Preparation of an ascorbic acid/PVA–chitosan electrospun mat: a core/shell transdermal delivery system

Abstract

Core/shell L-ascorbic acid/poly(vinyl alcohol)–chitosan (ASC/PVA–CS) nanofibers were successfully prepared utilizing coaxial electrospinning and their characteristics were compared with monolithic blend PVA–CS–ASC nanofibers. In coaxial electrospinning, a series of aqueous acetic acid solutions of PVA–CS were used as a shell solution and a variety of ASC concentrations in a stabilizing solvent (ethanol/propylene glycol/water) were utilized as a core solution. Characterization of the obtained nanofibers was followed by SEM and TEM. Results of the SEM showed that an increase in PVA concentration in the shell solution or ASC concentration in the core solution increases the average diameter of nanofibers and leads to smooth morphologies. Furthermore, coaxial architecture of nanofibers was investigated and confirmed by differential thermal analysis (DTA) and X-ray diffraction (XRD). A release study indicated that a higher concentration of CS in the shell part of the crosslinked coaxial nanofibers leads to a decreased release rate of the ASC. Also, a lower concentration of ASC in the core part decreases the drug release from the core/shell nanofibers.

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1. Introduction

Continuous exposure to an oxygen-rich atmosphere, ultra violet radiation, pollution or smoking leads to the generation of reactive oxygen species (ROS) in the outer layer of the body. Consequently, ROS can trigger a free radical cascade which causes photo-aging and skin cancer.^1–3 Topical administration of antioxidants such as L-ascorbic acid (ASC) can be considered as an efficient route to protect the skin. This vitamin decreases melanin synthesis by prevention of tyrosinase activity.⁴ Also, through hydroxylation of lysine and proline residues in collagen (the most important protein of the skin), ASC increases transcription of procollagen genes and stable procollagen mRNA, therefore, it plays an important role in wound healing and prevention of wrinkles.^1,2,5,6 ASC deserves the advantage of long-time retention in the epidermis over sunscreens for UV protection.⁴

As for the instability of ASC, fabrication of an appropriate lasting transdermal delivery formulation is a requisite strategy. However, stable derivatives of L-ascorbic acid such as magnesium ascorbyl phosphate, ascorbyl palmitate and their oxidized form, i.e. dehydroascorbic acid (DHA), cannot increase the level of ascorbic acid in the skin.^1,2

In recent years, with the emergence of nanotechnology, several attempts to prepare vitamin and antioxidant drug delivery-based nanocarriers for topical administration have been reported. To note some, encapsulation of ASC in an inorganic nanocapsule,⁷ vitamin E in nanoemulsion,⁸ vitamin A-loaded⁹ and α-lipoic acid-loaded solid lipid nanoparticles¹⁰ can be considered. Also, among these drug delivery systems, polymeric nanofibers provide advantages of increasing surface to volume, reduced cost and facile commercialization.^11–16

Regarding a variety of approaches to fabricate nanofibers, electrospinning is widely studied and electrospun mats of different polymers were prepared.¹⁷ Among different polymers utilized to fabricate electrospun mats, chitosan (CS) would be a promising natural polymer in transdermal delivery applications. CS is a polysaccharide and is obtained from deacetylation of chitin and used as an ingredient in cosmetic products due to the hydration and wetting effect on the skin. By reducing water loss from the epidermis, CS increases the bandwidth capacity of water and moisturizes the skin.¹⁸ As the electrospinning of pure CS is difficult, synthetic polymers such as polyethylene oxide (PEO) and poly(vinyl alcohol) (PVA) have been blended with CS.^19–23 Several studies have reported CS and PVA blend nanofibers as drug delivery carriers, wound dressings and scaffolds for tissue engineering^24–27 and thus, this blend can provide a suitable solution in cosmetic and drug delivery applications.

Recently, many technical changes are performed in the original electrospinning approach. Coaxial electrospinning is one of these interesting novelties that can provide the core/shell nanofibers.²⁸ In this process, two different materials would be electrospun without any influence on each other and therefore, has found applications in the development of drug delivery systems. Indeed, the coaxial nanofiber can protect drug molecules in the core part and also, support their sustained release profile.^29–31 Recently, different core/shell nanofibrous structures including PEO/CS,³² CS/PEO,³³ CS/PVA³⁴ were successfully prepared utilizing coaxial electrospinning.

In the present study, we successfully synthesized core/shell ASC/PVA–CS nanofibrous mats with different shell and core concentrations and the obtained coaxial nanofibers were compared to their monolithic counterpart. The structure and morphology of core/shell ASC/PVA–CS nanofibers were characterized by SEM, TEM, DSC and XRD. To increase the water stability of the prepared core/shell and monolithic nanofibers, samples were crosslinked using glutaraldehyde vapor method. Moreover, in vitro release studies of ASC from both coaxial and monolithic electrospun mats were conducted.

2. Materials and methods

2.1 Materials

Low molecular weight chitosan (CS, MW: ∼50 kDa, degree of deacetylation 91.2%), was purchased from Easter Group (Dong Chen) Co., Ltd, China. Poly(vinyl alcohol) (PVA, Gohsenol GH-17, MW: ∼70 kDa, saponification degree 86.5–9 mol%) was obtained from The Nippon Synthetic Chemical Industry Co., Ltd, Osaka, Japan. Glacial acetic acid, ethanol and propylene glycol were purchased from Merck Co., Germany. All of the materials were utilized without further purification. L-Ascorbic acid (ASC) was supplied from Osvah Pharmaceutical Co., Ltd, Iran. The electrospinning machine was provided by Fanavaran Nano-Meghyas Co. Ltd, Tehran, Iran.

2.2 Preparation of electrospinning solutions

CS solutions of 1.0 and 2.0 wt% were prepared in aqueous acetic acid (90%, v/v) under overnight constant stirring at room temperature. PVA was dissolved in distilled water to obtain a concentration range of 5.0–10.0 wt%. ASC was dissolved in stabilizing solvent (ethanol/propylene glycol/distilled water, 65/25/10, v%) in a series of 1.0, 3.0, 5.0, 7.0 and 10.0 wt% concentration and kept away from light and heat to prevent ASC oxidation.

2.3 Single-nozzle electrospinning

Normal electrospinning was carried out to prepare a monolithic blend mat of PVA (10.0 wt%)–CS (2.0 wt%) with 30/70 weight ratio. This polymer blend was mixed with 10.0 wt% ASC solution in a weight ratio of 50/50 for (PVA–CS)/ASC. Then, as-prepared solution was loaded into a standard 5 ml syringe that was connected to a blunt-end 18 gauge needle. The electrospinning parameters were set up at a high voltage of 20.0 kV, feeding rate of 0.60 ml h⁻¹, spinneret to collector distance of 13 cm and about 25 °C.

2.4 Coaxial electrospinning

To fabricate core/shell electrospun membranes, ASC and also, PVA–CS blend solutions (according to Table 1) were prepared. Afterwards, PVA–CS and ASC solutions were loaded separately into 5 ml syringes connected to concentrically arranged blunt-end 17 and 24 gauge needles. The experimental scheme utilized in coaxial electrospinning is illustrated in Fig. 1. All processes were performed by applying a high voltage of 20.0 kV, flow rates of 0.60 and 0.20 ml h⁻¹ for shell and core solutions, respectively, tip to collector distance of 12.0 cm and 25 °C. Coaxial nanofiber mats were collected on an aluminum foil, wrapped around a rotating drum.

Table 1 Coaxial electrospinning parameters

Exp.	Concentration (wt%)			Weight ratio CS/PVA
	PVA	CS	ASC
a1	5	1	7	70/30
a2	6	1	7	70/30
a3	7	1	7	70/30
a4	8	1	7	70/30
a5	10	1	7	70/30
a6	10	2	7	70/30
a7	10	2	1	70/30
a8	10	2	3	70/30
a9	10	2	5	70/30

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Fig. 1 Schematic illustration of coaxial electrospinning.

2.5 Crosslinking process

Monolithic and coaxial nanofibrous membranes were crosslinked utilizing glutaraldehyde vapor method.³⁵ Briefly, a Petri dish containing 5 ml glutaraldehyde (GTA, 25%) was put in a desiccator. Then, nanofiber mats were exposed to the GTA vapor in the desiccator for 24 h.

Furthermore, to examine water stability of the obtained membranes, crosslinked samples were soaked into the distilled water for 24 h and then, kept for more investigations.

2.6 Characterization

To investigate the surface morphology and diameter of nanofibers, scanning electron microscopy (SEM, XL 30, Philips, USA) was carried out at an accelerating voltage of 25.0 kV. A small piece of each sample was sputter-coated with gold prior to observation and electronic micrographs were analyzed by SemAfore software (4.01, JEOL Co.) to calculate the average diameter of about 50 nanofibers.

Coaxial electrospun nanofibers were then investigated by transmission electron microscopy (EM 208, Philips) at an operating voltage of 100 kV to demonstrate core/shell structure of the nanofibers. For this purpose, a grid was fixed on an aluminum foil and utilized as a collector in order to be coated with a very thin layer of nanofibers and thereafter, observed with TEM.

To confirm the successful preparation of electrospun core/shell nanofibers, the thermal behavior of the obtained samples, including blend PVA–CS (10.0–2.0% wt%, weight ratio of 30/70, respectively), blend PVA–CS/ASC (weight ratio of 50/50), coaxial ASC/PVA–CS mat (Exp. a₉) and also, ASC drug powder was studied with a simultaneously thermal analyzer (STA503, BÄHR, Germany). Differential thermal analysis (DTA) was performed under an argon purge and traces were recorded between 25 and 240 °C at a heating rate of 10 K min⁻¹.

To further investigate the crystal content and morphology of the blend PVA–CS (10.0–2.0% wt%, weight ratio of 30/70, respectively), blend PVA–CS/ASC (weight ratio of 50/50), coaxial core/shell ASC/PVA–CS (Exp. a₉) and pure ASC powder, X-ray diffraction patterns were obtained by utilizing an Inel X-ray diffractometer (EQUINOX 3000, France). A monochromatized CuKα₁ radiation with wave-length λ = 0.154 nm at 40 kV, 50 mA, and in a 2θ range of 5–30° was applied.

2.7 In vitro release study

Release profiles of ASC and dehydroascorbic acid (DHA) from nanofibers were investigated in 50 ml of the stabilizing solvent and phosphate buffer saline (PBS), respectively. For each study, 50.0 mg of crosslinked mats of both blend and coaxial nanofibers were soaked into the releasing media. Standard concentrations of ASC in stabilizing solvent and DHA in PBS (pH: 5.5) were utilized to draw the calibration curves. Release profiles were checked at wavelengths of 261 and 200 nm for ASC and DHA, respectively, using UV-Vis spectroscopy (9200-UV-VIS, Rayleigh, China).

3. Results and discussion

3.1 Morphological analyses and size distribution of nanofibers

Morphology and diameter of non-woven nanofibers could be controlled by different parameters including solution concentration, viscosity, needle tip to collector distance and applied voltage. The solution concentration is reported as one of the important factors affecting morphology and size of nanofibers.³⁶

Single-nozzle electrospinning of PVA–CS–ASC blend solution was successfully achieved and morphology and diameter of the composite nanofibers were analyzed. Fig. 2(A) shows the SEM image of blend non-woven nanofibers. The average diameter of nanofibers containing 5.0% ASC (wt%, corresponding to 50/50 for PVA–CS/ASC weight ratio) was 86 ± 24 nm. The micrograph depicts a heterogeneous morphology with some beads among nanofibers.

Fig. 2 SEM images of PVA–CS–ASC blend nanofibers (A), and ASC/PVA–CS core/shell nanofibers from Exp. a₁ (B), Exp. a₂ (C), Exp. a₃ (D), Exp. a₄ (E), Exp. a₅ (F).

Fig. 2(B–F) show SEM photographs of ASC/PVA–CS core/shell nanofibers, according to the Table 1. To investigate the effect of changes in shell concentration on the morphology and diameter of the core/shell nanofibers, various concentration of PVA (Exp. a₁–a₅) and CS (Exp. a₆) were studied meanwhile core concentration was fixed at 7.0% ASC (wt). It is observable in Fig. 2(B) that the coaxial nanofibers containing 5.0% PVA (wt) have a heterogeneous morphology consisting of droplets and beads among nanofibers. Increasing the PVA concentration gradually improved the nanofibrous structure and yielded to uniform and smooth morphologies (Fig. 2(C–F)). Furthermore, core/shell nanofiber mat composed of 10.0% PVA (wt) exhibited formation of thicker fibers in somewhat fused-fiber morphology, as shown in Fig. 2(F), compared to lower PVA concentrations.

Formation of beaded morphologies during electrospinning is a result of insufficient chain entanglements between polymers.³⁷ Indeed, it is well known that production of continuous electrospun fibers requires a minimum level of polymer chain entanglements. In this condition, fiber-bead morphology would be formed. Therefore, to eliminate beaded structures from electrospun mat, the polymer concentration must be increased.³⁸

Moreover, chitosan as a polyelectrolyte is positively-charged in acidic solutions. Thus, the repulsive forces among the amino groups would prevent the formation of chain entanglements at lower concentrations of PVA and result in beaded morphologies.³⁹

However, a higher concentration of PVA (10%) leads to an increased amount of chain entanglements that discourages the bending stability of the jet and thus helps fabricate thicker fibers.⁴⁰ Also, a faster solidification of the jet at an augmented polymer concentration is another reason for formation of thick fibers.⁴¹ Other studies have reported similar results when increasing the concentration of shell polymer solutions.^42,43

More SEM investigation (Fig. 3(A)) illustrated that a higher concentration of CS (2.0 wt%), compared to 1.0 wt% CS (Fig. 2(F)), leads to a smooth and uniform morphology with thinner nanofibers. The average diameter of coaxial nanofibers of Exp. a₅ (Fig. 2(F)) was 172 ± 85 nm whereas that of nanofibers obtained from Exp. a₆ (Fig. 3(A)) was 159 ± 34 nm. The smaller diameter of nanofibers from Exp. a₆ is related to the increased conductivity of solution in the presence of 2.0% CS (wt). As CS has amino groups in its structure, it is a polyelectrolyte in acidic solution and provides solution with a higher conductivity that even could be increased by using more concentrated solutions of CS. We measured the conductivity of the shell solutions containing 1.0 and 2.0 (wt%) in μS cm⁻¹ and it demonstrated that the conductivity of the PVA (10%)–CS (2%) was 1.10 times more than that of PVA (10%)–CS (1%) solution. Electrospinning solutions containing higher contents of CS have an increased charge density on their jets that stretches the solutions into finer nanofibers.^24,44 Also, this increased conductivity would lead to additional jet splitting that, in turn, results in much smaller fibers.⁴⁵

Fig. 3 SEM images of ASC/PVA–CS core/shell nanofibers from: Exp. a₆ (A), Exp. a₇ (B), Exp. a₈ (C) and Exp. a₉ (D).

Fig. 3(B–D) show SEM images of the ASC/PVA–CS core/shell nanofibers in various concentrations of core solution (Exp. a₇–a₉) that can be compared with specimen from Exp. a₅ (Fig. 3(A)), in which is composed of 7.0% ASC (wt) as core solution. The SEM micrographs of Fig. 3(B–D) demonstrate that all of the nanofibrous samples have a uniform and smooth morphology. Calculation of size distribution and average diameter of nanofibers illustrated that raising the concentrations of ASC as the core solution increases the size of resulting coaxial nanofibers that is in line with other studies on the preparation of electrospun core/shell nanofibers.^32,46 The average diameter of nanofibers in samples with 1.0, 3.0, 5.0 and 7.0 wt% ASC core solutions were calculated to be 92 ± 21 nm, 98 ± 21 nm, 109 ± 31 nm and 159 ± 34 nm, respectively.

Fig. 4(A) represents a typical TEM image of the obtained ASC/PVA–CS coaxial nanofibers from Exp. a₉ besides their SEM micrograph. In the TEM investigation, the interface between core and shell is clearly observable. This figure demonstrates formation of the core/shell structure with shell and core diameters of 50 and 17 nm, respectively. Feed rates of the core and shell solutions were set at 0.20 and 0.60 ml h⁻¹, respectively, to provide a stable Taylor cone (as higher flow rates caused instability and solution dropping at the needle tip) and this TEM image proves that these flow rates were fast enough to shape the coaxial nanofiber.

Fig. 4 SEM and TEM image of coaxial ASC/PVA–CS nanofibers from Exp. a₉ (A) and its cross-linked nanofibers before (B) and after water immersion (C).

Additional investigations on the coaxial nanofibers obtained from Exp. a₉ (Fig. 4(B and C)) illustrated the effect of crosslinking process on the morphology and size distribution of the electrospun samples before and after soaking in water. GTA is efficiently used as a cross-linker to improve the stability of water-soluble nanofibrous mats of PVA–CS polymers.⁴⁷ Apparently, crosslinking changed the morphology of nanofibers from uniform and smooth to rough morphology (Fig. 4(B)). After 24 h incubation of electrospun mat in distilled water, some fibers still remained fibrous structure. However, because of water absorption and swelling, nanofibers mostly lost their form and filled the pore spaces (Fig. 4(C)).

3.2 Crystalline structure of the nanofibers

DTA thermograms of different samples including blend electrospun PVA–CS and PVA–CS/ASC, coaxial mat (Exp. a₉) and also, ASC drug are presented in Fig. 5. The first broad peak in all polymeric curves is attributed to the evaporation of water.³² ASC curve represents a sharp endothermic melting peak around 199 °C. On the other hand, the blend mat containing ASC shows a melting transition at 165 °C. This decrease in the melting point would be a result of fast solvent evaporation during electrospinning that prevents the ASC crystals to be formed completely.⁴⁸ In comparison, this peak is not present in the blend mat lack of the ASC. In the thermogram of the core/shell nanofibers of Exp. a₉, there is a broad peak around 130 °C that would be resulted from the ASC core. Indeed, this curve shows that the coaxial structure hinders the complete crystallization of the ASC drug in the core part. Therefore, the thermograms of blend PVA–CS/ASC and coaxial ASC/PVA–CS mats are significantly different.

Fig. 5 DTA thermograms of the pure ASC drug, electrospun blend PVA–CS (10.0–2.0%, wt), blend (PVA–CS)/ASC (weight ratio of 50 : 50) and coaxial mat (Exp. a₉).

To further investigate the morphology and crystal content of the blend and coaxial nanofibers, X-ray diffraction patterns were compared. Fig. 6 shows the XRD patterns of the blend PVA–CS, blend PVA–CS/ASC, coaxial ASC/PVA–CS (Exp. a₉) and neat ASC powder. The diffraction scan of the neat ASC shows several feature peaks including 2θ = 10.60°, 17.50°, 21.50°, 22.50°, 27.50° and 28.40° that illustrate the crystalline structure of ascorbic acid. The blend PVA–CS/ASC sample shows the peaks at 14°, 16.8° and 25.7°. It indicates that after adding ASC to the PVA–CS, crystalline microstructures form. Probably, due to the fast evaporation of the solvent during electrospinning process, the crystalline structure of the ASC cannot build up.³² The XRD pattern of blend PVA–CS does not represent any peak. It is reported that in the electrospun blend PVA–CS nanofibers with a high ratio of CS, specific peaks of the PVA and CS become very weak or disappear as a result of strong interaction between PVA and CS molecules.⁴⁹ Similarly, the XRD pattern of the coaxial nanofibers does not show any characteristic peak. It demonstrates that the ASC is not present in the shell part and is completely covered. Indeed, the coaxial pattern is similar to that of the blend PVA–CS nanofibers lack of ASC. The XRD analysis is consistent with the DTA results.

Fig. 6 XRD patterns of the pure ASC drug, electrospun blend PVA–CS (10.0–2.0%, wt), blend (PVA–CS)/ASC (weight ratio: 50 : 50) and coaxial mat (Exp. a₉).

3.3 Release profiles of nanofibers

The ASC/PVA–CS coaxial nanofibrous system would be suitable for transdermal applications of L-ascorbic acid, as ASC requires to slowly penetrate into the skin⁷ and also, to be protected from exposure to the oxygen and light on the skin which can oxidize ASC to the inappropriate form (i.e. DHA).

Profiles of drug release from crosslinked blend PVA–CS/ASC (weight ratio of 50 : 50) and also, coaxial nanofibers (Exp. a₉, Table 1) in stabilizing solvent were monitored by periodically measuring the absorbance of ASC in 261 by UV-Vis spectroscopy. Furthermore, DHA release profiles from crosslinked coaxial nanofibers resulted from Exp. a₅, a₆ and a₉ were investigated in phosphate buffer saline (PBS, pH: 5.5) and the absorbance was measured at 200 nm.

Release profile of the ASC in stabilizing solvent (in triplicate) is presented in Fig. 7(A). During the first 4 h of study, release of ASC from crosslinked coaxial nanofibers was lower than crosslinked blend nanofibers. In this part of profile, the crosslinked blend nanofiber mat exhibits a burst release of the ASC (33%). In this respect, as the hydrophilic PVA is utilized as a part of composite blend nanofiber, the initial burst release is expected.⁵⁰ Also, as PVA and CS polymers have the capacity of water absorption and swelling, therefore, diffusion and polymer relaxation are involved in release mechanism.⁵¹

Fig. 7 In vitro release study of the ASC from electrospun blend (PVA–CS)/ASC (weight ratio of 50 : 50) and also, coaxial nanofibers (Exp. a₉) in stabilizing solvent (A) and DHA from coaxial mats (Exp. a₅, a₆ and a₉) in PBS (pH: 5.5) (B).

However, release of the ASC from core/shell nanofibers showed a smaller amount at the initial hours of release (27%), as the drug is encapsulated in the core part and takes time to diffuse across the shell. The shell polymer requires enough swelling and relaxation to let the ASC molecules to go through. Then, the slope of profiles gradually became smaller and after 12 h the release profile of coaxial nanofiber exceeded the blend nanofiber (as shown in Fig. 7(A)). It seems that as the core is composed of only the ASC solution, ASC molecules can more rapidly diffuse and liberate in the release medium after swelling of the shell polymers but in the case of blend nanofibers, ASC molecules must diffuse among the polymer chains which have filled the whole structure of the nanofibers. At 30 h, maximum amounts of ASC release from crosslinked blend and coaxial nanofibers were 63% and 74%, respectively. However, there is no significant difference in release profiles of the blend and coaxial mats.

In the second study, absorbance of DHA was recorded in PBS (pH: 5.5) at 200 nm. As noted before, ASC is sensitive to the aqueous solution and is oxidized to DHA. In this respect, release of DHA from crosslinked specimens of Exp. a₅, a₆ and a₉ were examined. The obtained profiles are presented in Fig. 7(B). As the concentration of the shell and core polymers can alter the controlled release manner of drug from the core/shell nanofibers, the release from mats of Exp. a₅, a₆ and also, Exp. a₆, a₉ were investigated. Mats from Exp. a₅, a₆ contain 1.0 and 2.0 (wt%) chitosan in their shell part, respectively, and the concentration of the core maintained at 7.0 (wt%). As noted in the crosslinking section, the crosslinking between amino groups of chitosan is a major reason for stability of the coaxial structure during release time. Therefore, the amount of successful crosslinking depends on the concentration of chitosan and consequently, controls the release of drug from mats. Indeed, in a higher crosslinked shell, chitosan chains provide a much packed barrier against outward diffusion of the core drug. Also, utilizing an augmented polymer concentration as the shell part of coaxial polymer is realized to lower the diffusion of core part through shell and thus, rendered a better control over release profiles.⁵² It is clear from the Fig. 7(B) that increasing the chitosan concentration from 1.0 to 2.0 (wt%) lowers the drug release rate from the coaxial electrospun membranes.

The comparative study of drug release from specimens obtained from Exp. a₆, a₉ is also, provided in Fig. 7(B). Mats of Exp. a₆, a₉ are comprised of 7.0 and 5.0 (wt%) drug as their core, respectively, and the shell composition is the same. The resultant profiles of the mentioned membranes showed a significant decrease in the release of ASC when its concentration is lower in the core part. It can be noted that a higher drug concentration in the core part provides more drug to be dissolved in water penetrated into the polymeric network of the shell and finally, more drug releases from the coaxial nanofibers.⁴⁹

Furthermore, a comparison of the profiles of Exp. a₅, a₉ demonstrates that a more efficient controlled release coaxial system would be developed by applying a more concentrated shell polymer solution and decreasing the core concentration.

4. Conclusion

Herein, core/shell nanofibrous membrane of ASC/PVA–CS was successfully synthesized through coaxial electrospinning. Effects of different concentrations of polymer and ASC solutions on morphology and diameter of nanofibers were investigated. SEM images of coaxial samples demonstrated that increase of PVA and ASC concentrations in shell and core, respectively, lead to an increase in the average diameter of the obtained nanofibers and also, an upper concentration of CS in the shell solution reduces the average size of nanofibers. TEM image depicted the core/shell architecture and also, results of DTA and XRD confirmed the coaxial structure of nanofibers and showed the difference in crystalline content of the blend (PVA–CS)/ASC and coaxial ASC/PVA–CS nanofibers. ASC release study demonstrated that crosslinked core/shell nanofibers containing a higher concentration of the CS in the shell and a lower ASC concentration in the core would provide a decreased release profile of the drug. This system could be promising in transdermal drug delivery system.

Acknowledgements

This research has been supported by Tehran University of Medical Sciences and Health Services grant no. 94-2-87-29108. The authors also would like to express their special gratitude to the electron microscopy section of the Science Faculty of Tehran University.

References

1. S. R. Pinnell, H. Yang, M. Omar, N. M. Riviere, H. V. DeBuys, L. C. Walker, Y. Wang and M. Levine, Dermatol. Surg., 2001, 27, 137–142.
2. F.-H. Lin, J.-Y. Lin, R. D. Gupta, J. A. Tournas, J. A. Burch, M. A. Selim, N. A. Monteiro-Riviere, J. M. Grichnik, J. Zielinski and S. R. Pinnell, J. Invest. Dermatol., 2005, 125, 826–832.
3. S. S. Shapiro and C. Saliou, Nutrition, 2001, 17, 839–844.
4. L. E. Espinal-Perez, B. Moncada and J. P. Castanedo-Cazares, Int. J. Dermatol., 2004, 43, 604–607.
5. R. I. Hata and H. Senoo, J. Cell. Physiol., 1989, 138, 8–16.
6. J. Fuchs and H. Kern, Free Radical Biol. Med., 1998, 25, 1006–1012.
7. J.-H. Yang, S.-Y. Lee, Y.-S. Han, K.-C. Park and J.-H. Choy, Bull. Korean Chem. Soc., 2003, 24, 499–503.
8. P. Relkin, J.-M. Jung and M. Ollivon, J. Therm. Anal. Calorim., 2009, 98, 13–18.
9. V. Jenning, A. Gysler, M. Schäfer-Korting and S. H. Gohla, Eur. J. Pharm. Biopharm., 2000, 49, 211–218.
10. E. Souto, R. Müller and S. Gohla, J. Microencapsulation, 2005, 22, 581–592.
11. K. Madhaiyan, R. Sridhar, S. Sundarrajan, J. R. Venugopal and S. Ramakrishna, Int. J. Pharm., 2013, 444, 70–76.
12. S. Suganya, J. Venugopal, S. Ramakrishna, B. Lakshmi and V. Dev, J. Biomater. Tissue Eng., 2014, 4, 9–19.
13. K. Saha, B. S. Butola and M. Joshi, J. Appl. Polym. Sci., 2014, 131 DOI:10.1002/app.40824.
14. X.-M. Wu, C. J. Branford-White, D.-G. Yu, N. P. Chatterton and L.-M. Zhu, Colloids Surf., B, 2011, 82, 247–252.
15. A. Fathi-Azarbayjani, L. Qun, Y. W. Chan and S. Y. Chan, AAPS PharmSciTech, 2010, 11, 1164–1170.
16. P. Taepaiboon, U. Rungsardthong and P. Supaphol, Eur. J. Pharm. Biopharm., 2007, 67, 387–397.
17. B. Sun, Y. Z. Long, H. D. Zhang, M. M. Li, J. L. Duvail, X. Y. Jiang and H. L. Yin, Prog. Polym. Sci., 2014, 39, 862–890.
18. R. Rodrıguez, C. Alvarez-Lorenzo and A. Concheiro, Eur. J. Pharm. Biopharm., 2003, 56, 133–142.
19. B. Duan, C. Dong, X. Yuan and K. Yao, J. Biomater. Sci., Polym. Ed., 2004, 15, 797–811.
20. M. Spasova, N. Manolova, D. Paneva and I. Rashkov, e-Polymers, 2004, 56, 1–12.
21. K. Ohkawa, D. Cha, H. Kim, A. Nishida and H. Yamamoto, Macromol. Rapid Commun., 2004, 25, 1600–1605.
22. E. Mirzaei, R. Faridi-Majidi, M. A. Shokrgozar and F. Asghari Paskiabi, Nanomed. J., 2014, 1, 137–146.
23. J. M. Park, M. Kim, H. S. Park, A. Jang, J. Min and Y. H. Kim, Int. J. Biol. Macromol., 2013, 54, 37–43.
24. Y.-T. Jia, J. Gong, X.-H. Gu, H.-Y. Kim, J. Dong and X.-Y. Shen, Carbohydr. Polym., 2007, 67, 403–409.
25. L. Li and Y.-L. Hsieh, Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.), 2005, 46, 6.
26. Y. Zhou, D. Yang, X. Chen, Q. Xu, F. Lu and J. Nie, Biomacromolecules, 2007, 9, 349–354.
27. Y. O. Kang, I. S. Yoon, S. Y. Lee, D. D. Kim, S. J. Lee, W. H. Park and S. M. Hudson, J. Biomed. Mater. Res., Part B, 2010, 92, 568–576.
28. H. Qu, S. Wei and Z. Guo, J. Mater. Chem. A, 2013, 1, 11513.
29. D. Li and Y. Xia, Adv. Mater., 2004, 16, 1151–1170.
30. A. J. Meinel, O. Germershaus, T. Luhmann, H. P. Merkle and L. Meinel, Eur. J. Pharm. Biopharm., 2012, 81, 1–13.
31. M. Rubert, Y.-F. Li, J. Dehli, M. B. Taskin, F. Besenbacher and M. Chen, RSC Adv., 2014, 4, 51537.
32. M. Pakravan, M.-C. Heuzey and A. Ajji, Biomacromolecules, 2012, 13, 412–421.
33. S. S. Ojha, D. R. Stevens, T. J. Hoffman, K. Stano, R. Klossner, M. C. Scott, W. Krause, L. I. Clarke and R. E. Gorga, Biomacromolecules, 2008, 9, 2523–2529.
34. V. M. A. Bagherzadeh and A. Khodaparast Haghi, presented in part at the 4th International Conference on Nanostructures (ICNS4), Kish, March, 2012.
35. Y. Z. Zhang, J. Venugopal, Z. M. Huang, C. T. Lim and S. Ramakrishna, Polymer, 2006, 47, 2911–2917.
36. E. Mirzaei, A. Amani, S. Sarkar, R. Saber, D. Mohammadyani and R. Faridi-Majidi, J. Appl. Polym. Sci., 2012, 125, 1910–1921.
37. M. G. McKee, G. L. Wilkes, R. H. Colby and T. E. Long, Macromolecules, 2004, 37, 1760–1767.
38. R. Casasola, N. L. Thomas, A. Trybala and S. Georgiadou, Polymer, 2014, 55, 4728–4737.
39. M. Pakravan, M. C. Heuzey and A. A. M. Pakravan, Polymer, 2011, 52, 4813–4824.
40. V. Jacobs, R. D. Anandjiwala and M. Maaza, J. Appl. Polym. Sci., 2010, 115, 3130–3136.
41. S. De Vrieze, P. Westbroek, T. Van Camp and K. De Clerck, J. Appl. Polym. Sci., 2010, 115, 837–842.
42. M. Gulfam, J. M. Lee, J. Kim, D. W. Lim, E. K. Lee and B. G. Chung, Langmuir, 2011, 27, 10993–10999.
43. L. Xiaoqiang, S. Yan, C. Rui, H. Chuanglong, W. Hongsheng and M. Xiumei, J. Appl. Polym. Sci., 2009, 111, 1564–1570.
44. Y. Zhou, D. Yang and J. Nie, J. Appl. Polym. Sci., 2006, 102, 5692–5697.
45. R. Nirmala, B. woo Il, R. Navamathavan, M. H. El-Newehy and H. Y. Kim, Macromol. Res., 2011, 19, 345–350.
46. X.-J. Han, Z.-M. Huang, C.-L. He, L. Liu and Q.-S. Wu, Polym. Compos., 2008, 29, 579–584.
47. H. Liao, R. Qi, M. Shen, X. Cao, R. Guo, Y. Zhang and X. Shi, Colloids Surf., B, 2011, 184, 528–535.
48. Y.-T. Jia, J. Gong, X.-H. Gu, H.-Y. Kim, J. Dong and X.-Y. Shen, Carbohydr. Polym., 2007, 67, 403–409.
49. W. K. Son, J. H. Youk, T. S. Lee and W. H. Park, Polymer, 2004, 45, 2959–2966.
50. S. K. Tiwari, R. Tzezana, E. Zussman and S. S. Venkatraman, Int. J. Pharm., 2010, 392, 209–217.
51. W. J. King and W. L. Murphy, Polym. Chem., 2011, 2, 476–491.
52. H. Yu, Y. Jia, C. Yao and Y. Lu, Int. J. Pharm., 2014, 469, 17–22.

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