Medicated structural PVP/PEG composites fabricated using coaxial electrospinning

2.1 Materials

ACY was bought from Huyu Biotechnology Co. Ltd. (Shanghai, China); PVP K60 (M=360,000) was purchased from BASF Co. Ltd. (Shanghai, China). PEG 6000 (M=6000), methylene blue, sodium hydrate, citric acid monohydrate, and anhydrous ethanol were obtained from a local Chemical Reagent Co. Ltd. (Sinopharm, Shanghai, China). All chemicals with analytical grade were used directly without further purification. Water was purified through double distillations just before use

2.2 Preparation of the medicated composites

The shell fluid was composed of 0.46 g of citric acid and 8.0 g of PVP K60 in 100 ml ethanol. The core solutions consisted of 10.0 g PEG 6000, 0.40 g sodium hydrate, and 4.0 g ACY in 100 ml ethanol aqueous solution (50:50, v:v). For observations of the coaxial process using a digital camera, 2 mg of methylene blue was added to a 10 ml polypropylene syringe holding the core fluids.

A voltage supply (ZGF60 kV/2 mA, Wuhan Huatian Corp., Hubei, China) and two types of syringe pumps (KDS100 and KDS200, Cole-Parmer^®, IL, USA) were used in the experiments. A self-made coaxial spinneret (with an outside and inner diameter of 1.2 mm and 0.3 mm, respectively) was exploited to carry out both single fluid and coaxial processes. For optimization, the applied voltage and collector-to-spinneret distance were fixed at 14 kV and 15 cm, respectively. The other parameters can be found in Table 1.

2.3 Characterization

3.1 The preparation of medicated polymeric nanocomposites

Two working solutions were prepared with the shell fluid (acid solution) having the spinnability and the unspinnable core fluid (basic solution) containing the drug. Later, coaxial processes were conducted with the spinnable solution as a shell fluid to guide the core solution for the formation of a core-shell nanostructure. The fast drying processes resulting from the high-voltage electrostatic field were able to solidify the structural composites all at once with the drug encapsulated in the core parts of nanofibers.

A digital picture of the electrospinning system is exhibited in Figure 1A, in which the inset shows the self-made spinneret. Figure 1B tells the connection of voltage supply with the spinneret through a metal line. Figure 1C is a typical coaxial process when the nanofibers F3 were prepared. When the core fluid was turned off, a single electrospinning process of the shell fluid was realized. Shown in Figure 1D is the Taylor cone of shell solutions consisting of PVP and citric acid, which was transparent. In comparison, when the shell fluid was closed, an electrospraying process happened due to the core fluid lacking sufficient viscoelasticity. Its Taylor cone is shown in Figure 1E and the inset gives a digital photo of the atomization process. The single fluid electrospraying process could not result in any solid products. With the indication of methylene blue and under the conditions for the preparation of nanofibers F3, the compound Taylor cone of the shell and core fluid was exhibited in Figure 1F, in which the blue core solution was well encapsulated by the transparent shell fluid in a conical shape.

Figure 1:

Preparation of the medicated polymeric nanocomposites: (A) the apparatus arrangement, the inset shows the coaxial spinneret; (B) connection between the spinneret and the voltage supply; (C) a typical coaxial electrospinning process for the fabrication of nanofibers F3; (D) Taylor cone of only shell fluid for fabricating nanofibers F1; (E) Taylor cone of only the core solution; (F) a complex Taylor cone for the preparation of fibers F3.

3.2 Morphology and structure of the medicated composites

Shown in Figure 2A is the morphology of nanofiber F1 resulting from the spinnable shell solution solely. Its inset shows an enlarged image of the fibers. From these observations, it is obvious that fibers F1 had linear structures, smooth surfaces and a diameter of 550±170 nm.

Figure 2:

Morphology of the medicated composites. (A) Nanofibers F1; (B) nanofibers F4; (C) structural composites F3; (D) TEM image of fiber F3.

Most recently, modified coaxial and tri-axial electrospinning processes have been reported in the literature, which is characterized by the unspinnable outer layer solutions, including pure solvent, electrolyte solutions, and dilute polymer solutions (13). However, the mainstream of this advanced nanotechnology is still the standard one, in which the shell fluid has good spinnability while the core fluid may be or may not be spinnable (14). When an un-spinnable liquid was used as a core fluid, the flow rate ratio was an important parameter for implementing a successful process. When a core-to-shell flow rate ratio of 0.5 was used, the resultant nanofibers F4 have a poor morphology such as beads and clumps on the fibers (Figure 2B). An even larger ratio of 1 made the coaxial process fail to create solidified products. When a ratio of 0.3 was exploited, the resultant fibers F3 have linear morphology, smooth surface, uniform structure (Figure 2C and its inset) and a diameter of 740±110 nm.

Figure 2D shows a TEM image of the core-shell composite nanofiber F3. It had a distinct core-shell structure, with the core part had a diameter of about 420 nm and the shell layer had a thickness of about 150 nm. No nanoparticles can be discerned from both the core part and also the shell layer, suggesting both of them were composites with a homogeneous structure (15).

3.3 Physical forms and compatibility of components

At room temperature, both ACY and citric acid are white powders, and PEG 6000 is a flaky material. Figure 3 shows the XRD patterns of the crude materials and the prepared medicated composites, with all the raw materials except PVP showing peaks indicative of crystallinity. The crude PVP has a diffuse background pattern with two diffraction halos, giving a hint that it is an amorphous polymer. Similarly, the nanofibers F1 show no characteristic reflections of the crude citric acid and instead comprises diffuse halos, suggesting that all the citric acid was converted into amorphous forms during the electrospinning process. The composites F3 show a pattern of superposition of nanofibers F1 and PEG, without the characteristic peaks of ACY. This indicates that ACY was amorphously encapsulated by PEG and fibers F3 is a new type of structural composites comprising ACY-loaded PEG and citric-loaded PVP.

Figure 3:

XRD curves of the raw materials (PVP, PEG, citric acid monohydrate and ACY), the nanofibers F1 and the medicated nanocomposites F3.

The molecular structures of the raw materials (PVP, PEG, citric acid and ACY), the ATR-FTIR spectra of them and also the two composites (F1 and F3) are shown in Figure 4. ACY has the characteristic peaks of 1712 and 1632 cm⁻¹ resulted from the vibrations of -C=O groups. Similarly, citric acid has the characteristic peaks at 1688, 1724 and 1756 cm⁻¹, representing the stretching vibrations of -C=O groups in its crystals in a different state. The characteristic peak of PVP at 1666 cm⁻¹ and peak at 1101 cm⁻¹ in PEG are assigned to the -C=O and C-O stretching, respectively.

Figure 4:

ATR-FTIR spectra of the crude materials (PEG, citric acid monohydrate and ACY), the nanofibers F1, the medicated nanocomposites F3 and the molecular structures of raw materials.

In the spectra of nanofibers F1, the characteristic peaks of citric acid disappeared except a shoulder at the bottom of 1657 cm⁻¹ (as indicated by “A” in Figure 4). In the fingerprinting regions of citric acid spectra, almost all peaks have shifted, decreased in intensity, or completely disappeared. Whereas the characteristic peak of PVP at 1666 cm⁻¹ has a slight shift to lower wavenumber of 1657 cm⁻¹. These phenomena indicated that hydrogen bonds were formed between PVP and citric acid, in which citric acid molecules act as proton donors and PVP molecules act as proton receptors.

Concerning medicated composites F3, it seems a superposition of the spectra of nanofibers F1 and PEG, as indicated by the shoulder (“B” in Figure 4) and the characteristic peak at 1105 cm⁻¹. The characteristic peaks of ACY could not be discerned from the spectra of nanofibers F3, suggesting that hydrogen bonds occurred between PEG and ACY within the core parts.

3.4 In vitro dissolution experiments

The in vitro dissolution results are shown in Figure 5. The medicated composites F3 could release all the contained ACY in 1 min, whereas the ACY crude particles dissolved slowly, releasing only 31.4% (wt) in 1 h. The extremely fast release of ACY from composites F3 should benefit from the following facts: 1) both PVP and PEG are hydrophilic polymers that are often used as carriers for poorly water-soluble drugs (16); 2) the unique physical properties of the nanocomposites such as huge surface, small diameter, web structure of the assembled nanofibers; and 3) the amorphous physical form of ACY in the core of medicated composites, meaning no need to overcome crystal lattice energy for its dissolution.

Figure 5:

In vitro release profiles (n=6).

The content of citric acid in the shell is (0.46/210.4)×1000 (210.4 is the molecular weight of the citric acid monohydrate)=2.23 mmol, and the content of base in the core is (0.4/40)×1000 (210.4 is the molecular weight of sodium hydrate)=10 mmol. The core-to-shell flow rate ratio is 0.3 for preparing medicated nanocomposites F3, thus, the formed salts of the acid-basic reaction should consist of 2/3 of the sodium dihydrogen citric and 1/3 of the citric acid di-sodium. This was demonstrated by a measured pH value of 6.9 from the dissolution media using a PHBJ-260 pH-meter (Jingke Industrial Co. Ltd., Shanghai, China). By the way, the total ACY released from the fibers F3 was 19.83±0.41 mg, almost equivalent to the calculated value, suggesting little drug loss during the composite preparation process.