Powder Technology 283 (2015) 260–265

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Preparation and characterization of solid dispersion using a novelamphiphilic copolymer to enhance dissolution and oral bioavailabilityof sorafenib

Duy Hieu Truong a, Tuan Hiep Tran a, Thiruganesh Ramasamy a, Ju Yeon Choi a, Han-Gon Choi b,Chul Soon Yong a,⁎, Jong Oh Kim a,⁎⁎a College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyeongsan 712-749, South Koreab College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea

⁎ Corresponding author. Tel.: +82 53 810 2812; fax: +⁎⁎ Corresponding author. Tel.: +82 53 810 2813; fax: +

E-mail addresses: csyong@ynu.ac.kr (C.S. Yong), jongo

http://dx.doi.org/10.1016/j.powtec.2015.04.0440032-5910/© 2015 Elsevier B.V. All rights reserved.

a b s t r a c t

a r t i c l e i n f o

Article history:Received 29 December 2014Received in revised form 12 February 2015Accepted 20 April 2015Available online 27 April 2015

Keywords:SorafenibSoluplusSolid dispersionDissolutionSolubilization

The objective of the current studywas to enhance dissolution and oral bioavailability of the poorly water-solubledrug, sorafenib (SFN), by solid dispersion (SD) technique using a novel amphiphilic copolymer, polyvinyl capro-lactam–polyvinyl acetate–polyethyleneglycol graft copolymer (Soluplus®). The SD formulations were preparedby the spray dryingmethodwith SFN, Soluplus, and sodium lauryl sulfate (SLS) at various weight ratios inwater.The optimized SD formulation, which showed the highest dissolution rate in distilled water, was further charac-terized for surface morphology, crystallinity, dissolution in pH 1.2, pH 4.0, and pH 6.8, and pharmacokinetics inrats. Powder X-ray diffraction and differential scanning calorimetry revealed the amorphous form of SFN in theformulation. In addition, at the oral dosage of 20 mg/kg SFN, the SD formulation showed increased Cmax andAUC0–48h by 1.5- and 1.8-fold, compared to those of SFN powder, respectively (p b 0.05). These findings suggestthat the preparation of SFN-loaded SD using Soluplus could be a promising strategy for improvement of oralbioavailability of SFN.

© 2015 Elsevier B.V. All rights reserved.

1. Introduction

Sorafenib (SFN), a novel bi-aryl urea derivative, strongly inhibitsRaf-1, a member of the RAF/MEK/ERK signaling pathway. SFN targetsseveral serine/threonine kinases and receptor tyrosine kinases, includ-ing vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3,platelet-derived growth factor receptor (PDGFR)-β, Flt-3, and c-KIT,which are related to tumor cell proliferation and angiogenesis [1,2].It has been approved by the U.S. Food and Drug Administration(US-FDA) for treatment of patients with advanced renal cell carcinoma,unresectable hepatocellular carcinoma, and differentiated thyroid carci-noma [3,4]. According to the Biopharmaceutical classification system(BCS), SFN belongs to BCS class II, which is characterized by low solubil-ity andhigh permeability. SFNhas very poor solubility in aqueousmediaat various pH values from pH 1.2 to pH 7.4 [5–8]. This leads to slow dis-solution rate in the gastrointestinal tract, which is supposed to be therate-limiting step for absorption and togetherwith thefirst-passmetab-olism results in low bioavailability and large inter-subject variability[9,10]. Therefore, some formulation strategies have been developed to

82 53 810 4654.82 53 810 4654.hkim@yu.ac.kr (J.O. Kim).

enhance the physiochemical properties and improve the bioavailabilityof the drug [7,8].

Solid dispersion (SD) is a simple and well-studied approach to in-crease the dissolution rate and bioavailability of poorly water-solubledrugs [11–21]. By definition, a pharmaceutical SD is a product preparedby transforming a drug–carrier combination into the solid state fromthe original fluid state [22]. Hydrophilic polymers are the most fre-quently used carriers for fabrication of SDs [23]. Selection of the rightcarrier(s) for formulation of the SD is very important. Recently, interestin use of Soluplus® as thematrix carrier in the SD system has increased[24,25]. Soluplus is a novel graft copolymer initially designed for solidsolutions by hot-melt extrusion [26]. Due to its amphiphilic chemicalstructure, it has bifunctional properties as a matrix polymer for solidsolutions and an active solubilizer with the ability to enhance solubilityof poorly water-soluble drugs.

In this study, SFN-loaded SDs were prepared with Soluplus andsodium lauryl sulfate by the spray-drying method. Scanning electronmicroscopy (SEM), differential scanning calorimetry (DSC) and powderX-ray diffraction (PXRD) were then applied in order to characterize thephysicochemical properties of the optimal solid dispersion formulation.In addition, a pharmacokinetic study was conducted in order to com-pare the effect of the solid dispersion on the bioavailability of the drugwith the pure SFN powder.

Table 2Compositions of sorafenib-loaded solid dispersion formulations.

Ingredients (g) F1 F2 F3 F4 F5

Sorafenib 1 1 1 1 1Soluplus 0.9 2.9 4.9 4.75 4.5SLS 0.1 0.1 0.1 0.25 0.5Drug/carrier (w/w) 1/1 1/3 1/5 1/5 1/5

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2. Materials and methods

2.1. Materials

Sorafenib tosylate was purchased from Green Stone SwissCo., Ltd. (China). Hydroxypropylmethyl cellulose (HPMC 2910), Polyvi-nylpyrrolidone (PVP K30), Polyoxyl 40 hydrogenated castor oil(Cremophor® RH40), Polyoxypropylene–polyoxyethylene blockcopolymer (Poloxamer 407, Poloxamer 188) and polyvinyl caprolac-tam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®)were purchased from BASF (Ludwigshafen, Germany). Polysorbate 20(Tween 20), polysorbate 80 (Tween 80), and sodium lauryl sulfate(SLS) were purchased from Duksan Chemical Co., Ltd. (Ansan, Korea).Polyoxyethylene 10 stearyl ether (Brij 76) and polyoxyethylene 20 cetylether (Brij 58) were purchased from Sigma-Aldrich, Korea. All otherchemicals and reagentswere of analytical grade andusedwithout furtherpurification.

2.2. Solubility study

The solubility study of SFN was performed according to thefollowing procedure. Excessive amounts of SFN were added to 1 mL ofaqueous solutions containing 1% carrier (w/v) in 2 mL capped tubes.These tubes were vortexed for 30 s and shaken at 37 ± 0.5 °C for 72 hin a thermostatically controlled water bath, then centrifuged at10,000 ×g for 10 min (5415C, Eppendorf, USA). The supernatant layerswere filtered through a 0.45-μm membrane filter (Whatman, UK), andthe SFN concentrations were analyzed by HPLC with prior suitabledilution.

2.3. Preparation of SFN-loaded SD

SD formulations of SFNwere prepared using a Büchi 190nozzle-typemini spray dryer (Flawil, Switzerland). Various amounts of Soluplus andSLS were dissolved in distilled water. Then, SFN was dispersed intothese solutions and the resulting dispersions were spray dried underthe following conditions: inlet temperature, 130 °C; resulting outlettemperature, 70–75 °C; feeding rate, 3mL/min,which delivered the dis-persions to a pneumatic nozzle (diameter of 0.7 mm) via a peristalticpump; aspiration, 80%; spray pressure, 4 kg/cm2; and drying air flow,600 L/h. The direction of air flowwas the same as that of sprayed prod-ucts [11,27–29]. The suspensionswere stirred continuously bymagneticstirrers during the spray drying process. The physical mixture wasprepared by mixing the same weight ratio of the SD formulation usinga mortar and a pestle.

Table 1Aqueous solubility of sorafenib.

Carrier Aqueous solubility(mg/mL)

Water N/AHydrophilic polymers

HPMC 2910 0.097 ± 0.001PVP K30 0.095 ± 0.001Soluplus 0.701 ± 0.072

SurfactantsSodium lauryl sulfate 1.838 ± 0.194Poloxamer 407 0.076 ± 0.013Poloxamer 188 0.097 ± 0.001Brij 76 0.181 ± 0.004Brij 58 0.243 ± 0.023Cremophor RH40 0.203 ± 0.004Tween 20 0.095 ± 0.009Tween 80 0.123 ± 0.014

Each value represents the mean ± standard deviation (n = 3).

2.4. Dissolution study

In vitro dissolution study of SFN powder and SFN-loaded SD formu-lations was carried out using USP dissolution apparatus 2 (UniversalScientific Co., Ltd., Seoul, Korea) in four media of 900 mL containing0.1% Tween 80: distilled water, hydrochloric acid solution (pH 1.2),acetate buffer solution (pH 4.0), and phosphate buffer solution (PBS,pH 6.8). Capsules (size 0) were filled with the drug powder and drug-loaded SDs (equivalent to 10 mg SFN powder) and placed in sinkersbefore dropping into the dissolution media. The dissolution mediawere maintained at 37 ± 0.5 °C and stirred at the paddle speed of50 rpm. At the predefined time points, 3 mL of the dissolution mediawaswithdrawn, filtered through a 0.45-μmmembrane filter and imme-diately replaced by the same volume of fresh dissolution media. Theconcentrations of dissolved SFN were analyzed using the HPLC methodas described below. All measurements were performed in triplicate.

2.5. Drug analysis

The drug concentrationswere analyzed using a Hitachi HPLC systemthat comprised of a pump (Model L-2130), and an ultraviolet detector(Model L-2400). Measurement was performed on a Cosmosil®C18-AR-II column: 5 μm, 4.6 × 150 mm (Nacalai Inc., USA). The mobilephase, consisting of methanol, acetonitrile, and 1% acetic acid solution(40:35:25, v/v) was eluted at the flow rate of 1.0 mL/min. The effluentwas detected at the wavelength of 265 nm.

2.6. Characterization of solid dispersion

2.6.1. Shape and surface morphologyScanning electron microscopy (SEM) was used to examine the

surfacemorphology of SFN, and the SD formulation (F5)with a scanningelectron microscope (S-4100, Hitachi, Japan). The samples wereattached to a metal sample holder using double-sided adhesive tapeand then made electrically conductive by coating with platinum

Fig. 1. Dissolution profiles of sorafenib powder, F1, F2, F3, F4 and F5 in distilled water.

(A) (B)

Fig. 2. SEM images of (A) sorafenib powder, and (B) SD formulation (F5).

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(6 nm/min) in a vacuum (6 Pa) using a Hitachi Ion Sputter (E-1030) for120 s at 15 mA prior to observation.

2.6.2. Powder X-ray diffraction (PXRD)The PXRD patterns of SFN powder, Soluplus, SLS, the physical

mixture, and the SD formulation (F5) were recorded using an X'PertPRO MPD diffractometer (PANalytical, Almelo, the Netherlands) withCuKα radiation (λ = 1.54 Å). The operating voltage and current were40 kV and 30 mA, respectively. Diffractograms were obtained in theangular range 2θ (diffraction angle) from 10° to 60° with a step size of0.02626°.

2.6.3. Differential scanning calorimetry (DSC)Thermal analysis of the drug powder, SLS, Soluplus, the physical

mixture, and the SD formulation was performed using a differentialscanning calorimeter (DSC-Q200, TA Instruments, USA). Accuratelyweighed samples (approximately 2–3mg) were sealed in an aluminumpan. The scans were performed over the temperature range of40–250 °C at a heating rate of 10 °C/min, under a nitrogen purge at aflow rate of 50 mL/min. The temperature and enthalpy of the DSCsystem were calibrated using a standard aluminum pan.

2.7. Pharmacokinetics

All animal care procedureswere performed according to theGuidingPrinciples in the Use of Animals in Toxicology as amended in 2008 bythe Society of Toxicology [30]. The study protocols were approved bythe Institute of Laboratory Animal Resources of Yeungnam University.

Fig. 3.X-ray powder diffraction of Sorafenib powder, Soluplus, sodium lauryl sulfate (SLS),the physical mixture, and SD formulation (F5).

Male Sprague–Dawley rats weighing 280 ± 20 g were fasted over-night prior to the experiments with free access to water. Six rats wererandomly divided into two groups (n = 3). Each rat was anesthetizedby diethyl ether, and the right femoral artery was cannulated for inser-tion of a polyethylene tube. The drug powder and the SFN-loaded SDformulation were dispersed into water, and administered orally to therats in each group at the dosage of 20 mg/kg SFN [9,31]. Then, approxi-mately 0.3 mL of blood was collected from the cannulated artery atpredefined time intervals into heparinized tubes, and centrifuged at10,000 ×g for 10 min (5415C, Eppendorf, USA). The supernatant layerswere collected and stored frozen at−20 °C until analysis.

The drug analysis was adapted from a previousmethodwith a slightmodification [7]. Plasma (40 μL) and acetonitrile (260 μL) were mixedand vortexed. The mixtures were then centrifuged at 10,000 ×g for10 min and the supernatant layers were collected. The drug concentra-tion in the supernatant layers was analyzed using the HPLC methodas described above. The standard calibration curve showed excellentlinearity (r = 0.999) in the concentration range of 0.1–20 μg/mL ofSFN in plasma.

Pharmacokinetic parameters, including the area under the plasmaconcentration versus time curve from zero to 48 h (AUC0→ 48h), theelimination rate (Kel) and half-life (t1/2) were calculated by non-compartmental analysis using WinNonlin® software (version 2.1;Pharsight Co., Mountain View, CA, USA). Themaximum plasma concen-tration (Cmax) and the time taken to reach Cmax (Tmax) were obtaineddirectly from plasma data.

Fig. 4. Differential scanning calorimetric thermograms of sorafenib powder, Soluplus,Sodium lauryl sulfate (SLS), the physical mixture and SD formulation (F5).

(B)

(C)

(A)

Fig. 5. Dissolution profiles of the drug from capsules containing sorafenib powder or thesolid dispersion at (A) pH 1.2, (B) pH 4.0, and (C) pH 6.8 media. The SD formulation(F5)was composed of sorafenib/Soluplus/SLS at theweight ratio 1/4.5/0.5. Each value rep-resents the mean ± standard deviation (n = 3).

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2.8. Statistical analysis

Statistical analysis of the samples was performed using a Student'st-test. A p-value b 0.05 was considered to indicate statistical signifi-cance. All datawere presented as themean±standarddeviation, unlessotherwise stated.

3. Results and discussion

3.1. Solubility studies

Excipient screening for the poorly water-soluble drug, SFN, can beconsidered as the first step in development of SD formulation [32].Thus, a solubility study of SFN in various solutions of hydrophilic poly-mers and surfactants was performed for selection of suitable carriersfor the SFN-loaded SD (Table 1). Among the hydrophilic polymerstested, Soluplus exhibited the highest solubility of the drug (0.701 ±0.072 mg/mL). Among the surfactants tested, SLS showed the highestsolubility of the drug (1.838 ± 0.194 mg/mL). Therefore, Soluplus andSLS were selected as the carriers in the SD formulations.

3.2. Optimization of SFN-loaded SD

Various formulations of SFN-loaded SD were prepared using a spraydrier with water, a hydrophilic polymer (Soluplus®) and a surfactant(SLS). Briefly, solutions of Soluplus and SLS were prepared in distilledwater and SFN was dispersed in these solutions. After stirring forabout 1 h at 37 °C, the homogenous suspensions were spray-dried. Tomeasure the effect of drug/carrier ratio, different SD formulations withvarying drug/carrier ratios and fixed amount of SLS were prepared(Table 2).

In order to understand the effect of drug/carrier ratio on SFN-loadedSD, the dissolution profiles of SFN from SDwere investigated. As shownin Fig. 1, all of the formulations showed significantly higher dissolutionrate than the SFN powder (p b 0.05). However, at the drug/carrier ratioof 1/5, formulation F3 exhibited significantly higher drug release after120 min than formulations F1 and F2 with the drug/carrier ratio of 1/1and 1/3, respectively (p b 0.05). Therefore, the drug/carrier ratio of 1/5was used to further evaluate the effect of Soluplus/SLS ratio on the dis-solution rate. When the amount of SLS was increased, the release wasincreased and reached approximately 100% at the drug/Soluplus/SLSratio of 1/4.5/0.5 in formulation F5. Thus, formulation F5 was chosenas the optimal formulation for further studies.

3.3. Characterization of the solid dispersion

The surface morphology of SFN powder and SFN-loaded SD wasvisualized by SEM (Fig. 2). As shown in Fig. 2A, the pure drug appearedas rectangular crystals ranging in size from 10 to 100 μm,while the soliddispersion formulation contained relatively rough surfaced particles(Fig. 2B). These results suggested that the carriers might be attachedto the surfaces of the drug particles.

The crystallinity of the SFN powder, Soluplus, SLS, the physicalmixture, and the solid dispersion formulation was determined byPXPD analysis. Typical diffraction patterns of SFN, Soluplus, SLS, thephysical mixture, and sorafenib-loaded solid dispersion are shown inFig. 3. The diffraction pattern of pure SFN showed various characteristic2θ peaks at 13.2°, 17.8°, and 21.5°, revealing a highly crystallinestructure. However, these distinctive peaks of SFN were absent in thepattern of the solid dispersion, indicating that the drug may be in theamorphous form or molecularly dispersed in the carrier matrix.

In addition, the thermal behaviors of SFN powder, Soluplus, SLS, thephysical mixture, and SFN-SD formulation were further characterizedby DSC (Fig. 4). The DSC curve of SFN displayed one large, sharp endo-thermic peak at about 238 °C, which corresponds to the melting pointof the tosylate salt form and one small endothermic peak at about200 °C which might be relevant to the melting point of the sorafenibbase form. The same phenomenon was observed in another study[33]. However, these peaks disappeared in the curve of the soliddispersion which confirms the molecular dispersion of sorafenib in thecarrier matrix.

The highmelting point of the drug is one of the causes of poor aque-ous solubility [34]. Thus, any strategy that disrupts the crystallinenature

Fig. 6. Plasma concentration-time profiles of sorafenib in rats after oral administration ofsorafenib powder and sorafenib-loaded SD formulation (F5). Data are presented as themean ± standard error (n = 3).

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and/or reduces the crystal lattice energy such as solid-state dispersionof the drug into water-soluble carrier matrix would result in a partialor total loss of crystallinity, thereby increasing the aqueous solubilityof the drug. For this approach, the water-soluble polymer Soluplus®has succeeded in inhibiting the crystallization of drugs, forming amor-phous solid dispersions with enhanced drug solubility and dissolutionrate [24,25].

The dissolution profiles of the optimal SD formulation werecompared with those of SFN powder in the three dissolution media(pH1.2, pH4.0, andpH6.8) (Fig. 5). In allmedia tested, SFNhad lowdis-solution rates because of its low aqueous solubility in these media andhydrophobic surface. At pH 1.2, the percentage of pure SFN dissolvedin 120 min was significantly higher than those in distilled water andother pH conditions (p b 0.05). This was because the aqueous solubilityof SFN is pH-dependent with lower pH resulting in higher solubility. Onthe contrary, the SD formulation exhibited significantly higher dissolu-tion rates due to the enhanced solubility and increased wettability/surface hydrophilization resulting from the attachment of hydrophiliccarriers (p b 0.05) [23].

3.4. Pharmacokinetic study

The pharmacokinetic profile of the SFN-loaded SD formulation wascomparedwith that of SFN powder in rats. Themean plasma concentra-tion of SFN versus time profiles after oral delivery of SFN powder andSFN-loaded SD formulation at the dose of 20 mg/kg of SFN are shownin Fig. 6, and the pharmacokinetic parameters (Cmax, Tmax, AUC, Kel, t1/2)are summarized in Table 3. The SD formulation showed significantlyhigher plasma concentration compared to the powder (p b 0.05). TheCmax (5.24 ± 0.40 μg/mL) and AUC (150.01 ± 33.96 h.μg/mL) values ofthe SD group were 1.5-fold and 1.8-fold higher than those of the SFNpowder group, respectively. The enhanced oral bioavailability of SFN inthe SD formulation might be due to the noticeable improvement in thedissolution rate and subsequent absorption of the drug in rats.

Table 3Pharmacokinetic parameters of sorafenib in rats after oral administration of sorafenibpowder or the SD formulation (F5).

Parameters Powder SD formulation (F5)

Cmax (μg/mL) 3.38 ± 0.73 5.25 ± 0.40⁎

Tmax (h) 4.00 ± 2.00 4.00 ± 0.00AUC (h·μg/mL) 82.01 ± 24.56 150.01 ± 33.96⁎

Kel (h−1) 0.036 ± 0.002 0.028 ± 0.004t1/2 (h) 19.37 ± 1.16 25.16 ± 3.26

Each value represents the mean ± standard deviation (n = 3).⁎ p b 0.05 compared with sorafenib powder.

4. Conclusion

The SD formulations of SFN with the use of a novel amphiphiliccopolymer, Soluplus®, were successfully prepared by the spray dryingtechnique. The preparation process does not require use of organic sol-vents that are toxic and unsafe. The drugwas changed from a crystallineform into an amorphous form in solid dispersion. The SFN-loaded SDformulationsmarkedly increased the dissolution rate of the drug. In ad-dition, the pharmacokinetic study in rats showed significantly higheroral bioavailability of SFN in the SD formulation group, compared withthe SFN powder group. Therefore, SFN-loaded SD using the amphiphilicpolymer Soluplus® could be an effective approach to delivery of SFNwith enhanced bioavailability.

Acknowledgments

This research was supported by Yeungnam University researchgrants in 2014.

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