio becomes a crucial


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parameter when only one fluid is electrospinnable or solidifiable; this consideration is also applied in other double-fluid electrohydrodynamic atomization processes, such as coaxial electrospinning41 and coaxial electrospraying.42,43 Regardless of traditional coaxial processes with an unspinnable core fluid and modified coaxial electrospinning method with unspinnable sheath fluid, the fluid rate of unspinnable liquid should be treated carefully to successfully prepare the desired nanostructures. Morphology and nanostructures. The SEM images of the surface morphology of nanofibers and their average diameter and size distribution are shown in Figure 3. Both F1 (monolithic) and F2 (Janus) nanofibers showed linear morphology without any beads or spindles (Figures 3a and 3b). As anticipated, excessive unspinnable fluids generated beads-on-a-string morphology (Figure 3c), which describes a simultaneous deposition of both electrospun and electrosprayed products. This result deviates from the spindles-on-a-string morphology, which illustrates a phenomenon in one working fluid without sufficient viscosity. The nanofibers F1 and F2 presented average diameters of 710 ± 60 and 630 ± 110 nm, respectively (Figure 3d). The cross sections were exhibited in the insets, suggesting that no solid phase separations occurred during both blending and side-by-side processes. The F2 nanofibers presented a slightly smaller diameter than the nanofibers F1. The unspinnable side fluid might have prolonged the time period when the side-by-side two fluids were drawn by electrical forces, thus resulting in Janus nanofibers with decreased size. Meanwhile, the unspinnable fluid should have a small surface tension to resist electrical drawing owing to the surfactant SDS.



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Figure 3. SEM images of the electrospun nanocomposites. (a) monolithic nanofibers F1. (b) Janus nanofibers (F2). (c) nanoproducts resulting from excessive unspinnable side fluids. (d) average diameters of nanofibers F1 and F2 and their size distribution. The insets in (a) and (b) show the cross sections of corresponding nanofibers. The TEM images of the Janus nanofibers F2 are shown in Figure 4a (the inset shows a possible detection angle). Unlike homogeneous nanofibers F1, which possessed a monolithic structure (Figure S2 in SI), F2 presented distinct side-by-side nanostructures. The side resulting from the unspinnable fluid presented a lower gray level than the other side formed from the electrospinnable fluid, and the estimated thicknesses of the sides were approximately 140 and 540 nm, respectively. During side-by-side electrospinning, the eccentric spinneret substantially influenced the formation of Janus nanofibers. A schematic comparing the charges on the working fluids with different kinds of side-by-side spinneret is illustrated in Figure 4b. When a traditional side-by-side spinneret comprising two parallel metal capillaries was exploited to lead the two working fluids into the electrical field, the electrical energy charged them evenly. The two parallel working fluids possessed the same electrical properties; however, the fluids only experience a small point of contact when they were pumped out from the spinneret nozzles (“B” in Figure 4b). According to case studies on side-by-side electrospinning, given that the two electrospinnable fluids are compatible 14 ACS Paragon Plus Environment

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with each other, the large viscosities would ensure sufficient binding forces to resist repelling forces in forming side-by-side straight fluid jets, going through the instable regions, and finally forming the Janus nanostructures. 44-46

Figure 4. TEM images of the Janus nanofibers (F2, a, the inset shows a possible detection angle) and a schematic showing the influences of charges on the working fluids (b). The strict conditions of two compatible and electrospinnable fluids markedly limit the use of a parallel side-by-side spinneret in generating Janus nanoproducts. The capability of treating unspinnable liquid, together with spinnable polymer solution simultaneously should substantially expand the applications of the side-by-side electrospinning processes, and this finding is similarly observed in coaxial and modified coaxial electrospinning. Thus, a new structural spinneret that can overcome these limitations can provide a new tool in this field. A diagram and a digital photo of the newly designed eccentric spinneret are shown in Figures 4b and 1b. Three elements confer evident advantages to the newly designed eccentric spinneret in comparison with the traditional parallel spinneret in implementing side-by-side electrospinning. First is a full round, full charge surface around the circle line of the outer metal capillary; this surface is different from the separate two-ring irregular charge area of the parallel spinneret. Second is the two working fluids that can pass through an enlarged arch area (“A” in Figure 4b) to ensure sufficient contact to prevent separation. The multiple 15 ACS Paragon Plus Environment


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diffusions of two side-by-side fluids can be ignored because the parallel fluids are solidified at an extreme speed.47 Third is the inner metal capillary in the eccentric spinneret that can slightly project over the surface of the outer metal capillary; this capillary can prevent the possible mutual diffusion of the two working liquids. This design feature cannot be implemented in a traditional spinneret with two parallel metal capillaries because the design can exacerbate the detachment of two working fluids at the earliest possible time. Physical status and compatibility. Both raw helicid particles and SDS powders are crystalline materials, as suggested by the sharp peaks in their XRD patterns and the colorful images under PM observation (Figure 5). Helicid is a typical needle crystalline, whereas SDS possesses an irregular morphology. PVP K10 and PVP K90 belong to the same kind of polymers, and no significant difference was observed in their XRD patterns. These patterns comprised two diffraction halos, suggesting that polymers were amorphous carriers. When the raw materials were treated using different electrospinning processes, the formed nanocomposites showed a similar XRD pattern with two diffraction halos.

Figure 5. XRD patterns and PM images of the raw materials. The DSC curves of the raw materials (helicid, SDS, PVP K10, and K90) and their


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nanocomposites are shown in Figure 6. As a crystalline material, helicid exhibited a sharp single endothermic response corresponding to its melting point of 200.2 °C. Pure SDS showed two sharp peaks at 181.9 °C and 213.1 °C, which are the melting point and decomposing temperature of SDS, respectively. As amorphous polymers, PVP K90 and K10 showed no sharp peaks in their DSC curves, but a broad endotherm that resulted from dehydration was observed. The monolithic nanofibers F1 showed no sharp peak of helicid in their thermogram, suggesting that helicid was totally converted into amorphous composites with the polymer matrix PVP K90. The Janus nanofibers F2 presented a similar DSC curve as F1 except for a sharp peak at 204.7 °C. Compared with the pure SDS curves, this peak was determined to be a result of SDS decomposition. However, this peak was sharper and earlier formed than that of SDS particles. The nanosized SDS-PVPK10 side in the F2 nanofibers presented a relatively large surface, the amorphous status of SDS, and the homogeneous distributions within PVP K10. Furthermore, randomly assembled 3D nonwoven mats with large porosity co-acted to induce a more rapid, earlier decomposition of SDS molecules compared with the raw SDS particles, thus resulting in a sharper peak at a slightly lower temperature.



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Figure 6. DSC curves of the raw materials and their nanocomposites. Hydrophilicity. The WCA value can provide useful information about the water-contact behaviors and related hydrophilicity of nanofiber mats.48 A 3 µL volume of water was placed on the nanofiber mats, and the behaviors of nanofibers F1 and F2 are shown in Figure 7. The needle leading the liquid water was 0.3 mm in outer diameter. The starting point of the needle tip was 2 mm from the fiber mats. When the needle was driven to place a droplet of water on the monolithic nanofibers, an average time period of 3.1 s ± 0.7 s was needed for the water droplets to totally disappear from the surface of nanofiber mats (referring to a zero degree of WCA). During the processes, two phenomena were captured: the competition between the needle tip and the F1 fiber mats and the transient formation of a small pool of water. The latter is demonstrated in the inset of Figure 7a. By contrast, when a droplet of water was placed on the Janus nanofiber mat, only 1.2 s ± 0.3 s elapsed until the drop totally disappeared from the surface (Figure 7b). The water competition between the needle and fiber mats and the small pool phenomena were not observed during the rapid absorbing and spreading processes of water droplets


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(the inset of Figure 7b). These differences suggested that the PVP K10-SDS sides in the Janus nanofibers performed important roles in altering water penetration behaviors and spreading rates. Although the nanofibers’ morphology and diameters might exert some influences on the disappearance processes of water droplets, the main reason should be the presence of surfactant SDS and PVP K10 on the surface of one side in the Janus nanofibers to further increase their hydrophilicity. This property is crucial for the oral sublingual drug delivery membranes because of the fast action of therapeutic effects required for the drugs.

Figure 7. WCA of monolithic nanofibers F1 (a) and Janus nanofibers F2 (b). In vitro dissolution tests. The in vitro drug release profiles of the raw helicid particles, monolithic nanofibers, and Janus nanofibers are exhibited in Figure 8a. Both nanofibers released the load within 1 min. However, the raw helicid particles released only 11.7% after 30 min. A series of factors guaranteed the slow release of the molecules of the raw helicid particles. These factors included high lattice energy, large drug particle size, limited surface area, and hydrophobicity. The drug molecules enter into the bulk solutions in a layer-by-layer manner from the surface of the drug particles (lower part of Figure 8b). By contrast, when the drug was incorporated into the polymer 19 ACS Paragon Plus Environment


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matrix to form the composite nanofibers F1, the drug molecules could be released at an extremely rapid rate because simultaneously overcoming lattice energy, nanoscale diameter, and large surface of the nanofibers and disintegrating the polymer matrices in the nanofiber mats are unnecessary. Although no significant differences were observed between F1 and F2 in the in vitro dissolution results, the Janus nanofibers could further improve their performances in enhancing fast dissolution, as suggested by the WCA tests. As shown in the upper part of Figure 8b, the fast dissolution processes for Janus nanofibers includes two steps: the dissolution of the PVP K10-SDS side and the dissolution of PVP K90-helicid side. In the past two decades, a number of new materials (including polymer, lipid, hydrogel, and even inorganic materials) in a wide variety of formats (such as microspheres, beads, nano-porous membrane, and fibers) and through different administration routes (such as injection, colon targeted, gastric retention, and oral sublingual deliveries) have been reported to provide pulsatile drug release profiles.49-55 Compared with the previous studies, the present method present the following advantages: 1) the usage of the most common pharmaceutical excipients (PVP and SDS) that have been authorized by FDA; 2) the simple one-step and straightforward fabrication process; and 3) the easy after-treatment of the electrospun nanofibers for developing potential solid dosage forms.


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Figure 8. In vitro dissolution profiles (a) and a diagram about the comparisons between raw helicid particles and hydrophilic Janus nanocpmposites F2 (b). Ex vivo permeation tests. The ex vivo permeation results are shown in Figure 9. The cumulative permeation percentages of drug after 30 min were 3.4% ± 2.7%, 52.5% ± 6.1%, and 75.3% ± 5.2% for the raw helicid particles, nanofibers F1, and Janus nanofibers F2, respectively. The permeation equations can be achieved through regression according to linear equation at the steady-state flux before the leveling-off stage, that is, Qhelicid = 1.552 + 0.139t (R = 0.9875, t ≤ 30 min), QF1 = 6.124 + 1.648t (R = 0.9519, t ≤ 30 min), and QF2 = 13.97 + 2.284t (R = 0.8831, t ≤ 30 min). Thus, the apparent permeation rates of drug particles, nanofibers F1, and Janus nanofibers F2 can be calculated as 0.053, 0.634, and 0.878 μg·min−1·cm−2, respectively. Compared with that of raw drug particles, the permeation rate of nanofibers F1 improved by 11.9 times, which is a direct result of the fast dissolution of helicid from the monolithic nanocomposites. The easy dissolution of the water-insoluble drug from the nanofibers F1can provide a high initial donor drug concentration, thus creating a large concentration gradient for the passive diffusion of helicid from the donor compartments to the receptor compartments. The Janusnanofibers F2 further increased the permeation rates, by 16.4 and 1.4 times relative to those of helicid particles and nanofibers F1 , respectively. The PVP K10-SDS sides in the Janus nanocomposites



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facilitated further improvement of functional performances. The permeation of sublingual mucosa is a passive diffusion process. More rapid drug dissolution translates to a larger drug concentration gradient at the mucosal surface; thus, rapid drug dissolution requires a large force that pushes the drug molecules to penetrate into and through the membrane. This effect was enhanced because of limited water supply for drug dissolution in the mouth. Meanwhile, in the Janus nanofibers F2, the pre-release of the transmembrane enhancer SDS from its PVP K10 sides improves permeation through extraction of certain intercellular lipids, which can act as rate-limiting barrier to drug transport. 56

Figure 9. Ex vivo permeation profiles. Complicated nanostructures, including core–shell, Janus nanostructures, their combinations, and assembled 3D structures, are extensively known in developing novel functional nanomaterials.57,58 Correspondingly, nanomedicines have shown increased emphasis on new properties and improved functional performances of medical nanomaterials through the control of structures at the nanoscale.59,60 However, the “bottom-up” methods for creating these complicated nanostructures typically entails a series of complicated and time-consuming steps that are difficult (and even impossible) 22 ACS Paragon Plus Environment

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to scaled up. As a simple “top–down” and easy scale process, electrospinning uniquely offers the generation of complex nanostructures in a one-step and straightforward manner by using a structural spinneret as a template.61,62 This work demonstrated the concept of synthesizing Janus nanofibers using an eccentric spinneret, which provided a better prototype than the traditional parallel spinneret. Furthermore, only about 100 polymers are electrospinnable, whereas numerous unspinnable working fluids are available; hence, the successful incorporation of unspinnable fluids into the processes would considerably expand the capabilities of this technology in generating new Janus nanoproducts. Certainly, inspired by hints from the related investigations,63-66 researchers can improve their ability of micro-/nanofabrication, achieve new knowledge about fluid-energy interactions, and create new applied functional nanomaterials. CONCLUSIONS A side-by-side electrospinning process was developed to create Janus nanoproducts from an electrospinnable fluid and an unspinnable fluid by using an eccentric spinneret. The eccentric spinneret can ensure a smooth and continuous preparation process due to a round nozzle-charging surface and enlarged contact areas of the two working fluids. The successfully fabricated medicated Janus nanocomposites F2 possessed PVP K90-helicid in one side and PVP K10-SDS in another. These structural nanocomposites presented linear morphology and evident Janus nanostructures, as demonstrated by SEM and TEM images, respectively. XRD patterns and DSC thermograms concurred that both the raw crystalline helicid and SDS particles were converted into amorphous



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polymer-based Janus structural composites. As demonstrated by WCA tests, the Janus nanofibers showed improved hydrophilicity than their counterparts, monolithic nanofibers from the traditional blending electrospinning process. Although nanofibers F1 and F2 showed no differences in the in vitro dissolution experiments with abundant dissolution media and both showed more than 10-fold transmembrane performance compared with the helicid particles, the structural Janus nanocomposites further improved the fast transmembrane permeation of helicid relative to monolithic nanocomposites.

The

side-by-side

electrospinning

process

and

structural

nanocomposites reported here paves a new pathway for developing novel kinds of functional nanomaterials for multiple fields. SUPPORTING INFORMATION Details of the Implementation of the ex vivo experiments; TEM images of the monolithic nanocomposites; Attenuated total reflectance fourier transform infrared (ATR-FTIR) results. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION * Corresponding authors: E-mail: [email protected] (DGY) E-mail: [email protected] (PL) Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS This work was supported by the National Natural Science Foundation of China (No. 51373101).


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Graphic abstract 32x12mm (300 x 300 DPI)

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Figure 1. A schematic of side-by-side electrospinning (a) and a digital picture of a side-by-side nozzle of the eccentric spinneret (b). 35x16mm (300 x 300 DPI)


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Figure 2. Observations of the working processes. (a) The connections of spinneret with the power supply and double working fluids; its inset shows the pass route of working fluids within the metal capillaries. (b) Blending electrospinning of the electrospinnable side for preparing the monolithic nanofibers F1; its inset is the corresponding Taylor cone. (c) A typical side-by-side electrospinning process for preparing Janus nanofibers F2; its inset is the compound Taylor cone. (d) A side-by-side electrospinning process with excess unspinnable fluid. 59x44mm (300 x 300 DPI)



Figure 3. SEM images of the electrospun nanocomposites. (a) monolithic nanofibers F1. (b) Janus nanofibers (F2). (c) nanoproducts resulting from excessive unspinnable side fluids. (d) average diameters of nanofibers F1 and F2 and their size distribution. The insets in (a) and (b) show the cross sections of corresponding nanofibers. 57x40mm (300 x 300 DPI)


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Figure 4. TEM images of the Janus nanofibers (F2, a, the inset shows a possible detection angle) and a schematic showing the influences of charges on the working fluids (b). 33x13mm (600 x 600 DPI)



Figure 5. XRD patterns and PM images of the raw materials. 43x23mm (300 x 300 DPI)


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Figure 6. DSC curves of the raw materials and their nanocomposites. 63x49mm (300 x 300 DPI)



Figure 7. WCA of monolithic nanofibers F1 (a) and Janus nanofibers F2 (b). 55x30mm (600 x 600 DPI)


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Figure 8. In vitro dissolution profiles (a) and a diagram about the comparisons between raw helicid particles and hydrophilic Janus nanocpmposites F2. 26x8mm (600 x 600 DPI)



Figure 9. Ex vivo permeation profiles. 60x45mm (300 x 300 DPI)


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Electrospun Hydrophilic Janus Nanocomposites for the Rapid Onset of

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