Controllable and switchable drug delivery of ibuprofen from temperature responsive composite nanofibers
© Tran et al.; licensee Springer. 2015
Received: 5 November 2014
Accepted: 17 March 2015
Published: 3 August 2015
Composited electrospun nanofibers made of temperature-responsive poly(N-isopropylacrylamide) (pNIPAM) and biodegradable poly (ε-caprolactone) (PCL) can be utilized for ‘on-demand’ and controlled drug release of ibuprofen without burst effect for potential pharmaceutical applications. Three types of nanofibers, PCL, pNIPAM and pNIPAM/PCL composite NFs containing ibuprofen were fabricated using electrospinning techniques. Ibuprofen release rates from PCL NFs are not affected by the temperature in the range of 22–34°C (less than 10%). In contrast, the ibuprofen release rates from pNIPAM NFs are very sensitive to the change in temperature, which is five times higher at 22°C compared to 34°C. However, there is a serious burst effect at 22°C. Compared to other two types of NFs, pNIPAM/PCL composite NFs prepared demonstrated a variable and controlled release at both room and higher temperature, due to the extra protection from the hydrophobic poly (ε-caprolactone). The rate at 22°C is 75% faster compared to that at 34°C. This kind of composite design can provide a novel approach to suppress the burst effect in drug delivery systems for potential pharmaceutical applications.
KeywordsPoly (ε-caprolactone) Poly(N-isopropylacrylamide) Nanofibers Ibuprofen Controlled release Temperature-responsive
Average cumulative amount of IP released from three types of NFs at 22 and 34°C
Cumulative amount of IP released at 1 hr
Cumulative amount of IP released at 2 hr
Cumulative amount of IP released at 3 hr
Cumulative amount of IP released at 4 hr
pNIPAM/PCL composite NFs 22°C
pNIPAM/PCL composite NFs 34°C
Modern electrospinning technology allows for drug delivery to be well controlled by tuning spinning parameters and materials. The cost, diameter, composition and structure of electrospun nanofibers can be facilely varied to regulate the drug delivery rates and kinetics. Poly (ε-caprolactone) (PCL) is one of those biocompatible and biodegradable polymers approved by US Food and Drug Administration (FDA) for use in many biomedical devices . PCL has been electrospun into nanofibers for tissue engineering and drug delivery applications due to its high porosity, interconnected pores and high surface area-to-volume ratio [10,11]. However, dosing rates can’t be varied under external stimulus. Poly(N-isopropylacrylamide) (pNIPAM) is a quite interesting biocompatible thermo-responsive polymer . When heated above 32°C (its lower critical solution temperature, LCST), pNIPAM undergoes a reversible phase transition from hydrophilic to hydrophobic, losing ~90% of its volume, resulting in the change of drug release rates . Topical administration of levothyroxine using poly vinyl alcohol (PVA) and pNIPAM composite nanofibers were investigated by Azarbayjani et al. But it was found that there were serious burst effects at both 25°C and 37°C due to the high water permeability of hydrophilic PVA . Electrospun nanofibers transdermal patches showed great capability for wound healing because they can efficiently absorb exudates due to extremely large surface area. [15,16] Most recently, antibiotic ciprofloxacin loaded hydrophilic biodegradable poly vinyl alcohol electrospun nanofibers have been successfully applied to in vivo wound healing treatment to prevent infections .
In this report, electrospun nanofibers made of temperature responsive pNIPAM and hydrophobic PCL polymers were used for controllable and variable ibuprofen (IP) release at both room temperature (22°C) and the temperature above its lower critical solution temperature (LCST) without any burst effects. These nanofibers can be applied to transdermal drug delivery that can significantly enhance the efficacy of drug addiction and abuse treatments .
PCL with an average Mn of 45,000 and pNIPAM with an average Mn of 19,000-30,000 were purchased from Sigma-Aldrich. Ibuprofen with a purity >99.0% was obtained from ACROS Organic. Ethanol and acetone with purity higher than 99.5% were purchased from EMD Millipore. Acetonitrile used for HPLC analysis was purchased from EMD Millipore also.
2.2 Fabrication of nanofibers
2.3 Characterization of nanofibers
The prepared samples were characterized using a Field Emission Electron Microscopy (JEOL JSM-7600 F) at Georgia Southern University for morphology examinations. Fourier-Transform Infrared (FTIR) spectra of nanofiber samples were recorded in the attenuated total reflection (ATR) mode using an IR spectrophotometer (Thermo-Nicolet AVATAR 370 FT-IR Spectrometer) in the range of 4000 to 650 cm−1 at Georgia Southern University.
2.4 Drug diffusion studies
All ibuprofen studies involving these three types of NFs were carried out using a 5 mL PermeGear Franz cell with a 10 mm diameter orifice for sampling. ~20 ± 1 mg NFs were wetted and suspended in the receptor chamber containing 4.0 mL of deionized water and a magnetic stirring bar. It was calculated that there were 4.8, 4.8 and 3.7 μmol of ibuprofen in PCL/IP, pNIPAM/IP and pNIPAM/IP/PCL fibers, respectively. 1 mL solution was pipetted from the receiver chamber per hour and stored into 1.8 mL amber glass vials for HPLC analysis. The chamber was back-filled with 1.0 mL deionized water after each sampling. All drug release profiles were averaged from triple measurements.
2.5 HPLC measurements and data analysis
All ibuprofen samples were analyzed by a Shimadzu LCAT High Performance Liquid Chromatography (HPLC) consisting of a SIL-20AHT autosampler, a LC-20AT HPLC pump, a SPD-20A dual UV/Vis absorbance detector set at a wavelength of 254 nm and utilizing LabSolutions software. Thermo Scientific HyPURITY C18 reversed-phase 5 μm column (250 mm × 4 mm; L × I.D.) was used for the separation. The mobile phase consisted of 0.1 wt% H3PO4 aqueous solution:acetonitrile (55:45) and flow rate of 1.0 mL/min. Calibration plots were prepared using IP standards with concentrations over a range of 20–100 μg/ml. The correlation coefficient (r2) obtained was ≥0.99 for standard curves. The cumulative quantity of drug collected in the receiver compartment was plotted as a function of time. This method was adapted from a literature reported method . The lower limit of quantification (LLOQ) was 2 μg/ml.
3 Results and discussion
Three types of polymeric nanofibers were fabricated using electrospinning method for drug delivery studies. Temperature has negligible effects on the IP diffusion rates from PCL/IP NFs. For pNIPAM/IP NFs, there is a significant burst effect at 22°C; whereas both diffusion rate and burst effect are dramatically depressed at a higher temperature. For pNIPAM/IP/PCL composite NFs, burst effect was significantly reduced for both 22°C and 34°C. The diffusion rate is higher at 22°C compared to that at 34°C by 75%. It can be naturally envisioned that such kind of controllable and switchable delivery systems could easily find many practical applications in both pharmaceutical and medical sciences.
JW, TT and MH sincerely acknowledge the COSM pilot funding and the COUR award provided by Georgia Southern University. We also deeply appreciate Mrs. Kathy Gay provides long term support of the manuscript preparation and Dr. Nathan Takas for technical supports.
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