Abstract
Nanofibers have many promising biomedical applications. They can be used for designing transdermal and dermal drug delivery systems. This project aimed to prepare and characterize polyvinylpyrrolidone-based nanofibers as a dermal and transdermal drug delivery system using pioglitazone. Pioglitazone is an oral antidiabetic drug. In addition, it can act as an inflammatory process modulator, making it a good candidate for managing different skin inflammatory conditions such as atopic dermatitis, skin ulcers, and diabetic foot wound healing. Several nanofiber formulations were prepared using the electrospinning method at different drug loadings, polyvinylpyrrolidone concentrations, and flow rates. A cast film with the exact composition of selected nanofiber formulations was prepared as a control. Nanofibers were characterized using a scanning electron microscope to calculate the diameter. Fourier-transform infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and powder X-ray diffraction were performed for physical and biochemical characterizations. In vitro release, drug loading efficiency, and swelling studies were performed. Ex vivo permeation studies were performed using Franz diffusion cells with or without applying a solid microneedle roller. Round uniform nanofibers with a smooth surface were obtained. The diameter of nanofibers was affected by the drug loading and polymer concentration. Fourier-transform infrared spectra showed a potential physical interaction between the drug and the polymer. According to X-ray diffraction, pioglitazone existed in an amorphous form in prepared nanofibers, with partial crystallinity in the casted film. Nanofibers showed a higher swelling rate compared to the casted film. The drug dissolution rate for nanofibers was 2.3-folds higher than the casted films. The polymer concentration affected the drug dissolution rate for nanofibers; however, drug loading and flow rate did not affect the drug dissolution rate for nanofibers. The application of solid microneedles slightly enhances the total amount of drug permeation. However, it did not affect the flux of the drug through the separated epidermis layer for pioglitazone. The drug permeation flux in nanofibers was approximately five times higher than the flux of the casted film. It was observed that pioglitazone is highly retained in skin layers.
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Acknowledgements
For Deanship of Research at Jordan University of Science and Technology for funding this project with Fund number (385/2020)
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Rana Obaidat: Design of the work; supervision, analysis, or interpretation of data for the work; and Final approval of the version to be published.
Ayat Abu Shameh: Performed the research in the lab, data acquisition, data analysis, and writing it as part of her master’s degree thesis.
Mohannad Aljarrah: contributed to design, characterization of the nanofiber preparation, characterization, and writing
Rania Hamed: contributed to the design of surface tension, rheology measurements, and writing.
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Highlights
• Round uniform nanofibers with a smooth surface were prepared.
• The diameter of nanofibers was affected by the drug loading and PVP concentration.
• FTIR spectra showed a potential physical interaction between the drug and the polymer.
• PGZ existed in an amorphous form in the prepared nanofibers, and with partial crystallinity in the casted film.
• Nanofibers showed a higher swelling rate compared to the casted film.
• The drug dissolution rate for Nanofibers was 2.3-folds higher than the casted films. The drug dissolution rate for Nanofibers was affected by the PVP concentration; however, drug loading and flow rate did not affect the drug dissolution rate for Nanofibers.
• The application of solid microneedles slightly enhances the total amount of drug permeation. However, it did not affect the flux of the drug through the separated epidermis layer for PGZ. The drug permeation flux was approximately five times higher than the flux of the casted film.
• It was observed that PGZ is highly retained in skin layers.
Appendices
Appendix
Testing various penetration enhancers to enhance permeation of PGZ through the skin
High-Performance Liquid Chromatography (HPLC)
Development of HPLC Method
A modified high-performance liquid chromatography (HPLC) method for PGZ analysis was developed and validated based on Akkala et al. (29). A C18 HPLC column with a particle size of 5 μm (150 mm x 4.6 mm) was used. The mobile phase was composed of methanol and 10mM potassium dihydrogen phosphate at a volume ratio of 70:30, respectively, with a pH of 6.8. The mobile phase was filtered through 0.45 μm membrane filters and was degassed before use.
The separation was carried out at room temperature (25 °C), at a flow rate of 1 mL/min, injection volume of 25 μL, and detection wave length of 267 nm.
A stock solution of PGZ with a concentration of 200 μg/ml was prepared by dissolving 10mg in 100 mL of methanol. Different standard solutions with concentrations ranging from 0.1 to 200 μg/ml were prepared by diluting specific volumes of stock solution using mobile phase.
Validation of HPLC Method
The developed HPLC method for PGZ was validated according to the ICH guidelines. Validation included:
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A)
Linearity
Linearity of the developed HPLC method was assessed by injecting freshly prepared standard solutions of PGZ (0.1–200 μg/ml in the mobile phase) into the HPLC system. The experiment was repeated six times, and calibration graphs were constructed by plotting the mean HPLC area under the curve versus the concentration of PGZ in each standard.
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B)
Accuracy and Precision
The developed HPLC method’s accuracy and precision were examined by replicating injections (n = 6) of three standard solutions of PGZ at a concentration of 0.5, 40, and 150 μg/ml. The samples were injected daily for three different days. The % accuracy was calculated from the measured PGZ concentration concerning its actual concentration. The relative standard deviations (%RSD) were calculated for each standard solution intra- and inter-daily.
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C)
Specificity
The specificity of the developed HPLC method was assessed to examine whether there is any potential interference between the peaks of excipients present in the formulation the peak of the drug. This was done by injecting a placebo solution containing all the possible sample ingredients except the drug and comparing the HPLC chromatograph of this placebo solution with PGZ solution.
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D)
Detection and Quantification Limits
The detection limit (DL) and quantification limit (QL) of the HPLC method were calculated from the slope of the calibration curve (S), which was obtained as described in section 2.3.1.2, and the standard deviation of the response (σ) of 6 blank samples, according to the following equations (73):
High-Performance Liquid Chromatography Results
Development of HPLC Method
A modified HPLC method for PGZ was developed based on the method of Akkala et al (29). The typical HPLC chromatograph of PGZ is presented in Figure 13. PGZ was eluted at a retention time of 5 minutes that was considered to be very suitable. Almost similar retention time of PGZ was observed in the method previously developed by Akkala et al.
Validation of HPLC Method
-
A)
Linearity
The linearity of the calibration curve over a range of 0.1–200 μg/mL was assessed by plotting the mean HPLC area under the curve versus the concentration of PGZ (Figure 14). The correlation coefficient (R2) of the observed curve was found to be 0.9995, which indicates the linearity of the HPLC method.
-
B)
Specificity
The specificity of the developed HPLC method was assessed by injecting a placebo solution containing all the possible sample ingredients except the drug (namely: PVP, ethanol, DMF, DMSO and Transcutol® P) and comparing the HPLC chromatograph of this placebo solution with that of PGZ solution. As shown in the HPLC chromatograph of this placebo solution (Figure 15), no interference peaks were observed or close to the drug's retention time.
-
C)
Accuracy and Precision
The developed HPLC method’s accuracy and precision were examined by replicating injections (n = 6) of three standard solutions of PGZ at a concentration of 0.5, 40, and 150 μg/ml. The intra- and inter-day accuracy and precision results for the HPLC method are presented in Table III.
The intra-day %recoveries were ranged from 95.8 to 100.8%, and the inter-day %recoveries were ranged from 95.02 to 100.51%. All %recovery values were within the acceptance criteria (90–110%), which indicates that the method is accurate (74). The intra-day %RSD ranged from 0.11 to 0.75%, and the inter-day %RSD ranged from 0.82 to 1.28%. All %RSD values were within the acceptance criteria (≤ 2%), indicating that the method is precise (73).
-
D)
Detection and Quantification Limits
The detection limit (DL) and quantification limit (QL) of the HPLC method were calculated from the slope of the calibration curve obtained in Figure 14 and the standard deviation of the response for six blank samples as described in equations 8 and 9, respectively. The detection limit was 0.022 μg/mL, and the quantification limit was 0.067 μg/mL.
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Obaidat, R., Shameh, A.A., Aljarrah, M. et al. Preparation and Evaluation of Polyvinylpyrrolidone Electrospun Nanofiber Patches of Pioglitazone for the Treatment of Atopic Dermatitis. AAPS PharmSciTech 23, 51 (2022). https://doi.org/10.1208/s12249-021-02204-6
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DOI: https://doi.org/10.1208/s12249-021-02204-6