Improved dissolution and anti-inflammatory effect of ibuprofen by solid dispersion

Abstract

The purpose of this study was to improve the dissolution rate and anti-inflammatory effect of ibuprofen by a solid dispersion (SD) method. Initial screening was developed based on drug solubility in carriers in the liquid state to select a suitable water-soluble carrier system for the preparation of SDs. The dissolution of ibuprofen in urea was higher than in PEG4000 or mannitol. Thus, urea was selected as the carrier for the preparation of SDs. SDs were characterized in terms of dissolution, differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM), and Fourier transform infrared (FTIR) spectroscopy. Solid dispersion-based (SDBT) and conventional (CT) tablets were prepared by the wet granulation method. The anti-inflammatory effect of SDBT was evaluated using the mouse ear edema test with xylene. In vitro release results indicated that the ibuprofen dissolution rate was improved by the SD. SD characterization results suggested that ibuprofen partly precipitates in crystalline and amorphous forms after SD preparation and that ibuprofen and urea do not interact. SDBT displayed more significant anti-inflammatory effects than CT. The dissolution rate and anti-inflammatory effect of ibuprofen were significantly enhanced by the ibuprofen-urea SD.

Keywords

ibuprofen / solid dispersion / physical mixture / dissolution / anti-inflammatory effect

Introduction

Ibuprofen, a non-steroidal antipyretic and anti-inflammatory drug, has a short half-life and low bioavailability, which can lead to excessive drug dosage and adverse reactions. Following oral administration of a drug, the extent and speed of its absorption are influenced by several processes. Relative to the formulation of the drug, these processes could include release of the active ingredient, dissolution in the stomach and/or the intestine, transport of the solid or dissolved active ingredient from the stomach into the intestine, and absorption of the substance through the mucosa. Ibuprofen is a relatively weak acid (pKa 4.4), and its solubility in water or acidic solutions is very low [1]; thus, relatively long residence times in the acid environment of the stomach and slowing of absorption of the substance could be expected. As the pH of the buffer medium increases, solubility increases and the drug can be better absorbed during dissolution in the intestine. Dissolution of ibuprofen is thus the rate-limiting step for its absorption, and the quick release of ibuprofen, as well as other poorly soluble drugs [2,3], in the gastrointestinal tract after oral administration is desirable. Ibuprofen serum concentrations and their analgesic effects have been shown to be correlated. Rapid ibuprofen absorption is a prerequisite for the quick onset of its action [4], and dissolution and in vitro dissolution rates of ibuprofen should be enhanced to improve its bioavailability and reduce drug dosages and occurrence of adverse reactions. The dissolution of poor water-soluble drugs that undergo dissolution rate-limited gastrointestinal absorption can generally be improved by many techniques, one of which is the preparation of solid dispersions (SDs) [5].

The use of SDs, in which drugs become highly soluble, to increase the dissolution rate of poorly soluble drugs has been studied extensively. Various water-soluble inert materials have been shown to improve the dissolution rate of many drugs [2,3]. This technique provides a means of reducing particle size to nearly molecular levels. As the soluble carrier dissolves, the insoluble drug becomes exposed to the dissolution medium as very fine particles for quick dissolution and absorption [6].

SDs may improve the anti-inflammatory effect of ibuprofen by increasing the drug dissolution rate and its saturation solubility in gastrointestinal fluids. This investigation was thus designed to determine a suitable water-soluble carrier system or SD formulation for ibuprofen. Selection was based on the solubility of the drug in hydrophilic materials and water binary mixtures. In recent years, studies on SDs have mainly focused on the development of new preparation methods and application of the new carriers obtained [3,7-11].

The objective of the present study is to obtain a solid product and improve the solubility and anti-inflammatory effect of ibuprofen. The influence of drug-carrier ratios on the dissolution rate of ibuprofen from SDs is also studied. In most cases, determination of whether the drug is present as a molecule, a crystalline particulate, or an amorphous particulate dispersion is difficult. Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and scanning electron microscopy (SEM) are employed to determine how the drug is dispersed within the matrix and study the nature of molecular interactions in the drug-carrier system. The anti-inflammatory effect of SD-based tablets (SDBTs) is evaluated for the first time using the ear-induced inflammation model with xylene. Ear edema measurements and histology were analyzed. Advantages of simplicity, economy, and improvements in both the dissolution rate and anti-inflammatory effects of ibuprofen in SDBTs indicate that the use of such a carrier system could have promising applications in the future.

Materials and methods

Materials

Medicinal grade ibuprofen was purchased from Baisitu (Fuchibiology, China); all other chemicals used were of analytical grade.

Animals

Male Kunming mice, weighing 17-25 g were used. The animals were housed in standard cages under controlled temperature conditions (25±2 °C) and 12 h light/dark cycle with free access to water and food.

Solubility studies

Solubility studies were carried out by placing excess ibuprofen in glass Erlenmeyer flasks containing 20 ml of different concentrations of dissolution media (i.e., 1%, 2%, 5%, 10% (w/v) urea, PEG4000, and mannitol). The solutions were placed in a water bath at 37±0.5°C with continuous shaking (120 r/min) for 48 h until no further solubilization of the drug was achieved. Resultant samples containing undissolved ibuprofen suspended in the test medium were centrifuged at 10 000 r/min for 5 min. The suspension was then filtered through a filter (0.22 µm, Whatman), and the filtrate was suitably diluted and analyzed spectrophotometrically (UV-2802PCS, Nick Long Instrument Co., Ltd., Shanghai, China) at 222 nm [12] to measure the amount of dissolved ibuprofen. Different concentrations of dissolution media were used as references. The solubility of ibuprofen in water alone at the same temperature was also determined following the same procedure. Experimental values are reported as the average of three replicates [13].

Preparation of ibuprofen-urea solid dispersion and ibuprofen-urea physical mixture

An ibuprofen-urea solid dispersion (IUSD) was obtained by the melt method. Urea was selected as the ibuprofen carrier for SD preparation according to the solubility study. SDs were prepared by melting urea at 140 °C for 5 min in a glass beaker, followed by the addition of ibuprofen (ibuprofen and urea at weight ratios of 1: 1, 1: 2, 1: 5, and 1: 10 were mixed). The mixture was continuously stirred, and the dissolution of ibuprofen in urea was visually recorded. The melt was abruptly cooled with cold water (<4 °C) for about 5 min. Solidified SDs were ground using a mortar and pestle, sieved through a 100-mesh screen, and then dried in vacuum desiccator at room temperature for further application [14]. Ibuprofen and urea at a weight ratio of 1:10 were mixed using a mortar and pestle to obtain an ibuprofen-urea physical mixture (IUPM). The IUPM was then sieved through a 100-mesh screen and stored in a dryer for further application [2].

Study of in vitro release

Wavelength selection

To avoid interferences from urea, the right wavelength must be selected. Spectral scanning of ibuprofen and urea was performed.

Assay of drug content

IUSD and IUPM (theoretical content of 10 mg ibuprofen) were dissolved in 0.1 mol/L NaOH separately. The solution was spectrophotometrically analyzed at 264 nm, a wavelength that is less prone to interferences from urea. A calibration curve was obtained by plotting the absorbance of standard drug solutions against concentration. Drug actual content was calculated from the ibuprofen calibration curve. The experimental values are reported as the average of three replicates [15].

In vitro release

In vitro release studies of ibuprofen, the IUPM, and the IUSD (equivalent to 40 mg of ibuprofen) were performed using an Rcz-6C2 model tablet dissolution test apparatus (Yellow Doping Test Instrument Co., Ltd., China). Release profiles were observed using a dissolution tester according to the paddle method at 100 r/min, with 500 ml of distilled water at 37±0.5 °C as the dissolution medium. Samples (5 ml) were withdrawn after 5, 10, 20, 30, 40, and 60 min and then replaced with distilled water. After filtration (0.22 µm, Whatman), the ibuprofen concentration was spectrophotometrically determined at 264 nm [16].

Mean dissolution time

The mean dissolution time (MDT) was used to compare the different preparations and examine ibuprofen dissolution rates in IUSD and IUPM by quantity. The dissolution data obtained from all the batches were treated according to Eq. (1).

(1)MDTinvitro={\displaystyle \frac{{\displaystyle \sum _{i=\mathrm{1}}^n{t}_{mid}\Delta M}}{{\displaystyle \sum _{i=\mathrm{1}}^n\Delta M}}}

where i is the dissolution sample number, n is the number of dissolution sample times, t_mid is the time midway between times t_i and t_i-1, and ΔM is the amount of ibuprofen dissolved (mg) between times t_i and t_i-1 [17].

Characterization of solid dispersions of ibuprofen with urea

Fourier transform infrared spectroscopy

FTIR spectra were obtained using an FTIR spectrometer (AVATAR-360, Nicolet, USA). The samples (ibuprofen, urea, 1:10 (w/w) IUPM, and 1:10 (w/w) IUSD) were ground and thoroughly mixed with potassium bromide at a sample: potassium bromide weight ratio of 1:5. Potassium bromide discs were prepared by compressing the powders. The spectra were obtained over the range of 4 000 cm^-1 to 400 cm^-1.

Differential scanning calorimetry

DSC measurements were performed using a differential scanning calorimeter (DSC-200pc, NETZSCN, Germany) with thermal analyzer. Approximately 1 mg of sample was placed in a sealed aluminum pan. Testing was performed from 25-200 °C at a scanning rate of 10 C°/min and nitrogen flow rate of 20 ml/min. An empty aluminum pan was used as a reference.

X-ray diffraction studies

Samples were studied by XRD using a diffractometer (D/max-rB, Rigaku Corporation, Japan) with Cu target radiation. The current used was 20 mA, and the voltage was 40 kV. The scanning angles ranged from 2θ of 10° to 70° at steps of 0.02°.

Scanning electron microscopy

The surface morphologies of ibuprofen, urea, 1:10 (w/w) IUPM, and 1:10 (w/w) IUSD were examined using a scanning electron microscope (GEOL, GSM-840, Japan). The powders were fixed on a brass stub using double-sided adhesive tape and made electrically conductive by coating in a vacuum with platinum. Using an accelerating voltage of 15 kV, images were collected at different magnifications.

Preparation of SDBT and analysis of anti-inflammatory effect

Preparation of solid dispersion-based tablet

The wet granulation method was used to prepare an SDBT. Powders of 1:10 (w/w) IUSD, dextrin, sucrose, and starch were mixed. About 20-25 ml of starch solution (8%, w/v) was sprayed on the surface of the mixture and stirred for 15 min. The wet granules were dried in a drying oven at 40 °C for 2 h and then sieved by passing through a 35-mesh screen. Magnesium stearate and sodium hydroxymethyl starch were mixed with the granules. The tablet was prepared using a TDP-5 single punch tablet press (Shanghai Develop Machinery Co., Ltd, China) at a compaction pressure of 10 kN. A conventional ibuprofen tablet was similarly prepared [2]. The conventional tablet (CT) and SDBT formulations are shown in Table 1.

Xylene application-induced mouse ear edema and ear edema measurement

Twenty-four mice were randomly divided into three groups. The oral administration dose of the SDBT and CT was equivalent to 10 mg/kg of ibuprofen. The control group received saline as treatment, once a day, and consecutive 5 days. About 30 min after the last administration, the mice were treated with 20 μl of xylene on the inner and outer surfaces of the right ear (10 μl on each side of the ear). Inflammation occurred after 30 min, and the animals were sacrificed through cervical dislocation. A 6 mm section from each ear was removed using a metal punch and then weighed [18]. Ear edema was determined by the difference in weights of the right and the left ears and expressed as edema weight, using Eq. (2):

(2)\text{Edema weight (\%) = wRE wLE}

where wRE is the circle weight of the right ear (inflamed) and wLE is the circle weight of the left ear (non-inflamed). The inhibition percentage (%) was expressed as the reduction in weight compared with the control group [19].

Histology

Ear biopsies were preserved in formalin, dehydrated, hyalinized, blocked in paraffin, and then sectioned using a microtome. Cross-sections were stained with hematoxylin and eosin to examine leukocyte accumulation and edema intensity [19]. A representative area was selected for qualitative light microscope analysis.

Statistical analysis

Results are presented as mean±S.E.M. The statistical significance of differences between the control and test groups was determined by means of one-way analysis of variance (ANOVA), followed by unpaired student’s t-test. P values less than 0.05 were considered significant [18].

Results

Solubility studies

The solubility profiles of ibuprofen in various aqueous concentrations of urea, PEG4000, and mannitol are shown in Fig. 1, which demonstrates that urea, PEG4000, and mannitol could enhance drug dissolution rates. The solubility of ibuprofen increased as the dissolution medium concentration increased. The dissolution of ibuprofen in PEG4000 and mannitol was lower than in urea. The solubility of ibuprofen clearly increased in the presence of the dissolution medium, with an approximately 17-fold rise noted for the highest concentration of urea compared with water. Hence, urea was selected for the preparation of SDs.

Release profiles of ibuprofen from IUSDs

Ibuprofen showed two characteristic absorption peaks, as can be seen in Fig. 2B. The absorbance at 264 nm was used for ibuprofen quantification, because it was less prone to interferences from urea than the corresponding absorbance at another characteristic absorption peak [20,21], as shown in Fig. 2A.

Drug content analysis confirmed the actual values of ibuprofen in the formulations. The ratios of the actual value and theoretical value ranged from 99.5%±1.8% to 111.1%±10.9%.

The dissolution profiles of pure ibuprofen, IUPM, and IUSDs were investigated, the results of which are shown in Fig. 3. The dissolution rate of ibuprofen from IUSDs was remarkably enhanced compared with that of pure ibuprofen. The dissolution rate of ibuprofen from 1:10 (w/w) IUSD was significantly higher than that from other IUSDs, IUPM, and pure ibuprofen. Solubility increased as the ratio of urea to ibuprofen increased.

The MDT values for pure ibuprofen, IUSDs, and IUPM were obtained by taking the mean of cumulative drug release. MDTs of 815, 897, 861, 745, and 671 s were obtained for the 1:10 (w/w) IUPM and 1:1, 1:2, 1:5, and 1:10 (w/w) IUSDs, respectively. The MDT of ibuprofen dissolved from 1:10 (w/w) IUSD was lower compared with that of other IUSDs, pure ibuprofen, and IUPM. In summary, dissolution rates were influenced by the drug-to-carrier ratio.

The characterization of solid dispersions of ibuprofen with urea

The FTIR spectra of pure ibuprofen, urea, IUPM, and IUSD are shown in Fig. 4. In the FTIR analysis, the spectrum of pure ibuprofen showed an intense, well-defined infrared band at around 1 721 cm^-1 (carbonyl-stretching of isopropionic acid group), another band at around 3 000 cm^-1 (hydroxyl group of carboxylic acid) [4], and a band at around 942 cm^-1 as fingerprints; urea showed broad characteristic bands at 1 698, 1 637, 1 469, and 1 159 cm^-1. IUSD and IUPM spectra were similar to the added spectra of their individual components. A decrease in the intensity of the ibuprofen peak was observed in IUSD and IUPM. These results suggest that ibuprofen and urea have no physicochemical interaction.

DSC thermograms (Fig. 5) of pure ibuprofen and urea show melting points at 74.86 °C and 140 °C, respectively. In IUSD and IUPM, a sharp peak was found at 140 °C and a small broad endothermic peak was observed at around 60-70 °C.

The powder XRD patterns of ibuprofen, urea, IUPM and IUSD are shown in Fig. 6. Ibuprofen exhibited high-intensity peaks at 12.08°, 16.40°, 17.52°, 18.92°, 20.02°, 22.14°, 28.34°, and so on. The diffraction spectra of pure ibuprofen show that the drug is highly crystalline in nature, as indicated by the numerous distinctive peaks obtained. Urea exhibited high-intensity peaks at 21.06°, 22.02°, 24.52°, 29.18°, 31.4°, 35.34°, and so on. Principal peaks from ibuprofen and urea were present in the IUPM and IUSD, although with lower intensities. In IUSD, the diffraction peaks of ibuprofen were low in intensity compared with those of pure ibuprofen. Thus, a small crystalline portion of ibuprofen is believed to exist in IUSDs.

SEM images of pure ibuprofen, urea, IUPM, and IUSD are shown in Fig. 7. Ibuprofen appeared as smooth-surfaced needle crystalline structures (A), and urea appeared as rectangular particles (B). IUPM contained individual ibuprofen and urea particles (C), and IUSD appeared as a uniform and homogeneously mixed mass with wrinkled surfaces (D).

Effect of SDBT and CT on xylene-induced mice ear edema

CT and SDBT exhibited inhibitory effects on inflammation induced by xylene (Table 2). At 10 mg/kg of ibuprofen, SDBT and CT caused significant edema reduction in ears sensitized with xylene.

Histology

Mice treated with CT and SDBT showed reductions in infiltration of inflammatory cells and lower dermis thickness of the ears (Figs. 8C and 8D) compared with the inflamed ear treated with saline (Fig. 8B); mice treated with SDBT (Fig. 8D) showed more obvious effects. According to our histological analysis, a significant increase in both dermis thickness and inflammatory cell infiltration was observed (Figs. 8B to 8D) in ears sensitized with xylene compared with non-inflamed ears (Fig. 8A).

Discussion

The solubility studies demonstrate that urea, PEG4000, and mannitol could enhance drug solubility. The dissolution of ibuprofen was higher in urea than in PEG4000 or mannitol. This result may be due to the wetting effect of the highly water-soluble urea in intimate contact with ibuprofen. Urea, an end-product of human protein metabolism, has a light diuretic effect and is non-toxic. Its solubility in water is greater than 1 in 1, and it exhibits good solubility in many common organic solvents [5]. The solubility of ibuprofen increased as the dissolution medium concentration increased. In other words, the solubility of ibuprofen is influenced by the type and concentration of the water-soluble carrier in which it is dissolved.

On the basis of the study of in vitro release, enhancements in ibuprofen dissolution from IUSDs may depend on the drug-to-carrier ratio. Our results show that the dissolution rate of the drug from IUPM was somewhat enhanced compared with pure ibuprofen. We can assume that when the IUPM was introduced into the dissolution medium, the urea rapidly dissolved and attained a very high vehicle concentration in the diffusion layer of the drug [13]. The presence of this dissolved urea increased the drug solubility in the diffusion layer, thereby increasing the dissolution rate of ibuprofen. The dissolution rate of ibuprofen from the 1:10 (w/w) IUSD was significantly higher than that from the 1:10 (w/w) IUPM or ibuprofen alone. The use of the IUSD is thus attributed for the improved wetting of the ibuprofen crystal surface due mainly to attached urea particles, which provoke solubilizing effects. The carrier attracted the dissolution medium and increased its amount in the immediate vicinity of the ibuprofen surface. Furthermore, the arrangement of the carrier physically separated drug particles, preventing their aggregation after introduction of the solid-dispersed system to the dissolution medium [22].

The FTIR spectrograms suggest that ibuprofen and urea have no physicochemical interaction (Fig. 4); the similar thermal behavior of IUSD and IUPM corroborates this finding. DSC thermograms of IUSD show a melting peak of urea at 140 °C and a small broad endothermic peak at around 60-70 °C, which suggests that a small crystalline portion of ibuprofen exists in the IUSD. Many studies have indicated that the melting behaviors of the SD and PM of the drug and carrier may be extremely similar and that the presence of the carrier in the molten state may itself lower the melting point of the drug [23].

The higher dissolution rate of the drug from the 1:10 (w/w) IUSD relative to that from the 1:10 (w/w) IUPM could also be ascribed to reductions in the crystal size of ibuprofen and the improved wetting of the ibuprofen crystal surface [22], as determined by SEM (Fig. 5); these features induce solubilizing effects. Alteration of the solid state of ibuprofen was confirmed by the decrease in ibuprofen diffraction peak intensity in the XRD patterns (Fig. 6). The crystallinity of ibuprofen was markedly low in IUSD, which suggests that the increased dissolution rates of ibuprofen from the SDs were a result of the decrease in its crystallinity. This finding suggests that IUSD can alter the solid state of the drug and thus enhance dissolution. Analogous phenomena were previously reported by many researchers [3,24].

XRD displayed the presence of ibuprofen peaks in IUSD and a perfect similarity between the diffraction spectra of IUPM and IUSD. These observations prove that ibuprofen remains unaltered after its manufacture as an SD and that crystallization of urea does not modify the crystalline structure of ibuprofen. Moreover, no new peaks were observed, suggesting the absence of interaction between ibuprofen and urea. These results suggest that ibuprofen and urea have no physicochemical interaction. Hence, ibuprofen showed complete chemical stability after its preparation as an SD.

Ear edema measurements and histological analysis of ears sensitized with xylene revealed that SDBT causes significant edema reduction. SD may improve the anti-inflammatory effect of ibuprofen by increasing its saturation solubility in gastrointestinal fluids.

In conclusion, the solubility and dissolution rate of ibuprofen were enhanced by the preparation of IUSDs through a relatively easy, simple, quick, and inexpensive method. The immediate release of free ibuprofen from IUSDs led to rapid absorption and improved anti-inflammatory effects compared with pure ibuprofen. The present study demonstrated the relevant topical anti-inflammatory effect of IUSDs on mouse ear edema induced by xylene and indicated its potential application as a treatment for inflammatory diseases. Preliminary results from this work suggest that the preparation of IUSDs could be a promising approach toward improving the solubility, dissolution, anti-inflammatory effect, and absorption rate of ibuprofen.

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