Preparation and characterization of solid dispersion using a novel amphiphilic copolymer to enhance dissolution and oral bioavailability of sorafenib

    Preparation and Characterization of Solid Dispersion Using a Novel Amphiphilic Copolymer to Enhance Dissolution and Oral Bioavailability of Sorafenib Duy Hieu Truong, Tuan Hiep Tran, Thiruganesh Ramasamy, Ju Yeon Choi, Han-Gon Choi, Chul Soon Yong, Jong Oh. Kim PII: DOI: Reference:

S0032-5910(15)00329-0 doi: 10.1016/j.powtec.2015.04.044 PTEC 10954

To appear in:

Powder Technology

Received date: Revised date: Accepted date:

29 December 2014 12 February 2015 20 April 2015

Please cite this article as: Duy Hieu Truong, Tuan Hiep Tran, Thiruganesh Ramasamy, Ju Yeon Choi, Han-Gon Choi, Chul Soon Yong, Jong Oh. Kim, Preparation and Characterization of Solid Dispersion Using a Novel Amphiphilic Copolymer to Enhance Dissolution and Oral Bioavailability of Sorafenib, Powder Technology (2015), doi: 10.1016/j.powtec.2015.04.044

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ACCEPTED MANUSCRIPT Preparation and Characterization of Solid Dispersion Using a Novel Amphiphilic

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Copolymer to Enhance Dissolution and Oral Bioavailability of Sorafenib

Duy Hieu Truonga, Tuan Hiep Trana, Thiruganesh Ramasamya, Ju Yeon Choia,

College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyeongsan 712-749,

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Han-Gon Choib, Chul Soon Yonga,**, Jong Oh Kima,*

South Korea.

College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang

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University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea.

Corresponding author:

**

Co-corresponding author:

Prof. Jong Oh Kim, Ph.D., Tel: +82-53-810-2813, Fax: +82-53-810-4654 E-mail:[email protected]

Prof. Chul Soon Yong, Ph.D. Tel: +82-53-810-2812, Fax: +82-53-810-4654 E-mail:[email protected]

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ACCEPTED MANUSCRIPT Abstract

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The objective of the current study was to enhance dissolution and oral bioavailability of

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the poorly water-soluble drug, sorafenib (SFN), by solid dispersion (SD) technique using a novel amphiphilic copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol

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graft copolymer (Soluplus®). The SD formulations were prepared by the spray drying method with SFN, Soluplus, and sodium lauryl sulfate (SLS) at various weight ratios in

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water. The optimized SD formulation, which showed the highest dissolution rate in distilled water, was further characterized for surface morphology, crystallinity, dissolution

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in pH 1.2, pH 4.0, pH 6.8, and pharmacokinetics in rats. Powder X-ray diffraction and differential scanning calorimetry revealed the amorphous form of SFN in the formulation.

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In addition, at the oral dosage of 20 mg/kg SFN, the SD formulation showed increased

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Cmax and AUC0–48h by 1.5- and 1.8-fold, compared to those of SFN powder, respectively (p<0.05). These findings suggest that the preparation of SFN-loaded SD using Soluplus

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could be a promising strategy for improvement of oral bioavailability of SFN.

Keywords: sorafenib, soluplus, solid dispersion, dissolution, solubilization.

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1. Introduction Sorafenib (SFN), a novel bi-aryl urea derivative, strongly inhibits Raf-1, a member

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of the RAF/MEK/ERK signaling pathway. SFN targets several serine/threonine kinases and receptor tyrosine kinases, including vascular endothelial growth factor receptor

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(VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-β, Flt-3, and cKIT, which are related to tumor cell proliferation and angiogenesis [1, 2]. It has been

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approved by the U.S. Food and Drug Administration (US-FDA) for treatment of patients with advanced renal cell carcinoma, unresectable hepatocellular carcinoma, and

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differentiated thyroid carcinoma [3, 4]. According to the Biopharmaceutical classification system (BCS), SFN belongs to BCS class II, which is characterized by low solubility and

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high permeability. SFN has very poor solubility in aqueous media at various pH values from pH 1.2 to pH 7.4 [5-8]. This leads to slow dissolution rate in the gastrointestinal tract,

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which is supposed to be the rate-limiting step for absorption and together with the first-

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pass metabolism results in low bioavailability and large inter-subject variability [9, 10]. Therefore, some formulation strategies have been developed to enhance the physiochemical properties and improve the bioavailability of the drug [7, 8]. Solid dispersion (SD) is a simple and well-studied approach to increase the dissolution rate and bioavailability of poorly water-soluble drugs [11-21]. By definition, a pharmaceutical SD is a product prepared by transforming a drug-carrier combination into the solid state from the original fluid state [22]. Hydrophilic polymers are the most frequently used carriers for fabrication of SDs [23]. Selection of the right carrier(s) for formulation of the SD is very important. Recently, interest in use of Soluplus® as the matrix carrier in the SD system has increased [24, 25]. Soluplus is a novel graft copolymer initially designed for solid solutions by hot-melt extrusion [26]. Due to its amphiphilic chemical structure, it has bifunctional properties as a matrix polymer for solid solutions

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ACCEPTED MANUSCRIPT and an active solubilizer with the ability to enhance solubility of poorly water-soluble

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drugs.

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In this study, SFN-loaded SDs were prepared with Soluplus and sodium lauryl sulfate by the spray-drying method. Scanning electron microscopy (SEM), differential

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scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were then applied in order to characterize the physicochemical properties of the optimal solid dispersion

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formulation. In addition, a pharmacokinetic study was conducted in order to compare the

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2. Materials and Methods

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effect of the solid dispersion on the bioavailability of the drug with the pure SFN powder.

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2.1 Materials

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Sorafenib tosylate was purchased from Green Stone Swiss Co., Ltd (China). Hydroxypropylmethyl cellulose (HPMC 2910), Polyvinylpyrrolidone (PVP K30), Polyoxyl 40 hydrogenated castor oil (Cremophor® RH40), Polyoxypropylene – polyoxyethylene block copolymer (Poloxamer 407, Poloxamer 188) and polyvinyl caprolactam–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 cetyl ether (Brij 58) were purchased from Sigma-Aldrich, Korea. All other chemicals and reagents were of analytical grade and used without further purification.

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ACCEPTED MANUSCRIPT 2.2. Solubility study

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The solubility study of SFN was performed according to the following procedure.

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Excessive amounts of SFN were added to 1 mL of aqueous solutions containing 1% carrier (w/v) in 2 mL capped tubes. These tubes were vortexed for 30 seconds and shaken at 37 ±

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0.5°C for 72 hours in a thermostatically controlled water bath, then centrifuged at 10000 x g for 10 minutes (5415C, Eppendorf, USA). The supernatant layers were filtered through a

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0.45-μm membrane filter (Whatman, UK), and the SFN concentrations were analyzed by

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HPLC with prior suitable dilution.

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2.3. Preparation of SFN-loaded SD

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SD formulations of SFN were prepared using a Büchi 190 nozzle-type mini spray dryer (Flawil, Switzerland). Various amounts of Soluplus and SLS were dissolved in

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distilled water. Then, SFN was dispersed into these solutions and the resulting dispersions were spray dried under the following conditions: inlet temperature, 130 °C; resulting outlet temperature, 70-75°C; feeding rate, 3 mL/min, which delivered the dispersions to a pneumatic nozzle (diameter of 0.7 mm) via a peristaltic pump; aspiration, 80%; spray pressure, 4 kg/cm2; drying air flow, 600 L/h. The direction of air flow was the same as that of sprayed products [11, 27-29]. The suspensions were stirred continuously by magnetic stirrers during the spray drying process. The physical mixture was prepared by mixing the same weight ratio of the SD formulation using a mortar and a pestle.

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ACCEPTED MANUSCRIPT 2.4. Dissolution study

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In vitro dissolution study of SFN powder and SFN-loaded SD formulations was

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carried out using USP dissolution apparatus 2 (Universal Scientific Co., Ltd, Seoul, Korea) in four media of 900 mL containing 0.1% Tween 80: distilled water, hydrochloric acid

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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

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to 10 mg SFN powder) and placed in sinkers before dropping into the dissolution media. The dissolution media were maintained at 37 ± 0.5°C and stirred at the paddle speed of 50

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rpm. At the predefined time points, 3 mL of the dissolution media was withdrawn, filtered through a 0.45-μm membrane filter and immediately replaced by the same volume of fresh

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dissolution media. The concentrations of dissolved SFN were analyzed using the HPLC

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method as described below. All measurements were performed in triplicate.

2.5. Drug analysis

The drug concentrations were analyzed using a Hitachi HPLC system that 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 x 150 mm (Nacalai Inc., USA). The mobile phase, 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 effluent was detected at the wavelength of 265 nm.

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ACCEPTED MANUSCRIPT 2.6. Characterization of solid dispersion

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2.6.1. Shape and surface morphology

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Scanning electron microscopy (SEM) was used to examine the surface morphology of SFN, and the SD formulation (F5) with a scanning electron microscope (S-4100,

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Hitachi, Japan). The samples were attached to a metal sample holder using double-sided

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adhesive tape and then made electrically conductive by coating with platinum (6 nm/min) in a vacuum (6 Pa) using Hitachi Ion Sputter (E-1030) for 120 s at 15 mA prior to

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observation.

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2.6.2. Powder X-ray diffraction (PXRD)

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The PXRD patterns of SFN powder, Soluplus, SLS, the physical mixture, and the

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SD formulation (F5) were recorded using an X’Pert PRO MPD diffractometer (PANalytical, Almelo, the Netherlands) with CuKα radiation (λ = 1.54 Å). The operating voltage and current were 40 kV and 30 mA, respectively. Diffractograms were obtained in the angular range 2θ (diffraction angle) from 10° to 60° with a step size of 0.02626°.

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 differential scanning calorimeter (DSC-Q200, TA Instruments, USA). Accurately weighed samples (approximately 2-3 mg) were sealed in an aluminium pan. The scans were performed over the temperature range of 40–250°C at a heating rate of 10 °C/min, under a nitrogen purge at a flow rate of 50 mL/min. The

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ACCEPTED MANUSCRIPT temperature and enthalpy of the DSC system were calibrated using a standard aluminum

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pan.

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2.7. Pharmacokinetics

All animal care procedures were performed according to the Guiding Principles in

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the Use of Animals in Toxicology as amended in 2008 by the Society of Toxicology [30]. The study protocols were approved by the Institute of Laboratory Animal Resources of

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Yeungnam University.

Male Sprague-Dawley rats weighing 280 ± 20 g were fasted overnight prior to the

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experiments with free access to water. Six rats were randomly divided into two groups

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(n=3). Each rat was anaesthetized by diethyl ether, and the right femoral artery was cannulated for insertion of a polyethylene tube. The drug powder and the SFN-loaded SD

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formulation were dispersed into water, and administered orally to the rats in each group at the dosage of 20 mg/kg SFN [9, 31]. Then, approximately 0.3 mL of blood was collected from the cannulated artery at predefined time intervals into heparinzed tubes, and centrifuged at 10,000 x g for 10 min (5415C, Eppendorf, USA). The supernatant layers were collected and stored frozen at −20 °C until analysis. The drug analysis was adapted from a previous method with a slight modification [7]. Plasma (40 μL) and acetonitrile (260 μL) were mixed and vortexed. The mixtures were then centrifuged at 10,000 × g for 10 min and the supernatant layers were collected. The drug concentration in the supernatant layers was analyzed using the HPLC method as described above. The standard calibration curve showed excellent linearity (r = 0.999) in the concentration range of 0.1 - 20 µg/mL of SFN in plasma.

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ACCEPTED MANUSCRIPT Pharmacokinetic parameters, including the area under the plasma concentration versus time curve from zero to 48h (AUC0→48h), the elimination rate (Kel) and half-life (t1/2)

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were calculated by non-compartmental analysis using WinNonlin® software (version 2.1;

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Pharsight Co., Mountain View, CA, USA). The maximum plasma concentration (Cmax)

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and the time taken to reach Cmax (Tmax) were obtained directly from plasma data.

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2.8. Statistical analysis

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Statistical analysis of the samples was performed using a Student’s t-test. A p-value < 0.05 was considered to indicate statistical significance. All data were presented as the

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mean ± standard deviation, unless otherwise stated.

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3. Results and discussion 3.1 Solubility studies

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

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ACCEPTED MANUSCRIPT 3.2. Optimization of SFN-loaded SD Various formulations of SFN-loaded SD were prepared using a spray drier with

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water, a hydrophilic polymer (Soluplus®) and a surfactant (SLS). Briefly, solutions of Soluplus and SLS were prepared in distilled water and SFN was dispersed in these

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solutions. After stirring for about 1 h at 37°C, the homogenous suspensions were spraydried. To measure the effect of drug/carrier ratio, different SD formulations with varying

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drug/carrier ratios and fixed amount of SLS were prepared (Table 2).

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In order to understand the effect of drug/carrier ratio on SFN-loaded SD, the dissolution profiles of SFN from SD were investigated. As shown in Fig. 1, all of the

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formulations showed significantly higher dissolution rate than the SFN powder (p < 0.05). However, at the drug/carrier ratio of 1/5, formulation F3 exhibited significantly higher

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drug release after 120 min than formulations F1 and F2 with the drug/carrier ratio of 1/1

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and 1/3, respectively (p < 0.05). Therefore, the drug/carrier ratio of 1/5 was used to further evaluate the effect of Soluplus/SLS ratio on the dissolution rate. When the amount of SLS was increased, the release was increased and reached approximately 100% at the drug/Soluplus/SLS ratio of 1/4.5/0.5 in formulation F5. Thus, formulation F5 was chosen as the optimal formulation for further studies.

3.3. Characterization of the solid dispersion The surface morphology of SFN powder and SFN-loaded SD was visualized by SEM (Fig. 2). As shown in Fig. 2A, the pure drug appeared as rectangular crystals ranging in size from 10 to 100 μm, while the solid dispersion formulation contained relatively rough

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ACCEPTED MANUSCRIPT surfaced particles (Fig. 2B). These results suggested that the carriers might be attached to

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the surfaces of the drug particles.

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The crystallinity of the SFN powder, Soluplus, SLS, the physical mixture, and the solid dispersion formulation were determined by PXPD analysis. Typical diffraction

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patterns of SFN, Soluplus, SLS, the physical mixture, and sorafenib-loaded solid dispersion are shown in Fig. 3. The diffraction pattern of pure SFN showed various

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characteristic 2θ peaks at 13.2°, 17.8°, and 21.5°, revealing a highly crystalline structure. However, these distinctive peaks of SFN were absent in the pattern of the solid dispersion,

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indicating that the drug may be in the amorphous form or molecularly dispersed in the

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carrier matrix.

In addition, the thermal behaviors of SFN powder, Soluplus, SLS, the physical

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mixture, and SFN-SD formulation were further characterized by DSC (Fig. 4). The DSC

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curve of SFN displayed one large, sharp endothermic peak at about 238 °C, which corresponds to the melting point of the tosylate salt form and one small endothermic peak at about 200 °C which might be relevant to the melting point of the sorafenib base form. The same phenomenon was observed in another study [33]. However, these peaks disappeared in the curve of the solid dispersion which confirms the molecular dispersion of sorafenib in the carrier matrix. The high melting point of the drug is one of the causes of poor aqueous solubility [34]. Thus, any strategy that disrupts the crystalline nature and/or reduces the crystal lattice energy such as solid-state dispersion of the drug into water-soluble carrier matrix would result in a partial or total loss of crystallinity, thereby increasing the aqueous solubility of the drug. For this approach, the water-soluble polymer Soluplus® has succeeded in

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ACCEPTED MANUSCRIPT inhibiting the crystallization of drugs, forming amorphous solid dispersions with enhanced

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drug solubility and dissolution rate [24, 25].

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The dissolution profiles of the optimal SD formulation were compared with those of SFN powder in the three dissolution media (pH 1.2, pH 4.0, and pH 6.8) (Fig. 5). In all

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media tested, SFN had low dissolution rates because of its low aqueous solubility in these media and hydrophobic surface. At pH 1.2, the percentage of pure SFN dissolved in 120

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min was significantly higher than those in distilled water and other pH conditions (p < 0.05). This was because the aqueous solubility of SFN is pH-dependent with lower pH

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resulting in higher solubility. On the contrary, the SD formulation exhibited significantly higher dissolution rates due to the enhanced solubility and increased wettability/surface

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hydrophilization resulting from the attachment of hydrophilic carriers (p < 0.05) [23].

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3.4. Pharmacokinetic study

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

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4. Conclusion

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The SD formulations of SFN with the use of a novel amphiphilic copolymer,

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Soluplus®, were successfully prepared by the spray drying technique. The preparation process does not require use of organic solvents that are toxic and unsafe. The drug was

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changed from a crystalline form into an amorphous form in solid dispersion. The SFNloaded SD formulations markedly increased the dissolution rate of the drug. In addition,

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the pharmacokinetic study in rats showed significantly higher oral bioavailability of SFN

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in the SD formulation group, compared with the SFN powder group. Therefore, SFNloaded SD using the amphiphilic polymer Soluplus® could be an effective approach to

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Acknowledgements

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delivery of SFN with enhanced bioavailability.

This research was supported by Yeungnam University research grants in 2014.

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nimesulide

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[34] R.A. Shoukri, I.S. Ahmed, R.N. Shamma, In vitro and in vivo evaluation of lyophilized

orally

disintegrating

tablets,

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Pharmaceutics and Biopharmaceutics, 73 (2009) 162-171.

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European

Journal

of

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

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Fig. 2. SEM images of (A) sorafenib powder, and (B) SD formulation (F5). Fig. 3. X-ray powder diffraction of Sorafenib powder, Soluplus, sodium lauryl sulfate

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(SLS), the physical mixture, and SD formulation (F5).

Fig. 4. Differential scanning calorimetric thermograms of sorafenib powder, Soluplus,

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Sodium lauryl sulfate (SLS), the physical mixture and SD formulation (F5). Fig. 5. Dissolution profiles of the drug from capsules containing sorafenib powder or the

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solid 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 the weight ratio 1/4.5/0.5. Each value

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represents the mean ± standard deviation (n=3). Fig. 6. Plasma concentration-time profiles of sorafenib in rats after oral administration of

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sorafenib powder and sorafenib-loaded SD formulation (F5). Data are presented as the

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mean ± standard error (n = 3).

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ACCEPTED MANUSCRIPT Table 1. Aqueous solubility of sorafenib. Aqueous solubility (mg/mL)

Water

N/A

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Carrier

Hydrophilic polymers

0.097 ± 0.001

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HPMC 2910 PVP K30

0.095 ± 0.001 0.701 ± 0.072

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Soluplus

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Surfactants

1.838 ± 0.194

Poloxamer 407

0.076 ± 0.013

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Sodium lauryl sulfate

0.097 ± 0.001

Brij 76

0.181 ± 0.004

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Poloxamer 188

0.243 ± 0.023

Cremophor RH40

0.203 ± 0.004

Tween 20

0.095 ± 0.009

Tween 80

0.123 ± 0.014

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Brij 58

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

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ACCEPTED MANUSCRIPT Table 2. Compositions of sorafenib-loaded solid dispersion formulations. F2

F3

F4

Sorafenib

1

1

1

1

Soluplus

0.9

2.9

4.9

SLS

0.1

0.1

0.1

1/1

1/3

1/5

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Drug/carrier (w/w)

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F1

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Ingredients (g)

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F5 1

4.75

4.5

0.25

0.5

1/5

1/5

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

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Powder

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Parameters

3.38 ± 0.73

5.25 ± 0.40*

Tmax (h)

4.00 ± 2.00

4.00 ± 0.00

Kel (h-1)

0.036 ± 0.002

t1/2 (h)

19.37 ± 1.16

150.01 ± 33.96* 0.028 ± 0.004

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82.01 ± 24.56

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AUC (h.µg/mL)

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Cmax (µg/mL)

25.16 ± 3.26

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

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* p < 0.05 compared with sorafenib powder.

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Figure 1

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(B)

(A)

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Figure 2

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Figure 3

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Figure 4

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Figure 5

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(A)

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(B)

(C)

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Figure 6

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Graphical abstract

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ACCEPTED MANUSCRIPT Highlights We prepared sorafenib (SFN) solid dispersion by spray drying technique.

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Solid dispersion was prepared using the amphiphilic polymer Soluplus.

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The SFN-loaded solid dispersion markedly increased the dissolution rate of SFN.

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It could be an effective approach to delivery of SFN with enhanced bioavailability.

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