Physicochemical characterization and in vivo evaluation of flurbiprofen-loaded solid dispersion without crystalline change

Abstract

To develop a novel flurbiprofen-loaded solid dispersion without crystalline change, various flurbiprofen-loaded solid dispersions were prepared with water, sodium carboxylmethyl cellulose (Na-CMC), and Tween 80. The effect of Na-CMC and Tween 80 on aqueous solubility of flurbiprofen was investigated. The physicochemical properties of solid dispersions were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared to commercial product. Unlike conventional solid dispersion systems, the flurbiprofen-loaded solid dispersion gave a relatively rough surface and changed no crystalline form of drug. These solid dispersions were formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in changing the hydrophobic drug to hydrophilic form. Furthermore, the flurbiprofen-loaded solid dispersion at the weight ratio of flurbiprofen/Na-CMC/Tween 80 of 6/2.5/0.5 improved ∼ 60-fold drug solubility. It gave higher AUC, T_max, and C_max compared to commercial product. The solid dispersion improved almost 1.5-fold bioavailability of drug compared to commercial product in rats. Thus, the flurbiprofen-loaded solid dispersion would be useful to deliver poorly water-soluble flurbiprofen with enhanced bioavailability without crystalline change.

Keywords::

• Solid dispersion
• no changeable crystal
• flurbiprofen
• solubility
• bioavailability.

Introduction

Flurbiprofen [2-(2-fluoro-4-biphenyl) propionic acid], a non-steroidal anti-inflammatory agent, is widely used to treat rheumatoid arthritis and other rheumatic disorder (Davies, 1995). However, it gave poorly oral bioavailability due to its poor water-solubility of 5–10 μg/ml (Anderson & Conradi, 1985). Various oral formulations of flurbiprofen such as dry elixir (Kim & Yoon, 1995), inclusion complex (Muraoka et al., 2004; Tokumura et al., 2009), salt formation (Gupta et al., 1997), microemulsion (Park et al., 1997;), and solid dispersion (Yuasa et al., 1993; Habib et al., 1998) were developed to improve the solubility of flurbiprofen.

One of the well established methods for increasing the solubility and bioavailability of poorly water-soluble drugs is a solid dispersion system (Chiou & Riegelman, 1971). Drugs in solid dispersion systems may exist as an amorphous form in polymeric carriers. This system improved the solubility and dissolution of drug compared with crystalline material, since the drugs dispersed in polymeric carriers may achieve the highest levels of particle size reduction and surface area enhancement (Taylor & Zografi, 1997; Craig, 2002). Several conventional methods such as melting, solvent evaporation, and solvent wetting method were previously reported to prepare solid dispersions (Leuner & Dressman, 2000). However, the solid dispersion prepared by melting method with high temperature might chemically decompose the drugs (Miller et al., 2007; Newa et al., 2008). In the case of solvent evaporation method and solvent wetting method, the drug in the solid dispersions changed to amorphous form, resulting that the drug might be unstable (Yamashita et al., 2003). Furthermore, the large amounts of hydrophilic carriers against drug in these conventional solid dispersions must be needed to improve the solubility of poorly water-soluble drugs.

In this study, to solve these problems of conventional solid dispersions and to improve the solubility of poorly water-soluble flurbiprofen without crystalline change, the flurbiprofen-loaded solid dispersions were prepared using a spray-drying technique with water, sodium carboxylmethyl cellulose (Na-CMC), and Tween 80. It gave the relatively lower ratio of carriers-to-drug and no organic solvent. The effects of Na-CMC and Tween 80 on the aqueous solubility of flurbiprofen were investigated. The physicochemical properties of solid dispersion were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability of solid dispersion were then evaluated compared to commercial product.

Materials and methods

Materials

Flurbiprofen was supplied from Kolon life science (Kwacheon, Korea). Labrafil M 2125 and Labrafil M 1994 were supplied from Gattefosse (Saint-Priest Cedex, France). Sodium carboxylmethyl cellulose (Na-CMC), polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), sorbitan monolaurate 20 (Span 20), sorbitan monooleate 80 (Span 80), polyethylene glycol 4000, and polyethylene glycol 6000 were purchased from Duksan Chemical Co. (Ansan, Korea). Poloxamer series were purchased from BASF (Ludwigshafen, Germany). The commercial product (Fluben^®; in a tablet form) was purchased from Samil Pharm. Co. (Anyang, South Korea). Hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone were of USP grade. All other chemicals were of reagent grade and used without further purification.

Solubility of flurbiprofen

Excess of flurbiprofen powder (∼ 100 mg) were added to 10 ml of 1% or 10% carriers shown in Table 1. Furthermore, an excessive amount of solid dispersions (∼ 100 mg) were added to 10 ml of water. They were shaken in a water bath at 25°C for 7 days, centrifuged at 3000 g for 10 min (Eppendorf, Hauppauge, NY, USA), and filtered through a membrane filter (0.45 μm) (Choi et al., 2007; Li et al., 2008). The concentration of flurbiprofen in the resulting solution (10 μl) was analyzed using the HPLC method as described below.

Table 1.  Aqueous solubility of flurbiprofen.

Carrier	Drug solubility (μg/ml)
Water	5.1 ± 0.2
Hydrophilic polymers^a
Sodium carboxymethyl cellulose	3,954.0 ± 116.9
Polyvinylpyrrolidone	3.5 ± 3.1
Hydrooxypropyl cellulose	11.3 ± 0.3
Hydroxypropylmethyl cellulose	44.1 ± 2.7
Surfactants^b
Polyethylene glycol 6000	71.2 ± 22.1
Polyethylene glycol 4000	46.3 ± 9.4
Poloxamer 188	487.0 ± 251.5
Poloxamer 407	2,351.0 ± 548.4
Labrafil M 1994	328.3 ± 1.4
Labrafil M 2125	428.2 ± 262.2
Span 20	496.8 ± 81.7
Span 80	553.5 ± 21.3
Tween 20	8,735.1 ± 1220.6
Tween 80	11,193.2 ± 3074.9

^a Each value means the solubility of flurbiprofen in the distilled water containing 1% hydrophilic polymer.

^b Each value means the solubility of flurbiprofen in the distilled water containing 10% surfactant.

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

Preparation of flurbiprofen-loaded solid dispersion

A Büchi 190 nozzle type mini spray-dryer (Meierseggstrasse, Flawil, Switzerland) was used for the preparation of flurbiprofen-loaded solid dispersion. Various amounts of Tween 80 and Na-CMC were dissolved in water. Then, 10 g flurbiprofen pre-sieved through 60 mesh screen was dispersed in this solution. The detailed compositions of flurbiprofen-loaded solid dispersions are given in Table 2. On continuous stirring using a magnetic bar, the resulting dispersed solutions were delivered to the nozzle (0.7 mm diameter) at a flow rate of 5 ml/min using a peristaltic pump, and spray-dried at 100°C inlet temperature and 65–70°C outlet temperature. The pressure of spray air was 4 kg/cm². The flow rate of drying air was maintained at the aspirator setting of 10 which indicated the pressure of aspirator filter vessel −25 mbar. The direction of air flow was the same as that of sprayed products (Lee et al., 1999; Li et al., 2008).

Table 2.  Compositions of flurbiprofen-loaded solid dispersions.

Ingredients (g)	I	II	III	IV	V	VI	VII
Flurbiprofen	6	6	6	6	6	6	6
Na-CMC	3	2.5	2	1.5	0.625	1.25	5
Tween 80	0	0.5	1	1.5	0.125	0.25	1

Dissolution

The flurbiprofen-loaded solid dispersions, powder, and commercial product equivalent to 200 mg of flurbiprofen were inserted into the basket and placed in a dissolution tester (Shinseang Instrument Co., Hwasung, South Korea). This dissolution tester was equipped with an outer water-bath in order to maintain the constant temperature and sink condition. Dissolution test was performed at 36.5°C using the basket method at 100 rpm with 900 ml water as a dissolution medium. At pre-determined intervals, 3 ml of the medium was sampled and filtered through a membrane filter (0.45 μm) (Yong et al., 2005; Windbergs et al., 2009). The concentration of flurbiprofen in the resulting solution (10 μl) was analyzed using HPLC method as described below.

Shape and surface morphology

The shape and surface morphology of flurbiprofen powder and flurbiprofen-loaded solid dispersion were examined using a scanning electron microscope (S-4100, Hitachi, Tokyo, Japan). The powders were fixed on a brass specimen club using double-side adhesive tape and made electrically conductive by coating in a vacuum (6 Pa) with platinum (6 nm/min) using Hitachi Ion Sputter (E-1030) for 300 s at 15 mA (Yamashita et al., 2003; Windbergs et al., 2009).

Thermal and structural characterization

The thermal characteristics of flurbiprofen powder, ingredients, physical mixture, and flurbiprofen-loaded solid dispersion were investigated using a differential scanning calorimeter (DSC-2010, TA Instruments, New castle, DE, USA). The physical mixture was prepared by physically mixing flurbiprofen, Na-CMC, and Tween 80 at the weight ratio of 6/2.5/0.5. About 2 mg of samples were placed in sealed aluminum pans, before heating under nitrogen flow (25 ml/min) at a heating rate of 10°C/min from 30–250°C. Furthermore, powder crystallinity of flurbiprofen-loaded solid dispersion was assessed by X-ray powder diffraction (D/MAX-2500, Rigacu, Tokyo, Japan) conducted at room temperature using monochromatic Cu K_α-radiation (Λ = 1.541,78 Å) at 100 mA and 40 kV in the region of 10° ≤ 2θ ≤ 50° with an angular increment of 0.02° per second (Venkateswarlu & Manjunath, 2004; Li et al., 2008).

Pharmacokinetics

In vivo experiments

Male Sprague–Dawley rats (7–9 weeks old, weighing 250–310 g) were purchased from Charles River Company Korea (Orient, Seoul, South Korea). The rats were fasted for 24–36 h prior to the experiments but allowed free access to water at a temperature of 20–23°C and a relative humidity of 50 ± 5%. Twelve rats, divided into two groups, were administered with commercial product and solid dispersion at a dose of flurbiprofen 20 mg/kg, respectively. All animal care and procedures were conducted according to the Guiding Principles in the Use of Animals in Toxicology, as adopted in 1989, revised in 1999, and amended in 2008 by the Society of Toxicology (SOT, 2008). Furthermore, the protocols for the animal studies were approved by the Institute of Laboratory Animal Resources of Yeungnam University.

Oral administration and blood collecting

Each rat, anesthetized in an ether-saturated chamber, was secured on a surgical board in the supine position with a thread. A polyethylene tube was inserted into the right femoral artery of the rat. The solid dispersions were filled in small hard gelatin capsules (#9, Suheung capsule Co., Seoul, South Korea), and the conventional products were cut as a very small oblong form using a cutter. They were orally administered to rats in each group, respectively. Then, 0.2 mL of blood was collected from the right femoral artery at pre-determined time intervals and centrifuged at 3000 g for 10 min using a centrifuge 5415C (Eppendorf, Hauppauge, NY, USA) (Kim & Yoon, 1995; Li et al., 2008; Newa et al., 2008; Yong et al., 2004).

Blood sample analysis

Plasma (0.1 ml) was mixed with 0.1 ml of acetonitrile solution containing acetaminophen (20 μg/ml) as an internal standard. It was vortexed for 2 min and centrifuged at 10,000 g for 10 min. Then, 10 μl of supernatant layer was analyzed by HPLC (Hitachi, Tokyo, Japan) equipped with an Inertsil ODS-3 C₁₈ column (GL science, 0.5 μm, 15 cm × 0.46 cm i.d.) and UV detector (Model L-7450). The mobile phase was composed of acetonitrile, water, and phosphoric acid (600/400/5, volume ratio). The eluent was monitored at 254 nm with a flow rate of 1.5 ml/min (Davies, 1995; Park et al., 1997; 1999).

Pharmacokinetic data analysis and statistical analysis

The area under the drug concentration–time curve from zero to infinity (AUC), the elimination rate constant (K_el), and half-life (t_1/2) were calculated using a non-compartmental analysis (WinNonlin; professional edition, version 2.1; Pharsight Co., Mountain View, CA). The maximum plasma concentration of drug (C_max) and the time taken to reach the maximum plasma concentration (T_max) were obtained directly from the plasma data (Gibaldi & Perrier, 1982). Levels of statistical significance (p < 0.05) were assessed using the Student t-test between two means for unpaired data. All data are expressed as mean ± standard deviation (SD) or as the median (ranges) for T_max.

Results and discussion

A novel solid dispersion system was prepared using a spray-drying technique with water, hydrophilic polymer, and surfactant, and without organic solvent. To select a hydrophilic polymer and surfactant as carriers suitable for flurbiprofen-loaded solid dispersion, we investigated the solubility of flurbiprofen in the distilled water containing 1% hydrophilic polymers or 10% surfactants (Table 1). Aqueous solubility of flurbiprofen is ∼ 5 μg/ml, which is in good agreement with an earlier reported study by Anderson and Conradi (1985). Among the hydrophilic polymers tested, Na-CMC showed maximum solubility of drug. Furthermore, among the surfactants tested, the solubility of flurbiprofen at Tween 80 was highest at ∼ 11,000 μg/ml. Thus, Na-CMC and Tween 80 were selected as carriers in the development of flurbiprofen-loaded solid dispersion.

In the conventional solid dispersion systems, the poorly water-soluble drug existed as an amorphous form in polymeric carriers since the drug and polymeric carriers were soluble in organic solvents followed by elimination of organic solvents. Furthermore, the drugs dispersed in polymeric carriers may achieve the highest levels of particle size reduction and surface area enhancement, leading to improved solubility and dissolution of drug (Taylor & Zografi, 1997; Craig, 2002). However, in the novel solid dispersion prepared in this study, relatively small amounts of Na-CMC and Tween 80 were dissolved in water and a poorly water-soluble flurbiprofen was dispersed in this solution. The resulting suspension was spray-dried, resulting in producing the flurbiprofen-loaded solid dispersion. In this novel solid dispersion, the dissolved carriers such as hydrophilic polymer and surfactant were attached to the surface of dispersed drug particles. This solid dispersion might change the hydrophobic drug to hydrophilic form, resulting in increased solubility and dissolution of poorly water-soluble drug. This mechanism suggested that, irrespective of pH, this novel solid dispersion might increase the solubility and dissolution of poorly water-soluble drug in the gastric-intestinal fluids as well as in distilled water. Since water is used as a solvent in this study, unlike conventional solid dispersion methods, this solid dispersion method has several advantages over other methods in an industry scale, such as the relatively lower ratio of carriers to drug, no crystalline change, no necessity to remove organic solvent, and no toxicity or explosion of organic solvent (Khan & Jiabi, 1998; Kachrimanis et al., 2000).

The effect of the ratio of Na-CMC/Tween 80 (Table 2, formulations I-II) on the aqueous solubility of flurbiprofen in the solid dispersion is shown in Figure 1. Formulations III and IV were sticky due to relatively larger amounts of Tween 80. Tween 80 has existed as a liquid form at room temperature (Zeng et al., 2006; Kaur et al., 2008). In this study, their solubility and dissolution data were not shown, because they were physically unsuitable solid dispersions due to their stickiness. The solid dispersions (formulations I–II) gave significantly higher solubility of drug compared to flurbiprofen powder. Furthermore, aqueous solubility of flurbiprofen in the solid dispersion was increased with decreased ratio of Na-CMC/Tween 80. Thus, formulation II was selected as an optimal formulation since this formulation with non-adhesive particles gave higher solubility of drug than did formulation I.

Figure 1.  Effect of solid dispersions on the solubility of flurbiprofen. Each value represents the mean ± SD (n = 3). The flurbiprofen-loaded solid dispersion was composed of flurbiprofen/Na-CMC/Tween 80.

On the other hand, to select an optimal formulation of flurbiprofen-loaded solid dispersion which increased the flurbiprofen solubility with the minimum amount of carriers, the effect of the amount of carriers with constant ratio of Na-CMC/Tween 80 (5:1) on aqueous solubility of flurbiprofen was investigated (Table 2, formulations II and V–VII). The aqueous solubility of flurbiprofen was increased with increased amount of carriers to 0.5 (Figure 1). However, formulation VII hardly increased the drug solubility compared to formulation II. Our results suggested that the optimal amount of carriers was needed to improve the solubility of flurbiprofen in the solid dispersion. In particular, formulation II improved ∼ 60-fold solubility of flurbiprofen (314.11 ± 11.35 vs 5.10 ± 0.20 μg/ml).

The effect of the ratio of Na-CMC/Tween 80 on the dissolution of flurbiprofen in the solid dispersion is given in Figure 2. The solid dispersions (formulations I–II) gave a significantly higher dissolution rate of drug compared to flurbiprofen powder (Figure 2). Furthermore, the more decreased ratio of Na-CMC/Tween 80 was, the more increased the dissolution rate of drug from the solid dispersion was. Our results suggested that Tween 80 greatly affected the dissolution of drug, if the total amounts of carriers were the same in the preparation of the flurbiprofen-loaded solid dispersion.

Figure 2.  Effect of solid dispersions on the dissolution of flurbiprofen. Each value represents the mean ± SD (n = 6). The flurbiprofen-loaded solid dispersion was composed of flurbiprofen/Na-CMC/Tween 80.

To evaluate the effect of amount of carriers with constant ratio of Na-CMC/Tween 80 (5:1) on the dissolution of drug in the solid dispersion, the dissolution studies on the formulations with the carriers/drug ratio of 0.125–1 (Table 1, formulations II and V–VII) were performed. As the amount of carriers was increased except formulation VII, the dissolution rate of drug in the solid dispersion was decreased. Formulation VII with relatively higher carrier rather decreased the dissolution of drug in the solid dispersion compared to other solid dispersion (Figure 2b). Our results suggested that the relatively high carrier rather retarded the dissolution of drug in the solid dispersion since Na-CMC was used as a coating material (El-Maradny, 2007; Mohamad & Dashevsky, 2007). Thus, in the preparation of this flurbiprofen-loaded solid dispersion, the optimal amount of carriers was needed.

From these findings, formulation II with the flurbiprofen/Na-CMC/Tween 80 at the weight ratio of 6:2.5:0.5 was selected as a flurbiprofen-loaded solid dispersion since it gave relatively small amounts of carriers, and increased solubility and dissolution, and non-adhesive property.

The scanning electron micrographs of flurbiprofen powder and flurbiprofen-loaded solid dispersion were shown in Figure 3. Flurbiprofen powder (Figure 3a) appeared as a smooth-surfaced rectangular crystalline in shape (Yamashita et al., 2003). However, the solid dispersion (Figure 3b) gave a relatively rough surface, suggesting that the hydrophilic polymer and surfactant were attached to the drug surface.

Figure 3.  Scanning electron micrographs: (a) flurbiprofen powder (×800); (b) flurbiprofen-loaded solid dispersion (×250).

Thermal behavior of drug powder, carriers, physical mixture, and solid dispersion are shown in Figure 4. The DSC curve showed that flurbiprofen appeared as a sharp endothermic peak at ∼ 110°C, corresponding to its melting, indicating its crystalline nature (Figure 4a). Na-CMC appeared to have no specific peaks from 30–250°C (Figure 4d). The melting peak appeared in drug peak was shown with reduced intensity in physical mixture (Figure 4c). Furthermore, unlike conventional solid dispersions, a sharp peak corresponding to drug was also observed in solid dispersion (Figure 4b). Thus, in the DSC curve of solid dispersion and physical mixture, the characteristic peaks of flurbiprofen were unchanged, indicating the absence of strong interactions between the drug and the carriers for the preparation of solid dispersion. Our results suggested that flurbiprofen was present in no changed crystalline state in the solid dispersion (Walser et al., 1997).

Figure 4.  Differential scanning calorimetric thermograms: (a) flurbiprofen powder; (b) solid dispersion; (c) physical mixture; (d) Na-CMC.

The powder X-ray diffractometry patterns are presented in Figure 5. Flurbiprofen had sharp peaks at diffraction angles showing a typical crystalline pattern (Figure 5a). Furthermore, all major characteristic crystalline peaks appearing in the drug were observed in physical mixture and solid dispersion (Figures 5b and c). Thus, like DSC results, flurbiprofen was present in no changed crystalline state in the solid dispersion (Doherty & York, 1987). Our results suggested that the enhanced solubility of flurbiprofen was not due to the transformation of the crystalline form into the amorphous state, but due to the attachment of the carriers to the surface of poorly water-soluble flurbiprofen, resulting in change in the hydrophobic drug to hydrophilic property in this solid dispersion.

Figure 5.  X-ray powder diffraction: (a) flurbiprofen powder; (b) physical mixture; (c) solid dispersion.

The dissolution of drug from the solid dispersion was compared with that from flurbiprofen-loaded commercial product (Fluben^®) (Figure 6). The dissolution rates of drug from solid dispersion were significantly higher compared with those in commercial product (p < 0.05). The initial dissolution rate of drug in the solid dispersion increased compared to commercial product in water. In particular, the amounts of drug dissolved from solid dispersion for 15 min increased ∼ 1.5-fold compared to commercial product (46.7 ± 2.2 vs 29.9 ± 1.6%). Thus, this solid dispersion was useful for improving the initial dissolution rate of flurbiprofen, since it changed from hydrophobic drug to hydrophilic form due to attachment of hydrophilic polymer to the drug surface.

Figure 6.  Dissolution profile of drug from solid dispersion and commercial product. Each value represents the mean ± SD (n = 6). * p < 0.05 compared with commercial product.

The pharmacokinetic parameters of flurbiprofen were determined after oral administration of commercial product and the solid dispersion. Figure 7 shows the change of mean plasma concentration of flurbiprofen after oral administration at the drug dose of 20 mg/kg to rats. The total plasma concentrations of drug in solid dispersion were higher compared with those in commercial product. In particular, the initial plasma concentrations of drug in solid dispersion, from 1 to 2 h, were significantly higher compared with those in commercial product (p < 0.05). Our results suggested that the higher initial plasma concentrations of flurbiprofen were due to the increased dissolution rate of drug in the solid dispersion (Kim & Yoon, 1995; Li et al., 2008).

Figure 7.  Plasma concentration-time profiles of drug after oral administration of solid dispersion and commercial product to rats. Each value represents the mean ± SD (n = 6). * p < 0.05 compared with commercial product.

The pharmacokinetic parameters are shown in Table 3. The solid dispersion gave significantly higher AUC and C_max of drug than did commercial product (p < 0.05). In particular, the AUC of drug from solid dispersion was ∼ 1.5-fold higher than that from commercial product. Furthermore, the solid dispersion showed a significantly higher T_max value than did commercial product (p < 0.05). From Figure 7, the C_max value at T_max (0.5 h) in the commercial product was similar to the plasma concentration at 0.5 h in the solid dispersion (27.56 ± 2.57 vs 28.45 ± 4.28 μg/ml). The plasma concentrations in the solid dispersion were increased to 36.43 ± 5.15 μg/ml at T_max (1.6 h). Our results suggested that higher T_max followed by higher C_max was due to more complete absorption of flurbiprofen in the solid dispersion. Thus, the enhanced oral bioavailability of flurbiprofen in the solid dispersion might be contributed to by the marked increase in the absorption rate of flurbiprofen due to the increased dissolution of drug in the solid dispersion in rats (Kim & Yoon, 1995). However, the Kel and t_1/2 values of drug from solid dispersion were not significantly different from those from commercial product. These results suggested that the flurbiprofen-loaded solid dispersion would be useful to deliver flurbiprofen in a pattern that allows fast absorption in the initial phase, leading to more complete absorption.

Table 3.  Pharmacokinetic parameters.

Parameters	Commercial product	Solid dispersion
Cmax (μg/ml)	27.56 ± 2.57	36.43 ± 5.15*
Tmax (h)	0.5 ± 0.0	1.6 ± 0.55*
AUC (h· μg/ml)	228.30 ± 16.74	345.09 ± 41.93*
t1/2 (h)	9.35 ± 2.23	7.26 ± 3.77
Kel (h^−1)	0.07 ± 0.02	0.06 ± 0.04

Each value represents the mean ± SD (n = 6).

* p < 0.05 compared with commercial product.

Conclusion

Unlike conventional solid dispersion systems, this solid dispersion prepared with water, Na-CMC, and Tween 80 gave a relatively lower ratio of carrier-to-drug, and no changed crystalline form of drug. Furthermore, the flurbiprofen-loaded solid dispersion at the weight ratio of flurbiprofen/Na-CMC/Tween 80 of 6/2.5/0.5 improved ∼ 60-fold drug solubility. It gave higher AUC, C_max, and T_max values compared to commercial product, indicating that it improved the oral bioavailability of flurbiprofen in rats. Thus, the flurbiprofen-loaded solid dispersion would be useful to deliver poorly water-soluble flurbiprofen with enhanced bioavailability without crystalline change.

Declaration of interest

This work was supported by Mid-career Researcher Program through NRF grant funded by the MEST (No. 2010-0000363) and a grant from the Korean Health Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A092018).