Electrosprayed core-shell solid dispersions of acyclovir fabricated using an epoxy-coated concentric spray head

Abstract

A novel structural solid dispersion (SD) taking the form of core-shell microparticles for poorly water-soluble drugs is reported for the first time. Using polyvinylpyrrolidone (PVP) as a hydrophilic polymer matrix, the SDs were fabricated using coaxial electrospraying (characterized by an epoxy-coated concentric spray head), although the core fluids were unprocessable using one-fluid electrospraying. Through manipulating the flow rates of the core drug-loaded solutions, two types of core-shell microparticles with tunable drug contents were prepared. They had average diameters of 1.36±0.67 and 1.74±0.58 μm, and were essentially a combination of nanocomposites with the active ingredient acyclovir (ACY) distributed in the inner core, and the sweeter sucralose and transmembrane enhancer sodium dodecyl sulfate localized in the outer shell. Differential scanning calorimetry and X-ray diffraction results demonstrated that ACY, sodium dodecyl sulfate, and sucralose were well distributed in the PVP matrix in an amorphous state because of favorable second-order interactions. In vitro dissolution and permeation studies showed that the core-shell microparticle SDs rapidly freed ACY within 1 minute and promoted nearly eightfold increases in permeation rate across the sublingual mucosa compared with raw ACY powders.

Keywords: coaxial electrospraying; core–shell microparticle; epoxy-coated spray head; poorly water-soluble drug; solid dispersion.

Figure 1

(A) Diagram of the coaxial electrospraying process. (B) Digital photograph of the epoxy-coated concentric spray head. (C and D) Contact angles of the shell fluid on a stainless steel plate and an epoxy-coated surface, respectively.

Figure 2

(A–F) Photographs of the coaxial electrospraying process setup and the optimization of parameters. (A) Arrangement of apparatuses used in this work; (B) connection of the spray head with the power supply; (C) typical coaxial electrospraying process under an applied voltage of 20 kV with sheath and core flow rates of 0.7 and 1.0 mL · hour⁻¹, respectively (“A” indicates the faster explosion processes of the droplets than photos taken by a camera); (D) divided electrospraying processes obtained under an excessive voltage of 25 kV; and (E and F) typical compound Taylor cone at a sheath flow rate of 1.0 mL · hour⁻¹ and core flow rates of 0.4 and 0.7 mL · hour⁻¹, respectively. The poorly water-soluble drug acyclovir (ACY) has poor solubility in a series of typical organic solvents, such as methanol, ethanol, chloroform, and acetone. ACY also has a high melting point (257°C). Therefore, reports on the use of this drug in solid dispersions (SDs) using traditional melt and solvent-evaporation technologies are few. Although ACY is soluble in dimethylacetamide (DMAc), polyvinylpyrrolidone (PVP) cannot be electrosprayed into microparticles under these conditions, because of its high boiling point (166°C) and poor volatility. Therefore, preparing microparticulate SDs of ACY by single-fluid electrospraying is impossible, because of the lack of appropriate solvent in which all components can dissolve together. Meanwhile, the solutions can be processed using electrospraying. For coaxial electrospraying, similar to coaxial electrospinning, the core solution does not need to be processable by electrospraying, and the shell solution acts as a guide and surrounds the core liquid. The shell solution is critical, and the selected shell systems should be processable by themselves to facilitate formation of a core–shell structure in the microparticles. Therefore, although the core solution consisted of 10% (w/v) PVP and 4% (w/v) ACY in a mixed solvent of DMAc:ethanol (4:6, v:v), the system was not processable by electrospraying. Nevertheless, the shell fluid consisting of 10% (w/v) PVP, 0.2% (w/v) sodium dodecyl sulfate, and 0.5% (w/v) sucralose in a mixed solvent of water:ethanol (0.5:9.5, v:v) was able to ensure a smooth coaxial electrospraying process and the formation of solid core–shell microparticles.

Figure 3

(A–D) Field-emission scanning electron microscopy images of the microparticles and their diameter distributions. (A) M1, (B) M4, (C) M2, and (D) M3.

Figure 4

Transmission electron microscopy images of (A) M2 and (B) M3.

Figure 5

(A) X-ray diffraction patterns of the raw materials and nanofibers. (B–F) Morphologies of acyclovir (ACY) particles, sucralose particles, sodium dodecyl sulfate (SDS) particles, polyvinylpyrrolidone (PVP) particles, and the prepared core–shell microparticles (M3), respectively, viewed under cross-polarized light.

Figure 6

Differential scanning calorimetry (DSC) thermograms of the raw materials and M2 and M3 microparticles. DSC and X-ray diffraction results demonstrated that the functional molecules (acyclovir [ACY]) and also the excipients (sucralose and sodium dodecyl sulfate [SDS]) were highly distributed throughout the polyvinylpyrrolidone (PVP) matrix, and were present in a complex manner where the original structure of pure materials was lost. Electrospraying, similar to electrospinning, is an inherently appropriate method for preparing solid dispersions. The fast-drying electrospraying process can randomly “freeze” the drug molecules in the solid-polymer matrix into a state comparable to a liquid form. This can prevent phase separation, eg, recrystallization of either drug or matrix, during solvent removal.

Figure 7

Attenuated total reflectance–Fourier-transform infrared spectra of the crude materials and microparticles, and molecular structures of polyvinylpyrrolidone (PVP), acyclovir (ACY), sucralose, and sodium dodecyl sulfate (SDS).

Figure 8

(A) In vitro drug-release profiles (n=6). (B and C) Recrystallization of acyclovir (ACY) after natural drying and fast dissolution of the spread M2 and M3 microparticles, respectively, when a drop of water was placed on them.

Figure 9

In vitro permeation profiles of acyclovir (ACY) powders and core–shell microparticles solid dispersions (n=6).