Fast Dissolving Oral Drug Delivery System based on Electrospun

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Fast Dissolving Oral Drug Delivery System based on Electrospun Nanofibrous Webs of Cyclodextrin/Ibuprofen Inclusion Complex Nanofibers Asli Celebioglu, and Tamer Uyar Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.9b00798 • Publication Date (Web): 22 Aug 2019 Downloaded from pubs.acs.org on August 26, 2019

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Molecular Pharmaceutics

Fast Dissolving Oral Drug Delivery System based on Electrospun Nanofibrous Webs of Cyclodextrin/Ibuprofen Inclusion Complex Nanofibers Asli Celebioglu* and Tamer Uyar* Department of Fiber Science & Apparel Design, College of Human Ecology, Cornell University, Ithaca, NY, 14853, USA *Corresponding

Authors: AC: [email protected]; TU: [email protected]

ACS Paragon Plus Environment

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Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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ABSTRACT: In this study, the polymer-free electrospinning was performed in order to produce cyclodextrin/ibuprofen inclusion complex nanofibers, which could have potentials as fast dissolving oral drug delivery system. Ibuprofen is a poorly water-soluble nonsteroidal antiinflammatory drug, but, the water solubility of ibuprofen can be significantly enhanced by inclusion complexation with cyclodextrins. Here, Hydroxypropyl-beta-cyclodextrin (HPβCyD) was chosen both as a nanofiber matrix and host molecule for inclusion complexation in order to enhance water solubility and fast dissolution of ibuprofen. Ibuprofen was inclusion complexed with HPβCyD in highly concentrated aqueous solutions of HPβCyD (200 %, w/v) having two different molar ratio; 1:1 and 2:1 (HPβCyD:ibuprofen). The HPβCyD/ibuprofen-IC (1:1) aqueous solution was turbid having some undissolved/uncomplexed ibuprofen whereas HPβCyD/ibuprofen-IC (2:1) aqueous solution was homogeneous and clear indicating that ibuprofen was totally complexed with HPβCyD and become water soluble.

Then, both

HPβCyD/ibuprofen-IC solutions (1:1 and 2:1) were electrospun into bead-free and uniform nanofibers having ~200 nm fiber diameter. The electrospun HPβCyD/ibuprofen-IC nanofibers were obtained as nanofibrous webs having self-standing and flexible character, which is appropriate for fast dissolving oral drug delivery systems. Ibuprofen was completely preserved during the electrospinning process and the resulting electrospun HPβCyD/ibuprofen-IC nanofibers were produced without any loss of ibuprofen by preserving the initial molar ratio of 1:1 and 2:1 (HPβCyD:ibuprofen). X-ray diffraction (XRD) and differential scanning calorimetry (DSC)

measurements

indicated

the

presence

of

some

crystalline

ibuprofen

in

HPβCyD/ibuprofen-IC (1:1) nanofibers whereas ibuprofen was totally in amorphous state in HPβCyD/ibuprofen-IC (2:1) nanofibers. Nonetheless, both HPβCyD/ibuprofen-IC (1:1 and 2:1) nanofibrous webs have shown very fast dissolving character when contacted with water or when


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wetted with artificial saliva. In brief, our results revealed that electrospun HPβCyD/ibuprofen-IC nanofibrous webs have potentials as fast dissolving oral drug delivery systems.

KEYWORDS:

Hydroxypropyl-beta-cyclodextrin,

poorly

water-soluble

drug,

inclusion

complex, electrospinning, nanofibers, fast dissolving, oral drug delivery


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1. INTRODUCTION Fast dissolving oral drug delivery systems are getting more attention in pharmaceutics.1-5 The fast dissolving oral drug delivery systems are prepared as films or strips made of edible and water soluble hydrophilic biopolymeric materials that can rapidly dissolve in oral cavity and therefore can deliver drugs, vitamins and refreshing flavor compounds.2,3 The fast dissolving oral films will offer advantage to deliver active compounds within oral cavity without the need of water for swallow, and therefore fast dissolving oral films can be alternative to tablets and pills.1,2 The fast-dissolving oral films containing drugs and bioactive compounds that can rapidly dissolve or disintegrate in the oral cavity would offer great advantage in terms of high efficiency absorption, enhancement of solubility, release, and bioavailability of such active agents. However, most of the drug molecules and bioactive compounds are quite hydrophobic and are not water-soluble or have very limited water solubility. Therefore, fast dissolving oral films are often prepared with hydrophilic polymers such as gelatin, starch, carboxymethyl cellulose (CMC),

hydroxypropyl

cellulose

(HPC),

pectin,

alginate,

chitosan,

pullulan,

polyvinylpyrrolidone (PVP), polyethylene glycol (PEO), polyvinyl alcohol (PVA).4 The most common technique for production of fast dissolving oral films is by film casting or hot melt extrusion where active compounds are dispersed and encapsulated within hydrophilic biopolymeric matrices.5 The fast dissolving oral films should have certain mechanical integrity not be damaged during handling and transportation, yet, they should properly disintegrate in the mouth. Therefore, the fast dissolving oral films should be mechanically strong and yet, they should be soft, elastic and flexible.6 Recently, the use of electrospinning technique is also shown to be a very promising approach for developing controlled drug delivery systems7-9 and fast dissolving nanofibrous mats in pharmaceutics.10,11


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Lately, electrospun nanofibrous materials are gaining prominent interest in bioapplications due to their very large surface area and highly porous characteristics along with their soft and flexible nature.9 The electrospinning technique allows producing self-standing nanofibrous mats and such nanofibrous mats do possess adequate mechanical integrity to be proper candidates for fast dissolving oral delivery systems.11,12 The encapsulation of drugs and bioactive agents within the nanofiber matrix is straightforward where the mixture of hydrophilic biopolymer and active agents are prepared in common solution and thereafter the polymer/active agent solutions are electrospun into nanofibrous mats. Typically, single nozzle electrospinning setup is used since it is a very simple and versatile setup to produce functional nanofiber matrix incorporating drugs or other bioactive agents. Moreover, the electrospinning of multiple-fluids is also possible by using advanced nozzle systems such as, core-shell electrospinning13-15, side-byside electrospinning16 and tri-axial electrospinning17 in order to produce functional nanofibrous materials for drug delivery systems. The production of electrospun nanofibrous materials containing drugs or bioactive molecules can be done on a much larger scale, which makes this technique practical for industrial applications.18 The electrospinning of nanofibers incorporating drugs has shown to be a very promising approach for developing fast dissolving nanofibrous mats for oral drug delivery.11,12,15,18-25 The self-standing electrospun nanofibrous mats made of hydrophilic polymeric nanofibers incorporating bioactive agents having very large surface area and highly porous structure would readily dissolve with water contact, and therefore such nanofibrous mats can be ideal candidates for fast dissolving oral drug delivery systems. For instance, electrospun nanofibrous mats encapsulating various drug molecules have been developed by using water-soluble hydrophilic polymeric matrix such as polyvinylpyrrolidone (PVP)21,23, hypromellose24, hydroxypropyl


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methylcellulose (HPMC)25, gelatin19,22,26, poly (vinyl alcohol) (PVA)27, Eudragit L-10020, etc. Recently, we have also shown that electrospun nanofibrous mats of polymer-free cyclodextrin inclusion complex nanofibers incorporating drugs (e.g., sulfisoxazole28, paracetamol12) have fast dissolving character. Besides being a nanofibrous carrier matrix for active agents, cyclodextrins are highly water-soluble and significantly improve the water solubility of hydrophobic drug molecules and bioactive agents by inclusion complexation. Therefore, such fast dissolving electrospun nanofibrous webs produced from cyclodextrin inclusion complexes would be suitable for fast dissolving oral delivery in pharmaceutics and nutrition, etc. The use of cyclodextrins (CyDs) is very common in pharmaceutics since drug molecules become highly water soluble with cyclodextrin inclusion complexation and such CyD/drug inclusion complex systems can also enhance the bioavailability, stability and shelf-life of the drug molecules.29-31 CyDs are doughnut-shaped molecules of cyclic oligosaccharides which are produced

from

enzymatically

hydrolyzed

starch

by

the

action

of

cyclodextrin

glucosyltransferase. Due to their unique molecular structure having truncated cone-shaped hydrophobic cavity, CyDs act as host for variety of molecules including drugs to form noncovalent host-guest type inclusion complexes. CyDs are classified as GRAS (Generally Recognized as Safe) by the U.S. Food and Drug Administration (FDA) and CyDs are already being used in variety of drug and food formulations for the solubility increase, protection, masking the odor and bitter taste and the controlled/sustained delivery of these active agents.29,32 Functional electrospun nanofibers have been developed by encapsulating CyD/drug inclusion complexes within biopolymeric nanofiber matrix for the purpose of sustained/controlled release of drugs33-36 or fast dissolving drug delivery systems.19,33 The polymer-free electrospinning of CyD/drug inclusion complexes without using any polymeric matrix has also been shown to


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develop fast dissolving nanofibrous materials.12,18,28,37,38 Although electrospinning of nanofibers from pure CyD/drug inclusion complex systems12,18,28,37-39 without using a polymeric matrix is more challenging compared to electrospinning of polymeric systems, recently it has been shown that electrospinning technique could produce high amount of CyD/drug inclusion complex nanofibrous materials (e.g., voriconazole/sulfobutylether-β-cyclodextrin) that can be alternative to freeze drying method.18 Ibuprofen (2-(4-Isobutylphenyl)propanoic acid) is one of the common nonsteroidal antiinflammatory drug that is generally used for reducing fever and treat pain or inflammation caused by headache, migraines, toothache, back pain, arthritis, menstrual cramps, etc. Ibuprofen is a poorly water-soluble drug, yet, it has been shown that inclusion complexation with CyDs significantly improve the water solubility of ibuprofen.40-42 Ibuprofen can form 1:1 molar ratio (Ibuprofen:CD) with β-cyclodextrin (β-CyD)40-42 and β-CyD derivatives40-42 such as methyl-βCyD, hydroxyethyl-β-CyD, and hydroxypropyl-β-CyD. Studies related to encapsulation of ibuprofen within polymeric electrospun nanofiber matrix for controlled released of ibuprofen43-48 or fast-dissolution of ibuprofen23,49 were also reported. Typically, biodegradable polymeric electrospun nanofiber matrices are used for the controlled released of ibuprofen43-48, on the other hand, water soluble hydrophilic polymers are chosen for the fast dissolving nanofibrous webs.1927

Studies related to electrospun nanofibrous webs containing CyD/drug inclusion complexes

have shown that CyDs are very effective to increase the solubility of drug molecules and also control the release of drugs when compared to same nanofibrous webs containing only drug molecules without CyDs.14,33-35 Very recently, it has been reported that electrospun nanofibers of poly-ɛ-caprolactone (PCL) containing CyD(α-CyD and β-CyD)/ibuprofen has been studied as a controlled drug delivery system.50 Nonetheless, to the best of our knowledge, there is no study


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related to fast dissolving nanofibrous webs based on polymer-free CyD/ibuprofen electrospun nanofibers. Hydroxypropyl-beta-cyclodextrin (HPβCyD) is a highly water soluble modified CyD type which is very suitable for drug formulations for solubility enhancement of hydrophobic drugs,29 in addition, HPβCyD is one of common CyD type which can be easily electrospun into nanofibers by electrospinning without the need of using a carrier polymer matrix.12 On the other hand, ibuprofen is one of most widely used drug but it is a poorly water-soluble drug which suffers from its low solubility. The favorable inclusion complex formation and proper size-match between ibuprofen and βCyD/derivates and the solubility enhancement of ibuprofen with CyD inclusion complexation were already reported in the previous studies.40-42 Here, we have produced fast dissolving nanofibrous webs from HPβCyD/ibuprofen inclusion complexes by electrospinning technique without using any polymeric additive. Ibuprofen was complexed with HPβCyD by two different molar ratios (1:1 and 2:1, HPβCyD:ibuprofen), and the structural characteristics and properties of these HPβCyD/ibuprofen inclusion complex nanofibers were investigated by using proper characterization techniques. It is also important to note that the electrospinning was performed from aqueous solutions of HPβCyD/ibuprofen inclusion complex which has a great advantage since ibuprofen become water soluble by HPβCyD. Therefore, it is possible to use only water for the electrospinning of HPβCyD/ibuprofen inclusion complex nanofibers whereas toxic organic solvents are used to dissolve polymeric matrix and hydrophobic drugs for the electrospinning of polymer/drug based fast dissolving nanofibers.11,15 2. EXPERIMENTAL SECTION 2.1. Materials. Ibuprofen (97-103%, Spectrum), deuterated dimethylsulfoxide (d6DMSO, deuteration degree min. 99.8% for NMR spectroscopy, Cambridge Isotope) and chemicals for buffer; sodium phosphate dibasic heptahydrate (Na2HPO4, 98.0-102.0%, Fisher


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Chemical), potassium phosphate monobasic (KH2PO4, ≥99.0%, Fisher Chemical), sodium chloride (NaCl, >99%, Sigma Aldrich) and o-phosphoric acid (85% (HPLC), Fisher Chemical) were obtained commercially and used without further purification. Hydroxypropyl-betacyclodextrin (HPβCyD) was kindly donated by Wacker Chemie AG (USA). The high-quality distilled water was used from the Millipore Milli-Q ultrapure water system. 2.2. Electrospinning of HPβCyD and HPβCyD/Ibuprofen-IC nanofibers. 2.2.1. Preparation of electrospinning solutions. Hydroxypropyl-beta-cyclodextrin (HPβCyD) was completely dissolved in distilled water by 200% (w/v) solid concentration. Then, ibuprofen was added to the clear HPβCyD solutions to get 1:1 and 2:1 HPβCyD:ibuprofen molar ratios, separately. The HPβCyD/ibuprofen mixtures were stirred at room temperature for 24 hour to form inclusion complexes. After 24 hour of mixing, 1:1 and 2:1 HPβCyD/ibuprofen systems resulted in turbid and clear solutions, respectively. The comparative studies were performed with pristine HPβCyD nanofibers; therefore 200% (w/v) concentrated pure HPβCyD solution was prepared in distilled water as well for the electrospinning. 2.2.2. Electrospinning process. HPβCyD and each HPβCyD/ibuprofen inclusion complex solution (1:1 and 2:1, HPβCyD:ibuprofen) was placed in 1 mL syringes fitted with 27 G (outer/inner diameter; 0.4 mm/0.2 mm) metal needle, separately. The loaded syringe was placed onto the syringe pump (New Era, USA) which ensured the flow rate of 0.5 mL/h solution during the electrospinning process. The high voltage power supply (EPR series, Matsusada, Japan) was used at a voltage of 15 kV, and the nanofibers were deposited on aluminum foil sheet that was wrapped to a grounded metal collector at a distance of 15 cm from the tip of the needle. The electrospinning process was carried out in an enclosed Plexiglass, which was positioned inside


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the fume cabinet. The ambient humidity and the temperature were recorded as 55% and 20 oC, respectively. The electrospun nanofibers produced from 1:1 molar ratio of HPβCyD:ibuprofen and 2:1 molar ratio of HPβCyD:ibuprofen inclusion complex solutions and pristine HPβCyD solution were denoted as HPβCyD/ibuprofen-IC (1:1) nanofibers, HPβCyD/ibuprofen-IC (2:1) nanofibers and HPβCyD nanofibers, respectively. Additionally, the physical mixture of HPβCyD/ibuprofen (1:1) system was prepared for comparison. The pristine HPβCyD nanofibrous web (~25 mg) was homogenously blended with ibuprofen powder (~3.5 mg) to obtain HPβCyD/ibuprofen (1:1) physical mixture. 2.3. Characterization of Samples. 2.3.1. Morphological analysis. The surface morphology of HPβCyD/ibuprofen-IC (1:1) nanofibers, HPβCyD/ibuprofen-IC (2:1) nanofibers and HPβCyD nanofibers was evaluated using scanning electron microscope (SEM, Tescan MIRA3, Czech Republic). Prior the examination, samples were fixed to carbon tapes which were stacked onto SEM stubs. Then, samples were sputtered with thin layer of Au/Pd to render them electrically conductive. Images were taken at the working distance of 10 mm and the accelerating voltage of 12 kV. ImageJ software was used to calculate the average fiber diameter (AFD) by measuring the size of approximately 100 fibers. The two main parameters influencing the morphology of nanofibers; conductivity and viscosity were also determined as a part of this study. The conductivity of HPβCyD/ibuprofen-IC and HPβCyD solutions were determined by conductivity-meter (FiveEasy, Mettler Toledo, USA) at room temperature. The viscosity of the same solution systems was measure by rheometer (AR 2000 rheometer, TA Instrument, USA) equipped with 20 mm cone/plate accessory (CP 20−4 spindle type, 4o) under the shear rate range of 0.01-1000 s-1 at 22 oC.


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2.3.2. 1H-NMR analysis. Proton nuclear magnetic resonance (1H-NMR) spectra were recorded by nuclear magnetic resonance spectrometer (Bruker AV500) with autosampler at 25 oC.

The 1H-NMR was utilized to calculate the molar ratio between ibuprofen and HPβCyD in

HPβCyD/ibuprofen-IC

nanofibers.

Ibuprofen

powder,

HPβCyD

nanofibers

and

HPβCyD/ibuprofen-IC nanofibers were dissolved in DMSO‑d6 at the 30 g/L sample concentration. 1H-NMR spectra were scanned 16 times for each sample. Mestranova software was applied to get the integration of chemical shifts (δ, ppm). Then, the discrete peaks of HPβCyD (-CH3; 1.03 ppm) and ibuprofen (aromatic protons; 7.2-7.5 ppm) were taken into account to calculate the molar ratio of HPβCyD:ibuprofen in HPβCyD/ibuprofen-IC nanofibers. 2.3.3. FTIR analysis. The Fourier transform infrared (FTIR) spectra of ibuprofen powder, HPβCyD nanofibers and HPβCyD/ibuprofen-IC nanofibers were obtained by Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrometer (PerkinElmer, USA). Each spectrum (64 scan) was recorded between 4000 and 600 cm−1 at a resolution of 4 cm−1. 2.3.4. Thermal behavior analysis. Thermogravimetric analyzer (TGA, Thermal Analyzer Q500, TA Instruments, USA) and differential scanning calorimeter (DSC, Thermal Analyzer Q2000, TA Instruments, USA) were operated to investigate the thermal characteristic of the samples. TGA measurements were carried under nitrogen atmosphere. The samples placed onto platinum TGA pan were heated from room temperature to 600 °C at a heating rate of 20 °C/min. For DSC analyses, samples were sealed into Tzero aluminum pan, and heated at a flow rate of 10 oC/min

from 0 oC to 250 oC under nitrogen atmosphere. 2.3.5. XRD analysis. X-ray diffraction (XRD) patterns of ibuprofen powder, HPβCyD

nanofibers, HPβCyD/ibuprofen-IC nanofibers and HPβCyD/ibuprofen (1:1) physical mixture


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were recorded by powder X-ray diffractometer (Bruker D8 Advance ECO) by applying Cu-Kα radiation. The samples were examined for the angles 2ϴ between 5o and 30o. The voltage and current were set to 40 kV and 25 mA, respectively. 2.4 Pharmacotechnical properties of HPβCyD/ibuprofen-IC nanofibers. Phase solubility profile of ibuprofen was investigated according to method reported by Higuchi and Conners.51 A fixed amount of ibuprofen exceeding its solubility and HPβCyD with an increasing concentration (0-10 mM) were weighed into a glass vials to which were added 5 mL water. The vials were sealed and shaken for 24 h on incubator shaker (Fisherbrand) at 25 oC and 450 rpm, shielded from the light. After equilibrium for 1 day, the suspensions were filtered with 0.45 µm PTFE filter. The aliquot from each vial was measured using UV-Vis spectroscopy (PerkinElmer, Lambda 35) to determine the amount of ibuprofen dissolved. The experiments were performed in triplicate (n=3), the results were averaged and used to calculate the binding constant from the following equation;

𝐾𝑠 =

𝑠𝑙𝑜𝑝𝑒 𝑆𝑜 (1 ― 𝑠𝑙𝑜𝑝𝑒)

where S0 is the intrinsic solubility of ibuprofen in the absence of HPβCyD. UV-Vis spectroscopy was also used to indicate the solubility enhancement of ibuprofen which is encapsulated in inclusion

complex

nanofibers.

For

this

purpose,

2

mM

ibuprofen

powder

and

HPβCyD/ibuprofen-IC nanofibers that include the same amount of ibuprofen were stirred in distilled water for 24 h. Afterwards, solutions were filtered by 0.45 µm PTFE filter and their UVVis absorbance were measured in the range of 240–290 nm.


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For the dissolution test, ibuprofen (~5 mg), HPβCyD/ibuprofen-IC (1:1) (~38 mg) and HPβCyD/ibuprofen-IC (2:1) (~72 mg) nanofibrous webs having the equivalent ibuprofen content were weighted into glass vials. In order to follow the dissolution, a video was recorded concurrently with the addition of distilled water (3 mL) into vials. Bi et al. reported a method at which the physiological conditions under the surface of a moist tongue were simulated.52 Here, the disintegration profiles of HPβCyD/ibuprofen-IC nanofibrous webs were examined with slightly modified version of this technique. A proper size of filter paper was located in plastic petri dishes (10 cm), and then they were wetted with 10 mL of artificial saliva (2.38 g Na2HPO4, 0.19 g KH2PO4 and 8 g NaCl were dissolved in 1 L distilled water, pH was adjusted to 6.8 by the addition of phosphoric acid). After excess saliva was completely removed from the petri dishes, a piece of HPβCyD/ibuprofen-IC nanofibrous web was placed at the center of the filter paper. The time required for the disintegration of HPβCyD/ibuprofen-IC nanofibrous webs was recorded as video. 3. RESULTS AND DISCUSSION 3.1. Electrospinning of HPβCyD and HPβCyD/Ibuprofen-IC Nanofibers. The aqueous

solutions

of

HPβCy/ibuprofen-IC

having

molar

ratio

of

1:1

and

2:1

(HPβCyD:ibuprofen) were prepared by using very high concentration of HPβCyD (200%, w/v) (Figure 1). Such high concentration of HPβCyD is needed for the polymer-free electrospinning of CyD solutions since high content of CyD aggregates in highly concentrated solution facilitate the fiber formation during the electrospinning process.53,54 HPβCyD can form 1:1 (HPβCyD:ibuprofen) inclusion complex with ibuprofen in diluted solutions.40,42 Hence, we first prepared the aqueous solution of HPβCy/ibuprofen-IC (1:1), but this solution was turbid due to the presence of some uncomplexed/undissolved ibuprofen (Figure 2b). This is possibly because


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of the very high concentration (200%, w/v) and high viscosity of HPβCyD solution in which ibuprofen molecules couldn’t interact efficiently with HPβCyD cavity to form 1:1 complexation, and therefore some ibuprofen molecules remained uncomplexed/undissolved. Then, we doubled the amount of HPβCyD, and prepared the aqueous solution of HPβCy/ibuprofen-IC (2:1). The HPβCyD/ibuprofen-IC aqueous solution having 2:1 ratio was clear and homogeneous indicating that ibuprofen was totally dissolved by inclusion complexation with HPβCyD (Figure 2c).

Figure 1. The chemical structure of ibuprofen and HPβCyD. The schematic representation of inclusion complex formation between ibuprofen and HPβCyD molecules, and the electrospinning of HPβCyD/ibuprofen-IC nanofibers.


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Figure 2. The photographs of electrospinning solutions and the resulting electrospun nanofibrous webs, and the representative SEM images. (a) pure HPβCyD nanofibers (b) HPβCyD/ibuprofenIC nanofibers (1:1) and (c) HPβCyD/ibuprofen-IC (2:1) nanofibers. The electrospinning of both HPβCyD/ibuprofen-IC aqueous solutions having 1:1 and 2:1 ratio was carried out in order to produce HPβCyD/ibuprofen-IC nanofibers (Figure 1). The electrospinning of pure HPβCyD nanofibers without ibuprofen was also performed for comparative studies. Figure 2a-c displays SEM images of the electrospun HPβCy/ibuprofen-IC nanofibers (1:1 and 2:1) and the pure HPβCyD nanofibers. Under the optimized electrospinning conditions/parameters, uniform nanofibers with bead-free morphology were obtained from HPβCyD/ibuprofen-IC (1:1 and 2:1) and the pure HPβCyD systems. The average fiber diameter of HPβCy/ibuprofen-IC (1:1) nanofibers, HPβCy/ibuprofen-IC (2:1) nanofibers and pure HPβCyD nanofibers was measured as 180±95 nm, 210±55 nm and 215±65 nm, respectively (Table 1). The same concentration of HPβCyD (200%, w/v) was used for the preparation of inclusion complex and pure HPβCyD aqueous solutions. The viscosity of these solutions was in the range of ~1.2-1.5 Pa•s and the conductivity of the solutions are in the range of ~35-45 µS/cm (Table 1). The viscosity and the conductivity of the HPβCyD/ibuprofen-IC and pure HPβCyD


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aqueous solutions were not very different from each other, and therefore the average fiber diameter of the resulting electrospun nanofibers from inclusion complexes and pure HPβCyD systems were similar to each other. Nevertheless, the presence of ibuprofen caused a decrease in viscosity but the solution conductivity was increased a bit, therefore, thinner fibers were produced from inclusion complex systems compared to pure HPβCyD system. The viscosity of the HPβCyD/ibuprofen-IC (1:1) solution was lower and its conductivity was slightly higher than the HPβCyD/ibuprofen-IC (2:1) solution, so, the electrospinning of HPβCyD/ibuprofen-IC (1:1) system resulted in nanofibers with slightly thinner diameter. These observations are well correlated with the literature findings, where the electrospinning of lower viscosity and higher conductivity solutions yielded thinner fibers due to more stretching of the jet during the electrospinning process.55,56 More importantly, the electrospun HPβCyD/ibuprofen-IC nanofibers were obtained as nanofibrous webs having self-standing and flexible character (Figure 2b-c), which could be very appropriate for fast dissolving oral drug delivery systems. Table 1. The solution properties and the fiber diameters of resulting electrospun nanofibers Sample HPβCyD HPβCyD/ibuprofen-IC (1:1) HPβCyD/ibuprofen-IC (2:1) 3.2.

Structural

Molar ration of HPβCyD:ibuprofen 1:1 2:1 Characterization

of

Viscosity (Pa•s) 1.533 1.192 1.380 HPβCyD

Conductivity (µS/cm) 36.3 45.9 44.3 and

Average fiber diameter (nm) 215±65 180±95 210±55

HPβCyD/Ibuprofen-IC

Nanofibers. The initial molar ratios between HPβCyD and ibuprofen in HPβCyD/ibuprofen-IC solutions were 1:1 and 2:1, but after the electrospinning, the molar ratio of HPβCyD:ibuprofen may change depending on the encapsulation efficient during the electrospinning process. Hence, 1H-NMR

analysis was performed to determine the molar ratio between HPβCyD and ibuprofen

in electrospun HPβCyD/ibuprofen-IC nanofibers. The 1H-NMR technique enables the calculation


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of molar ratio by using the proportion of the integrated peaks of ibuprofen and HPβCyD. For both HPβCyD/ibuprofen-IC (1:1) nanofibers and HPβCyD/ibuprofen-IC (2:1) nanofibers, the – CH3 protons of HPβCyD at 1.03 ppm and aromatic protons of ibuprofen at 7.2-7.5 ppm were used for the calculations (Figure 3).57 The designated peaks of ibuprofen at 7.2-7.5 ppm and HPβCyD at 1.03 ppm are quite proper for the calculations, because these peaks are not overlapped with the other peaks of both ibuprofen and HPβCyD (Figure 3). The initial molar ratio for HPβCyD/ibuprofen-IC solutions was prepared as 1:1 and 2:1 (HPβCyD:ibuprofen) prior to electrospinning, and it is important to have the same or similar loading of ibuprofen after electrospinning in order to achieve high yield of drug encapsulation for HPβCyD/ibuprofen-IC nanofibers. The 1H-NMR analysis revealed that the molar ratio of HPβCyD/ibuprofen-IC (1:1) nanofibers and HPβCyD/ibuprofen-IC (2:1) nanofibers was determined as ~1:1 and ~2:1 (HPβCyD:ibuprofen), respectively. It can be concluded from these results that, ibuprofen was completely

preserved

during

the

electrospinning

and

the

resulting

electrospun

HPβCyD/ibuprofen-IC nanofibers were produced without any loss of ibuprofen having the initial molar ratio of 1:1 and 2:1 (HPβCyD:ibuprofen). As it will be discussed later, the XRD and DSC analyses revealed that there is some uncomplexed ibuprofen in case of HPβCyD/ibuprofen-IC (1:1) nanofibers. Yet, ibuprofen is not a volatile compound and the DMSO-d6 used for NMR measurement could dissolve the uncomplexed ibuprofen in the nanofiber matrix, therefore the exact molar ratio of 1:1 was calculated from

1H-NMR

of HPβCyD/ibuprofen-IC (1:1)

nanofibers. To conclude, there was almost no loss of ibuprofen during the electrospinning process and during the storage of the HPβCyD/ibuprofen-IC nanofibers. This confirms that electrospinning is a very efficient encapsulation technique where the formulation of


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HPβCyD/ibuprofen-IC nanofibers can be effectively adjusted along with the predetermined ibuprofen content.

Figure 3.

1H-NMR

spectra of (a) pure ibuprofen, (b) pure HPβCyD nanofibers, (c)

HPβCyD/ibuprofen-IC (1:1) nanofibers and (d) HPβCyD/ibuprofen-IC (2:1) nanofibers. The 1HNMR spectra were recorded by dissolving the samples in DMSO-d6. The characteristic peaks of ibuprofen and HPβCyD are highlighted with yellow and purple color, respectively. The existence of ibuprofen in the HPβCyD/ibuprofen-IC nanofibers was also proved using FTIR technique. FTIR is an expedient technique to investigate the formation of inclusion complexes between CyD and guest molecules in which FTIR spectrum may show the disappearance, attenuation, broadening and/or shifts for the characteristic absorption peaks of guest molecules upon interaction within CyD cavity.58,59, Figure 4 presents the FTIR spectra of pure ibuprofen powder, HPβCyD nanofibers and HPβCyD/ibuprofen-IC nanofibers. The broad


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and noticeable stretching peak exists between 3000 and 3600 cm−1 is the characteristic of the – OH groups located at the primary and secondary hydroxyl groups of HPβCyD.12,28 In addition, the vibrations of coupled C–C/C–O stretching and antisymmetric C–O–C glycosidic bridge stretching are apparent around 1020 and 1150 cm−1 region.12,28 This region hardly gives evidence about the inclusion complexation because the higher content of CyD in the inclusion complex formulation cause significant overlapping and so the masking of characteristic peaks of ibuprofen. On the other hand, the strong absorption band of ibuprofen displaying at 1706 cm-1 corresponds to the carbonyl stretching (C=O) was recorded for pure ibuprofen and this peak was also observed for HPβCyD/ibuprofen-IC nanofibers (Figure 3b).60,61 The presence of C=O stretching confirms the existence of ibuprofen in HPβCyD/ibuprofen-IC nanofibers. Additionally, C=O peak of ibuprofen is reduced in intensity and shifts from 1706 cm-1 to 1720 cm-1 for HPβCyD/ibuprofen-IC nanofibers (Figure 4b). This agrees with the previous reports indicating that the intermolecular hydrogen bonding existing through the ibuprofen crystals breakdown and the C=O groups of ibuprofen form hydrogen bonds with hydroxyl groups of CyD.40,60 Another ibuprofen stretching band, which is not as strong as carbonyl group, observed at 1507 cm-1 also shifted to 1514 cm-1 and has reduced intensity in HPβCyD/ibuprofen-IC nanofibers due to the interaction with HPβCyD cavity. In short, the FTIR study confirms the presence of ibuprofen in HPβCyD/ibuprofen-IC nanofibers and suggests that the ibuprofen is in the state of inclusion complexation with HPβCyD cavity.


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Figure 4. (a) The full and (b) expanded range FTIR spectra of pure ibuprofen powder, pure HPβCyD nanofibers, HPβCyD/ibuprofen-IC (1:1) nanofibers and HPβCyD/ibuprofen-IC (2:1) nanofibers. XRD is a useful technique to confirm the inclusion complex formation between CyD and guest molecules. The alteration in XRD patterns of inclusion complex components such as; disappearance of crystalline peaks, shifts, decrease in the peak intensity or appearance of new peaks mostly due to the amorphization and/or complexation.58,59 Figure 5a depicts the XRD patterns of pure ibuprofen powder, HPβCyD nanofibers, HPβCyD/ibuprofen-IC nanofibers and


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HPβCyD/ibuprofen (1:1) physical mixture. Pure ibuprofen displays a crystalline structure with the sharp diffraction peaks at 6.1°, 16.6° and 22.3°. The diffraction pattern of HPβCyD nanofibers has two broad halos at 10.2° and 18.6° demonstrating the amorphous nature of HPβCyD. For HPβCyD/ibuprofen-IC (2:1) nanofibers retains the amorphous pattern of HPβCyD with broad halos. On the contrary, XRD pattern of HPβCyD/ibuprofen-IC (1:1) nanofibers has shown the typical diffraction peaks of ibuprofen suggesting the presence of some ibuprofen crystals in the nanofibers. This correlates with the appearance of HPβCyD/ibuprofen-IC (1:1) solution where the solution was turbid due to presence of some uncomplexed and undissolved ibuprofen crystals (Figure 2b). In case of HPβCyD/ibuprofen-IC (2:1) nanofibers, the absence of ibuprofen peaks suggests the total encapsulation of ibuprofen molecules inside the HPβCyD cavities, since the inclusion complexation hinders the formation of ibuprofen crystals by separating ibuprofen molecules from each other. The solution of HPβCyD/ibuprofen-IC (2:1) was also clear and homogeneous without any visible ibuprofen crystals (Figure 2c), so, the electrospun HPβCyD/ibuprofen-IC (2:1) nanofibers have totally amorphous ibuprofen. For HPβCyD/ibuprofen-IC (1:1) nanofibers, the XRD peaks for crystalline ibuprofen was present but the peak intensity was reduced suggesting that the amount of crystalline ibuprofen was minimal. The SEM images (Figure 2b) didn’t show any presence of ibuprofen crystals for HPβCyD/ibuprofen-IC (1:1) nanofibers further suggest that the amount of ibuprofen crystals was not in high quantity. The HPβCyD/ibuprofen (1:1) physical mixture is another evidence for the less amount of uncomplexed ibuprofen existing in HPβCyD/ibuprofen-IC (1:1)-IC nanofibers (Figure 5a). HPβCyD/ibuprofen (1:1) physical mixture contains the same amount of ibuprofen with HPβCyD/ibuprofen-IC (1:1) nanofibers, however the intensity of the XRD peaks of ibuprofen is significantly higher in case of physical mixture compared to HPβCyD/ibuprofen-IC


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(1:1) nanofibers. It is because there is no complex formation in case of HPβCyD/ibuprofen (1:1) physical mixture and it contains total ibuprofen crystals (Figure 5a) whereas only some uncomplexed ibuprofen was present in crystalline form in HPβCyD/ibuprofen-IC (1:1) nanofibers resulting less peak intensity in XRD. In short, complete amorphization of ibuprofen was achieved for HPβCyD/ibuprofen-IC (2:1) nanofibers whereas some ibuprofen crystals were present in HPβCyD/ibuprofen-IC (1:1) nanofibers due to the presence of some uncomplexed ibuprofen.


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Figure 5. (a) XRD patterns and (b) DSC thermograms of pure ibuprofen powder, pure HPβCyD nanofibers, HPβCyD/ibuprofen-IC (1:1 and 2:1) nanofibers and HPβCyD/ibuprofen (1:1) physical mixture. The solid-state interaction between CyD and guest molecules can lead to changes in the thermal behavior of complex components.58,59 The disappearance, shift, reduction and/or broadening of the endothermic melting peaks of guest and/or CyD molecules are evidence for the complete or partial complexation.58,59 DSC thermograms of pure ibuprofen powder, pure HPβCyD nanofibers, HPβCyD/ibuprofen-IC (1:1 and 2:1) nanofibers and HPβCyD/ibuprofen (1:1) physical mixture are depicted in Figure 5b. While the DSC thermogram of pure HPβCyD nanofibers indicates the characteristic broad peak of dehydration, ibuprofen thermogram displays a sharp melting peak at 77 °C confirming its crystalline nature. For HPβCyD/ibuprofen-IC (2:1) nanofibers, the absence of ibuprofen melting peak demonstrated the complete inclusion complex formation between HPβCyD and ibuprofen.12,28,60 In case of HPβCyD/ibuprofen-IC (1:1) nanofibers, the endothermal peak intensity/area of ibuprofen was reduced compared to HPβCyD/ibuprofen (1:1) physical mixture. The melting point peak area of ibuprofen is measured as 5.1 J/g for HPβCyD/ibuprofen-IC (1:1) nanofibers whereas the physical mixture of HPβCyD/ibuprofen-IC (1:1) has the melting point peak area of 13.5 J/g. Considering the presence of same amount of ibuprofen in HPβCyD/ibuprofen-IC (1:1) nanofibers and physical mixture of HPβCyD/ibuprofen-IC (1:1), the ~2/3 reduction of peak intensity/area of ibuprofen in HPβCyD/ibuprofen-IC (1:1) nanofibers suggested that ibuprofen was mostly in amorphous state and being complexed with HPβCyD, yet, some uncomplexed and crystalline ibuprofen was present in HPβCyD/ibuprofen-IC (1:1) nanofibers. The DSC data correlates with XRD analysis,


23


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HPβCyD/ibuprofen-IC (1:1) nanofibers contain partially amorphous ibuprofen whereas the total amorphization of ibuprofen was achieved for HPβCyD/ibuprofen-IC (2:1) nanofibers. The thermo-analytic analyses of pure ibuprofen, pure HPβCyD nanofibers and HPβCyD/ibuprofen-IC (1:1 and 2:1) nanofibers were performed by using TGA (Figure 6). The ibuprofen powder exhibits one-step mass loss from ~150 °C up to 222 °C. For pure HPβCyD nanofibers, there are two main weight losses from 25 °C to 400 °C which correspond to water loss (up to 100 °C) and the main degradation of HPβCyD (max. temp 358 °C). On the other hand, three steps mass losses were observed in both HPβCyD/ibuprofen-IC (1:1) and HPβCyD/ibuprofen-IC (2:1) nanofibers thermograms; i) water loss, ii) main degradation of ibuprofen and iii) main degradation of HPβCyD. As seen from the derivative curves, the main degradation of ibuprofen shifts to lower temperature of 192 °C and 205 °C for HPβCyD/ibuprofen-IC (1:1) and HPβCyD/ibuprofen-IC (2:1) nanofibers, respectively. The slightly lower

degradation temperature of ibuprofen in HPβCyD/ibuprofen-IC nanofibers

supports the amorphous distribution of ibuprofen molecules in these samples unlike its crystalline powder form.62 Since HPβCyD/ibuprofen-IC (1:1) nanofibers contain higher amount of ibuprofen (12.9% (w/w), with respect to total sample amount) than HPβCyD/ibuprofen-IC (2:1) nanofibers (6.9% (w/w), with respect to total sample amount), the degradation of ibuprofen probably shifts to lower temperature in case of HPβCyD/ibuprofen-IC (1:1) nanofibers (192 °C) compared to HPβCyD/ibuprofen-IC (2:1) nanofibers (205 °C). It is also possible to calculate the components ratios in the samples by using TGA technique. When the weight loss up to 270 °C is considered from TGA thermograms of HPβCyD/ibuprofen-IC nanofibers, the amount of ibuprofen was determined to be ~8.8% (w/w, with respect to total sample amount) and ~5.4% (w/w, with respect to total sample amount) for HPβCyD/ibuprofen-IC (1:1) nanofibers and


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HPβCyD/ibuprofen-IC (2:1) nanofibers, respectively. These findings are not totally correlated with the 1H-NMR results and initial ratios of 12.9% (w/w) and 6.9% (w/w) ibuprofen were used for the preparation of HPβCyD/ibuprofen-IC (1:1) nanofibers and HPβCyD/ibuprofen-IC (2:1) nanofibers, respectively. However, it is actually obvious from the TGA derivate curves that there was an additional degradation step between 270 °C and 320 °C for both HPβCyD/ibuprofen-IC nanofibers, which is partially buried under the main degradation of HPβCyD (Figure 6b). The higher degradation temperature of ibuprofen possibly originated from stronger interactions between ibuprofen and HPβCyD compared to ibuprofen which has low temperature degradation observed at ~200 °C. Actually, the increase in thermal stability of guest molecules is very common for CyD inclusion complex systems and such improved thermal stability for the guest molecules is considered as an evidence of inclusion complexation.59 Here, the TGA data suggest that ibuprofen has different strengths of interactions with HPβCyD in HPβCyD/ibuprofen-IC nanofibers. The exact amount of ibuprofen in HPβCyD/ibuprofen-IC nanofibers could not be accurately calculated from the TGA thermograms due to overlapped degradation steps. Nonetheless, the TGA analysis revealed the inclusion complexation state between ibuprofen and HPβCyD in HPβCyD/ibuprofen-IC nanofibers by means of altered degradation temperature of ibuprofen.


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Figure 6. (a) TGA thermograms and (b) derivates of pure ibuprofen powder, pure HPβCyD nanofibers, HPβCyD/ibuprofen-IC (1:1) nanofibers and HPβCyD/ibuprofen-IC (2:1) nanofibers. 3.3. Pharmacotechnical Properties of HPβCyD/Ibuprofen-IC Nanofibers. Phase solubility analyses are widely performed for CyD and hydrophobic drug complexes to get information about the solubilizing effect of CyD on drug molecules and to calculate the stability constants of inclusion complexes.63,64 Here, the dynamic equilibrium was reached up to 24 h and UV-Vis spectroscopy technique was used to examine the filtered aliquot of HPβCyD/ibuprofen solutions having different HPβCyD concentrations. The phase solubility diagram (Figure 7a) indicates the solubility manner of ibuprofen against increasing HPβCyD concentrations from 0 to


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10 mM. It is obvious from the findings that the ibuprofen solubility was increased ~7 times in the 10 mM concentrated solution of HPβCyD due to the complex formation. As described by Higuchi and Connors method51, phase solubility diagrams can be obtained with different profiles depending on the types of CyD and guest molecules.51 A-type phase solubility diagram has subtypes of AL, AN and AP which stands for linear increases in guest solubility as a function of CyD concentration, positively deviation of isotherms and negatively deviation of isotherms, respectively.51,63 In our case, the phase solubility diagram exhibit the AN-type pattern suggesting the highest HPβCyD concentration of 10 mM is the approximate limits and less effective for the solubilization of ibuprofen. On the other hand, the straight-line portion of the diagram enables the calculation of the stability constant (Ks) from its slope. The Ks value essentially represents the binding strength between guest molecules and CyD cavity and it was calculated as 810 M-1 for the HPβCyD/ibuprofen system.


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Figure 7. (a) Phase solubility diagram of HPβCyD/ibuprofen-IC system. (b) UV-Vis spectra of aqueous solutions of ibuprofen, HPβCyD/ibuprofen-IC (1:1) nanofibers and HPβCyD/ibuprofenIC (2:1) nanofibers. The solubility enhancement of ibuprofen was also proved by comparing the dissolution of pure ibuprofen and HPβCyD/ibuprofen-IC nanofibers in water. For this purpose, ibuprofen and HPβCyD/ibuprofen-IC nanofibers including the same amount of ibuprofen were dissolved in water in a definite period of time (24 h), and then UV–Vis spectroscopy measurements were performed for the resulting aqueous solutions. Prior the measurements, the solutions were


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filtered to eliminate the undissolved parts of ibuprofen if present. Figure 7b displays the UV-Vis spectra of aqueous solutions of ibuprofen and HPβCyD/ibuprofen-IC nanofibers in which the characteristic absorptions of ibuprofen were clearly recorded. It is obvious from the UV-Vis spectra that the absorption intensity of the solutions in which HPβCyD/ibuprofen-IC nanofibers were dissolved is much higher than the solution in which pure ibuprofen powder was prepared having the same amount (2 mM). This higher intensity occurrence in UV–Vis-spectra for ibuprofen clearly indicated that ibuprofen became water soluble due to the inclusion complexation between HPβCyD and ibuprofen in HPβCyD/ibuprofen-IC nanofibers. When dissolved, the HPβCyD/ibuprofen-IC (1:1) nanofibers and the HPβCyD/ibuprofen-IC (2:1) nanofibers depict almost the same intensity at UV-Vis spectra, because HPβCyD/ibuprofen-IC (1:1) (~17 mg) and HPβCyD/ibuprofen-IC (2:1) (~30 mg) nanofibers were weighted so as to include the same amount of ibuprofen for the measurement. This result also suggests that ibuprofen was completely dissolved in water for both samples of HPβCyD/ibuprofen-IC nanofibers even though HPβCyD/ibuprofen-IC (1:1) nanofibers had some uncomplexed crystalline ibuprofen. This is possibly because the experiment was performed in more diluted aqueous environment compared to electrospinning solution and HPβCyD/ibuprofen-IC (1:1) nanofibers were dissolved and stirred for 24 h prior the UV-Vis measurement which is quite enough time for uncomplexed ibuprofen molecules to form inclusion complexes with free HPβCyD molecules. The rapid dissolution of webs of HPβCyD/ibuprofen-IC nanofibers was examined by adding 3 mL of water to the vials which contain equivalent amount of ibuprofen (~5mg) (Figure 8a). Same amount of pure ibuprofen powder was also tested for comparison. The HPβCyD/ibuprofen-IC nanofibrous webs collapsed in the first seconds by the addition of water


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and clear solutions were obtained in less than few seconds for HPβCyD/ibuprofen-IC nanofibers (Figure 8a, Video S1). To have the same amount of ibuprofen in HPβCyD/ibuprofen-IC nanofibrous webs, we used almost double amount of HPβCyD/ibuprofen-IC (2:1) nanofibrous web (~72 mg) compared to HPβCyD/ibuprofen-IC (1:1) nanofibrous web (~38 mg). Even so, the fast dissolving character was observed for both HPβCyD/ibuprofen-IC nanofibrous webs resulting complete dissolution of the webs and clear solutions without any indication of undissolved ibuprofen. In contrast, the pure ibuprofen powder remained at the bottom of the vial over this period time without dissolution showing that it is a poorly water-soluble drug (Figure 8a). The disintegration of HPβCyD/ibuprofen-IC nanofibrous webs was further investigated using wet filter paper to simulate the moist environment of oral cavity.52 As it is observed in Figure 8b, and Video S2, the HPβCyD/ibuprofen-IC nanofibrous webs were rapidly adsorbed by artificial saliva and dissolved instantly. The high water solubility of HPβCyD31 is a considerable factor for the high dissolution and disintegration rate of the HPβCyD/ibuprofen-IC nanofibrous webs. In addition, the highly porous structure and high surface area of nanofibers provide remarkable penetration path and interaction side for aqueous system through the nanofibrous webs, which also ensure the rapid disintegration and dissolution of the nanofibers.11 To conclude, saliva can be easily penetrate through the pores of the HPβCyD/ibuprofen-IC nanofibrous webs when it is placed in the mouth and the fast disintegration of the HPβCyD/ibuprofen-IC nanofibrous webs can guarantee the instant release of ibuprofen.


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Figure 8. (a) The dissolution behavior of pure ibuprofen powder, HPβCyD/ibuprofen-IC (1:1) and HPβCyD/ibuprofen-IC (2:1) nanofibrous webs in distilled water. (b) The disintegration behavior of HPβCyD/ibuprofen-IC (1:1) and HPβCyD/ibuprofen-IC (2:1) nanofibrous webs at the artificial saliva environment. The pictures were captured from the videos which were given as Video S1 and Video S2.


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4. CONCLUSION Cyclodextrins (CyDs) are very effective for water solubility enhancement for poorly water-soluble drugs by forming inclusion complexation. The electrospinning of nanofibers from CyD/drug inclusion complexes is very promising approach to produce fast dissolving nanofibrous webs for oral drug delivery systems. Here, we have chosen hydroxypropyl-betacyclodextrin (HPβCyD), a highly water soluble CyD derivative which is being used for drug formulations, in order to function both as a nanofiber matrix and complexation agent in order to enhance water solubility and fast dissolution of poorly water-soluble ibuprofen. The electrospinning process was successfully performed to produce bead-free and uniform HPβCyD/ibuprofen-IC nanofibers having ~200 nm fiber diameter. The percent loading of drug could be adjusted since HPβCyD/ibuprofen-IC solutions having different molar ratios (e.g.; 1:1 and 2:1, HPβCyD:ibuprofen) can be electrospun into nanofibers in the form of self-standing and flexible nanofibrous webs. The HPβCyD/ibuprofen-IC nanofibrous webs have shown very fast dissolving character when contacted with water or when wetted with artificial saliva suggesting that such electrospun HPβCyD/ibuprofen-IC nanofibrous webs have shown potential as fast dissolving oral drug delivery system. It is also noteworthy to mention that the electrospinning of HPβCyD/ibuprofen-IC nanofibers was performed in water since ibuprofen become water soluble by HPβCyD. The use of only water provides a great advantage in terms of industrial processing aspect for the development of such fast dissolving oral drug delivery systems based on CyD/drug inclusion complex nanofibers. In brief, CyDs can form inclusion complexation with variety of drug molecules; so, this proof-of-concept study with ibuprofen can be extended with other drug molecules in order to develop fast dissolving oral drug delivery systems based on electrospun nanofibrous webs of CyD/drug inclusion complex nanofibers.


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ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: The comparative dissolution (Video S1) and disintegration (Video S2) profile of Ibuprofen powder and HPβCyD/ibuprofen-IC nanofibers. AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] (A.C.) *E-mail: [email protected] (T.U.) ORCID ID Tamer Uyar: 0000-0002-3989-4481 Present Addresses Department of Fiber Science & Apparel Design, College of Human Ecology, Cornell University, Ithaca, NY, 14853, USA Author Contribution: T. U. and A.C. designed the study. A.C. performed the experimental studies. A.C. and T. U. wrote the manuscript and have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This work made use of the scanning electron microscope (SEM) and X-Ray diffractometer (XRD) of the Cornell Center for Materials Research Shared Facilities which are supported


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through the NSF MRSEC program (DMR-1719875). Prof. Uyar acknowledges the startup funding from the College of Human Ecology at Cornell University. The partial funding for this research was also graciously provided by Nixon Family (Lea and John Nixon) thru College of Human Ecology at Cornell University.

For Table of Contents Only


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Fast Dissolving Oral Drug Delivery System based on Electrospun

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