Abstract
Objectives: This study aimed to improve the solubility in water and bioavailability in vivo of lurasidone hydrochloride (LUR). Methods: The saturated aqueous solution method was used to prepare an inclusion complex of LUR with sulfobutylether-β-cyclodextrin, or SBE-β-CD (LUR-SBE-β-CD). A single-factor test was used for the preliminary screening of important preparing conditions including the ethanol concentration, the SBE-β-CD concentration, temperature, and pH. Then central composite design response surface methodology (CCD) was adopted for the optimum craft. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and powder X-ray diffraction (PXRD) were used to confirm the formation of LUR-SBE-β-CD. The in vitro release profiles of LUR-SBE-β-CD were determined at different pHs and in simulated gastrointestinal fluid. Results: The dissolution studies revealed that the dissolution of LUR in LUR-SBE-β-CD was much improved in the four media and simulated gastrointestinal fluid. Similar profiles of LUR-SBE-β-CD were obtained in pharmacokinetic studies whether beagle dogs took food or not. Conclusions: The bioavailability of LUR can be improved and the food effect can be eliminated by LUR-SBE-β-CD.
Keywords: Lurasidone hydrochloride, sulfobutylether-β-cyclodextrin, inclusion complex, bioavailability, food effect
Introduction
Solubility studies of drugs have shown that 40% of agents are found to be poorly soluble in water. This percentage has even reached 80~90% in various therapeutic areas [1,2]. This is according to the Biopharmaceutics Classification System (BCS), in which BCS II drugs, which have high permeability but poor aqueous solubility, have poor oral bioavailability [3,4].
Lurasidone hydrochloride (LUR), an antagonist of dopamine (D2) and serotonin (5-HT2A), is a novel benzisothiazole, second-generation and orally antipsychotic agent (Latuda®) [5,6], which has been used in the treatments of adult schizophrenia [7,8]. LUR, a drug that belongs to BCS II drug category, is poorly soluble in water (only 0.224 mg/ml in plain water), which leads to low bioavailability (estimated to be about 9 to 19%). Taking the drug in the fed state may influence the dissolution and absorption of LUR in the gastrointestinal tract (GI) [9]. Previous research showed that lurasidone absorption was affected by food consumption. Compared with a fasted state, the absorption of lurasidone increased by two-fold when administered with food, as well as the maximum concentration (Cmax ) increased by three-fold. Moreover, the Tmax was prolonged by 0.5~1.5 h in the fed state. Because food can affect the LUR bioavailability significantly, a minimum of 350 calories of food is recommended before the taking of the drug [10,11]. Therefore, enhancing the solubility and dissolution properties of LUR might improve its absorption in the GI, as well as the bioavailability of LUR. To sum up, improving oral bioavailability without food effect should be taken into account.
A good amount of research has been conducted on improving the solubility and oral bioavailability of LUR. Miao [12] found that a self-nanoemulsifying technology can improve the bioavailability of LUR and diminished food interference. Kumar and Burgess [13] adopted the Nano suspensions system of LUR to increase the dissolution. However, shortcomings are existent; for example, the low drug loading and poor stability of these drug delivery systems limit their development.
Cyclodextrin is a cyclic oligosaccharide [14] in which the inner central cavity is hydrophobic and the outer surface is hydrophilic. Those molecules can partly or all enter the interior cavity of cyclodextrin [15-17]. The physicochemical characteristics of molecules encapsulated may be affected, such as their dissolution, solubility, and bioavailability. But the low aqueous solubility restricts the practical application of the natural form. So, modified cyclodextrins that possess better physical and chemical properties emerged as required, including carboxymethyl-β-cyclodextrin (CM-β-CD), methyl-β-cyclodextrin (M-β-CD), sulfobutylether-β-cyclodextrin (SBE-β-CD). SBE-β-CD [18] (its trade name is Captisol®), a biocompatible and non-toxic CD derivative, exhibits complexing abilities and better solubility than the parent β-CD [19,20]. It has been widely applied to the field of pharmacy. Compared with other CD derivatives, the outer hydrophilic and inner hydrophobic residues are more obvious due to the repulsion of the end group’s negative charge coupled with the four-carbon butyl chain of SBE-β-CD [21,22]. Hence, inclusion complexes with cyclodextrin should be an effective method to solve the problems above.
A saturated aqueous solution method was utilized to prepare LUR-SBE-β-CD. Single-factor test and CCD are used for the optimization of important preparing conditions of LUR-SBE-β-CD.
In the research, the saturated aqueous solution method was used. Single-factor test and CCD are used for the optimization of important preparing conditions of LUR-SBE-β-CD. The phase solubility was studied and PXRD, DSC, SEM, and FTIR were used to characterize LUR-SBE-β-CD. Also, the dissolution studies of LUR-SBE-β-CD were evaluated. In the end, the pharmacokinetics and bioavailability of LUR-SBE-β-CD were evaluated in beagle dogs by oral medication.
Materials and methods
Materials
SBE-β-CD (DS = 7; Mw = 2241) was obtained from Yuanzhu Technology Co. Ltd (Taizhou, China). LUR was presented by Nhwa Pharmaceutical Co. Ltd (Xuzhou, China). Latuda® (40 mg, tablet) was purchased from Sumitomo Dainippon Pharma. Co. Ltd (Japan).
Phase solubility studies
The effect of SBE-β-CD on the solubility of LUR was evaluated in this experiment. Briefly, A series concentration (5, 10, 20, 30, and 40 m/v) of SBE-β-CD solutions with excess LUR were prepared for this experiment. Samples were vibrated at 25°C for 24 h with an oven-controlled oscillator. LUR concentration was measured by the validated method based on HPLC analysis. The chromatographic system (Shimadzu, Japan) was purchased from Japan. 20 µL volume of samples was injected into a Baseline® C18 Column (4.6 × 250 mm, 5 µm) and the detection wavelength was 230 nm. The flow rate was 1.0 ml/min with a 50:50 (v/v) mixture of acetonitrile and 10 mM of phosphate buffer (pH 3.0) at 30°C. The following equation was used to calculate the complex formation constant (Ks) (Equation 1):
 |
Where slope represents the and slope of linear equation and S0 represent the solubility of LUR with SBE-β-CD.
Method of preparing LUR-SBE-β-CD
LUR-SBE-β-CD was prepared with a saturated water solution. First, the pH of the SBE-β-CD aqueous solution was adjusted with 0.1 M NaOH or HCl. Next, LUR was dissolved in ethanol and dropped into SBE-β-CD aqueous solution slowly. After that, the mixed suspension was dried for the soft paste at 50°C and it was washed three times by methylene chloride to further separate the uncomplexed LUR. Finally, the inclusion complex was harvested by drying in a vacuum drying oven at 35°C for 4 h and sieving through a 50-mesh sieve (the aperture of which is 300 μm).
Evaluation index
Typically, encapsulation efficiency (EE) and drug loading efficiency (DE) are determined to evaluate the inclusion efficiency. In this study, samples were obtained by dissolving LUR-SBE-β-CD in ethanol through ultrasound. LUR content in the inclusion complex was detected by HPLC. The following equations were used for the calculation of EE and DE (Equations 2, 3).
 |
 |
Single-factor test
The EE and DE of LUR-SBE-β-CD were affected by ethanol concentration, temperature, the amount of SBE-β-CD and pH. The initial conditions were 40°C, 20% ethanol, 20% SBE-β-CD and pH 4 for the single-factor experiment. When one of these factors varied, the other values of factors were fixed. All preparation processes are described above in Method of preparing LUR-SBE-β-CD.
Central composite design response surface methodology (CCD)
Factors that significantly affect DE and EE of LUR-SBE-β-CD were optimized by CCD with Design-Expert 8.0.6 software. The CCD with three factors and five levels was designed. The values of pH, concentration of ethanol, and SBE-β-CD were selected. The interrelated CCD are presented in Table 1.
Table 1.
Three factors and five levels of central composite design
| Variables | Scopes and levels | ||||
|---|---|---|---|---|---|
|
| |||||
| -1.682 | -1 | 0 | 1 | 1.682 | |
| Concentration of ethanol (A, %) | 3.18 | 10 | 20 | 30 | 36.82 |
| pH (B) | 2.32 | 3 | 4 | 5 | 5.68 |
| Concentration of SBE-β-CD (C, %) | 8.18 | 15 | 25 | 35 | 41.82 |
Characterization and solubility studies
FTIR studies
FTIR spectrometer (Shimadzu Corporation, Japan) was used in this experiment. Before the experiment, KBr mixed with samples was finely ground. Infrared transparent matrices were obtained with a hydrostatic press and spectra must be collected from 400~4000 cm-1, and the resolution was 4 cm-1.
DSC studies
LUR, SBE-β-CD, physical mixtures and LUR-SBE-β-CD were characterized using Phoenix DSC-204 thermal instrument (Phoenix Corporation, Selb, Germany). Samples were added in pans and heated from 40°C to 400°C with a rate of 10°C/min.
PXRD studies
Crystal forms of LUR, SBE-β-CD, physical mixture, and LUR-SBE-β-CD were characterized by PXRD analysis. This study was performed employing a Philips FW 1700 X-ray diffractometer with a voltage of 40 kV. Samples were scanned from 5° to 50° with a speed of 0.02°/s.
SEM studies
LUR, SBE-β-CD, physical mixture, and LUR-SBE-β-CD were studied by SEM (JSM-5800, JOEL, Tokyo, Japan) at 15 kV for the surface morphology. Before SEM observation, samples coating with platinum were fixed on a brass stub in the vacuum.
Saturation solubility
Solubility studies of samples were determined by the excess amount of LUR API and LUR-SBE-β-CD in four dissolution media: hydrochloric acid (pH 1.2), acetum (pH 4.5), phosphate buffer (pH 6.8) and water (pH 7.0). Vibrating the solutions was done for 48 h, with the temperature stable at 37°C, then, filtering the solutions was done and the HPLC method was used as mentioned above to determine solubility. The experiments were repeated three times.
In vitro dissolution studies
Dissolution studies of LUR-SBE-β-CD and Latuda® were conducted in the paddle method by using a six-vessel dissolution tester (Shanghai Huanghai Instrument Co. China). Four dissolution mediums with different pH were added with the temperature of 37°C and stirred at 50 rpm. At 5, 10, 15, 20, 30, 45, 60 and 90 mins, 5 mL of the sample was taken and the equivalent volume of temperature equilibrated medium was added in 15 s. The samples were filtered and determined by HPLC.
The similarity factor f2 was determined to estimate the similarity degree of dissolution curves of LUR-SBE-β-CD and Latuda® in different media. The following equation was used for the calculation of f2 [23] (Equation 4).
 |
In the equation, n is the number of the time points, Rt represents the accumulated release rate of Latuda® and Tt is the accumulated release rate of LUR-SBE-β-CD.
For two profiles, the value of f2 was between 0~100. The larger f2 is, the higher the similarity between the two dissolution curves. The value of f2 from 50 to 100 means that the release profiles have a similarity. On the contrary, the value of f2 from 0 to 50 means that the two release profiles have no similarities.
Pharmacokinetics studies in dogs
Given relevant research [19], 8 healthy beagle dogs (female and male each half, 2~3 years old), weighing 14.85±1.37 kg, were used in our experiments (The experiment was approved by the Nanjing Medical University Institutional Animal Care and Use Committee (No. 201410113). All experimental operations adhered to the “Principles of Laboratory Animal Care”). In a light-controlled room, every standard cage only had one beagle dog. The temperature of the room was 20°C.
The pharmacokinetic study of LUR-SBE-β-CD (6.98 mg/kg, 103.7 mg) and reference formulation of Latuda® (1.25 mg/kg, 18.56 mg) were tested in beagle dogs with the 4 × 4 crossover experiment. Beagle dogs were tested in two states: fasted and fed conditions (washout period is 7 days). Before the experiment, the total of 8 beagle dogs were randomly divided into 4 groups (half male and half female) and the specific experimental design was shown in Table 2. In fasted studies, beagle dogs had fasted for 12 h, and the dogs were free to drink water. After 24 h of experimental study, dogs could be free to eat dry dog food. At 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 h, 4 ml blood samples were collected from the forelimb of dogs with sodium heparin tubes. Before analysis, the samples were centrifuged at 4000 rpm for plasma.
Table 2.
Dosage regimen of LUR-SBE-β-CD inclusion complex and Latuda® in beagle dogs (n = 2)
| Group | Period 1 | Period 2 | Period 3 | Period 4 |
|---|---|---|---|---|
| 1 | A | D | B | C |
| 2 | B | A | C | D |
| 3 | C | B | D | A |
| 4 | D | C | A | B |
A: Commercial product (fasted). B: Commercial product (fed). C: LUR-SBE-β-CD (fasted). D: LUR-SBE-β-CD (fed).
Then, 1 mL plasma was mixed with 40 μL Ziprasidone (2 μg/mL, internal standard) and then mixed with 5.0 mL ethyl acetate. The supernatant was collected and dried with N2. Finally, the samples were analyzed with the HPLC method above. Pharmacokinetic parameters were calculated according to the non-compartment model.
Statistical analysis
All statistical values in this experiment were analyzed with Origin 8.6. and shown as the M ± SD. All statistical comparisons were performed using one-way ANOVA, and P-value <0.05 was considered significant.
Results and discussion
Phase solubility studies
Results of the phase solubility equilibrium diagram from Figure 1 indicated that the concentration of LUR and SBE-β-CD have a linear relationship between 0~25 mM. The complexation between LUR and SBE-β-CD was extrapolated to be an AL-type based on Higuchi and Connors by linear fitting (y = 0.568x + 0.138) with a correlation coefficient of 0.999. The type of plot showed a stoichiometric rate of 1:1 molecular complexation between SBE-β-CD and LUR. The complex formation constant, Ks, was 9527.6 M-1, indicating that the stability of LUR-SBE-β-CD was good.
Figure 1.
Phase solubility diagram plotted with concentration of LUR against increasing concentration of SBE-β-CD in water.
Experimental design
Single-factor test
To obtain the desired EE and DE, preparing conditions were filtered through the single-factor test. As shown in Figure 2A, the EE and DE acquired a rapid growth as the temperature was rising in the initial of reaction, and obtained a maximum value at about 50°C. There was no obvious trend in growth when the temperature was over 50°C. According to Figure 2B, the concentration of ethanol was one of the most significant factors. As depicted in Figure 2C, pH was also a vital factor. The curve showed a characteristic of a downtrend when pH was below 3 or over 5, which indicated that the optimum pH range was 3~5, corresponding to the pKa (4.65) of LUR. Figure 2D shows that encapsulation efficiency and drug loading efficiency increased with the concentration of SBE-β-CD.
Figure 2.
Effect of temperature (A), concentration of ethanol (B), pH (C) and concentration of SBE-β-CD (D) on loading efficiency and encapsulation efficiency (n = 3).
The concentrations of SBE-β-CD, ethanol, and pH were found to be the most important factors while the temperature was the least important factor in this study. The single-factor test was an impactful test that underlay the further optimization.
Central composite design and statistical analysis
20 experiments investigated the influence of the preparing conditions on the EE and DE. Times of experiments were produced by software and the relevant data of 20 experiments are shown in Table 3. Experimental data and the two polynomial equations under the coding factor were analyzed by Design-expert 8.0.6 software.
Table 3.
The central composite design and response value of each factor level
| Run | Critical factor | Response | |||
|---|---|---|---|---|---|
|
|
|
||||
| Concentration of ethanol (%) | pH | Concentration of SBE-β-CD (%) | Drug loading efficiency (%) | Encapsulation efficiency (%) | |
| 1 | 10.00 | 3.00 | 15.00 | 15.90 | 82.59 |
| 2 | 36.82 | 4.00 | 25.00 | 14.50 | 78.38 |
| 3 | 10.00 | 3.00 | 35.00 | 15.88 | 83.56 |
| 4 | 20.00 | 4.00 | 25.00 | 17.90 | 89.32 |
| 5 | 20.00 | 4.00 | 25.00 | 18.00 | 90.30 |
| 6 | 20.00 | 4.00 | 8.18 | 16.09 | 84.32 |
| 7 | 30.00 | 5.00 | 35.00 | 15.02 | 82.97 |
| 8 | 20.00 | 4.00 | 25.00 | 17.81 | 91.25 |
| 9 | 20.00 | 4.00 | 41.82 | 16.81 | 85.78 |
| 10 | 30.00 | 3.00 | 35.00 | 15.06 | 82.98 |
| 11 | 20.00 | 2.23 | 25.00 | 16.03 | 84.01 |
| 12 | 30.00 | 5.00 | 15.00 | 15.99 | 83.66 |
| 13 | 20.00 | 5.68 | 25.00 | 16.56 | 85.00 |
| 14 | 20.00 | 4.00 | 25.00 | 17.97 | 90.56 |
| 15 | 20.00 | 4.00 | 25.00 | 17.88 | 91.38 |
| 16 | 30.00 | 3.00 | 15.00 | 15.98 | 83.75 |
| 17 | 3.18 | 4.00 | 25.00 | 14.83 | 78.22 |
| 18 | 10.00 | 5.00 | 35.00 | 15.38 | 82.99 |
| 19 | 10.00 | 5.00 | 15.00 | 15.83 | 82.09 |
| 20 | 20.00 | 4.00 | 25.00 | 17.79 | 89.88 |
DE = 17.89 - 0.11 × A + 0.021 × B - 0.084 × C + 0.068 × A × B - 0.018 × A × C - 0.06 × BC - 1.15 × A2 - 0.57 × B2 - 0.52 × C2
EE = 90.42 - 0.18 × A + 0.036 × B + 0.21 × C + 0.12 × A × B - 0.42 × A × C + 0.0012 × BC - 4.1 × A2 - 1.9 × B2 - 1.71 × C2
Where the concentration of ethanol, pH, and the concentration of SBE-β-CD are represented by A, B and C. The variation of samples in DE and EE was attributable to the experimental factors because the correlation coefficient (R2) were 0.9984 and 0.9806. From Figure 3A and 3B, DE and EE showed an initial increase and then decrease slightly with the increase of ethanol concentration. As shown in Figure 3C and 3D, DE and EE increased slowly as the SBE-β-CD grew. Figure 3E and 3F implied that DE and EE decreased with the decrease of pH value. The best formulation conditions for preparing LUR-SBE-β-CD could be predicted by the equation and the response surface. The optimized conditions that were determined were: concentration of ethanol 19.88% (v/v), pH 4.01, concentration of SBE-β-CD 24.88% (w/v) and the predicted DE and EE was 17.9% and 90.4%. According to the optimum conditions, the DE and EE of LUR-SBE-β-CD prepared were 17.65% and 89.2%, which is close to the predicted values. Finally, the conditions above were selected as the best process for preparing LUR-SBE-β-CD.
Figure 3.
Response surface plots showing the effects of concentration of ethanol (A and B), concentration of SBE-β-CD (C and D) and pH (E and F) on drug loading efficiency and encapsulation efficiency.
Characterization and solubility studies
FTIR studies
As shown in Figure 4, LUR-associated peaks of LUR and physical mixture were nearly identical. The characteristic peak of LUR in LUR-SBE-β-CD at 1687 cm-1 was markedly reduced. The diagnostic peaks of LUR in inclusion complexes located at 1562 cm-1 and 778 cm-1 also disappeared, suggesting LUR-SBE-β-CD was successfully prepared and LUR entered the cavity of SBE-β-CD. In addition, no new chemical bonds were found in LUR-SBE-β-CD, which indicated that there were no chemical reactions in the process.
Figure 4.
Infrared spectrogram of LUR (A); SBE-β-CD (B); physical mixture of LUR and SBE-β-CD (C) and LUR-SBE-β-CD inclusion complex (D).
DSC studies
DSC thermogram of LUR, SBE-β-CD, physical mixture, and LUR-SBE-β-CD are presented in Figure 5. LUR has one endothermic peak at 277°C and one exothermic peak at 281°C, while SBE-β-CD has one endothermic peak at 279°C. The DSC curve of the physical mixture was more like an overlap of endothermic peaks from LUR and SBE-β-CD. The curve of LUR-SBE-β-CD revealed the complexation of LUR in SBE-β-CD, indicating that no chemical reactions occurred during the preparation of LUR-SBE-β-CD.
Figure 5.
DSC of SBE-β-CD (A); LUR (B); LUR-SBE-β-CD inclusion complex (C); physical mixture of LUR and SBE-β-CD (D).
PXRD studies
As can be seen from Figure 6, LUR was crystalline as demonstrated by numerous distinct peaks, while no obvious diffraction peaks in SBE-β-CD. The physical mixture of LUR and SBE-β-CD showed multiple diffraction peaks, which could be regarded as the superposition of the diffraction peaks of two substances. On the other hand, the crystalline of the drug in the inclusion complex was reduced or a change was induced in the crystal orientation, illustrating LUR and SBE-β-CD can strongly affect each other.
Figure 6.
Powder X-ray diffraction patterns of LUR (A), SBE-β-CD (B), physical mixture (C) and LUR-SBE-β-CD inclusion complex (D).
SEM studies
Morphology of SBE-β-CD exhibited a round and smooth state while obvious crystallite structure was provided with LUR API (Figure 7A). The physical mixture (Figure 7C) contained individual LUR and SBE-β-CD particles with irregular morphology. No crystallites associated with LUR or heterogeneous phases were observed in LUR-SBE-β-CD (Figure 7D), demonstrating the complete entrapment of LUR into the cavities of SBE-β-CD.
Figure 7.
Scanning electron micrographs of LUR (A); SBE-β-CD (B); Physical mixture of LUR and SBE-β-CD (C); Inclusion complex of LUR and SBE-β-CD (D).
Solubility studies
LUR-SBE-β-CD and LUR API were tested in four dissolution mediums (pH 1.2, pH 4.5, pH 6.8 and pH 7) and shown in Figure 8. Compared with LUR API, the solubility of LUR in inclusion complex was dramatically enhanced, over 29.8, 5.4, 39.3 and 37 times higher in the different media, which indicated that LUR-SBE-β-CD was a successful formulation to solubilize LUR.
Figure 8.
Saturation solubility of LUR and LUR-SBE-β-CD in pH 1.2, 4.5, 6.8 and water (pH 7). All values were shown as mean ± SD (n = 3).
In vitro dissolution studies
Dissolution profiles of LUR-SBE-β-CD and Latuda® in different dissolution mediums were given in Figure 9. From the figures, Latuda® acquired the highest cumulative dissolution in pH 1.2 (>85%) and the lowest dissolution in pH 6.8 (<3%). The precipitation would occur when commercial product in pH 4.5 solution. In contrast, LUR-SBE-β-CD showed a higher release characteristic of more than 85% in the four solutions. This revealed that the inclusion complex might diminish the effect of pH variability on LUR. As the results showed, the cumulative dissolution of LUR was increasing when LUR-SBE-β-CD was formed and almost not affected by pH. Figure 10 describes the in vitro dissolution curves of LUR-SBE-β-CD and Latuda®. From Figure 10A, the cumulative dissolution of the commercial product was 35% in Fasted State Simulating Gastric Fluid (FaSSGF) and 87% in Fed State Simulating Gastric Fluid (FeSSGF) at 90 min. The precipitation phenomenon appeared and the dissolution rate decreased in the later period. Notably, the commercial products showed an incomplete dissolution and no similarity in FaSSGF and FeSSGF. From Figure 10B, the cumulative dissolution of LUR in LUR-SBE-β-CD was 86% in FaSSGF and 96% in FeSSGF. From Figure 10C, in FaSSIF/FeSSIF, the cumulative dissolutions of commercial tablets was 25% and 49%, respectively. The release profile of the two drugs in vitro was not alike because the value of f2 value was 30. As Figure 10D shows, the cumulative dissolution of LUR in the inclusion complex was up to 90%. The similarity factor f2 of release profiles was 57. Generally, the higher the value of f2 , the more similar the two release profiles. This revealed that the dissolution curves of LUR-SBE-β-CD were similar in FaSSIF/FeSSIF, which diminished the effect of gastrointestinal tract environments and preliminarily proved that food had no influence on LUR-SBE-β-CD. The food effect on LUR could not be completely explained by this study, thus the explanation of potential food interactions was further studied in vivo by pharmacokinetics studies in beagle dogs.
Figure 9.
Dissolution profiles of LUR-SBE-β-CD inclusion complex and commercial product in pH 1.2 (A), pH 4.5 (B), water (pH 7) (C) and pH 6.8 (D).
Figure 10.
Drug release profiles of commercial product (A: Latuda® in simulated gastric fluid; C: Latuda® in simulated intestinal fluid) and LUR-SBE-β-CD (B: LUR-SBE-β-CD in simulated gastric fluid; D: LUR-SBE-β-CD in simulated intestinal fluid).
Pharmacokinetics studies in dogs
The pharmacokinetic curves of LUR-SBE-β-CD and Latuda® in beagle dogs with food or not are given in Figure 11 and the pharmacokinetic parameters are presented in Table 4. LUR was absorbed rapidly after oral administration. The values of Tmax of commercial products in fasted and fed states were 1.0±0.5 h and 0.9±0.4 h. Similarly, the values of Tmax of inclusion complex in fasted and fed state observed from Table 4 were 1.0±0.3 h and 0.9±0.6 h, respectively. The bioavailability of Latuda® in the fed state was taken as the reference (100%). The relative bioavailability of commercial products in the fasted state was only 69.0%, indicating that absorption of the commercial products was affected by food. In contrast, the relative bioavailability of LUR-SBE-β-CD was the same in fasted (98.8%) and fed (109.0%) states. Statistical analysis reveals that value of Cmax , AUC (0-t) and AUC (0-∞) of the commercial product was different (P<0.05) in fasted and fed state. However, these parameters were almost the same in the inclusion complex in the two states (P>0.05). This shows that the LUR-SBE-β-CD inclusion complex had successfully improved the oral bioavailability of LUR without taking food; as a result, it was rarely affected by food.
Figure 11.
Mean dose-normalized lurasidone concentration-versus-time profiles after administration of LUR-SBE-β-CD complex and commercial product (tablet, Latuda®) in fasted and fed dogs (n = 8).
Table 4.
Pharmacokinetic values of LUR in beagle dogs after oral administration of LUR-SBE-β-CD complex and commercial product (Latuda®) (n = 8)
| Commercial product (fed) | Commercial product (fasted) | LUR-SBE-β-CD (fed) | LUR-SBE-β-CD (fasted) | |
|---|---|---|---|---|
| Cmax (ng/ml) | 384.9±78.1 | 210.0±64.5# | 415.7±83.9* | 368.7±69.9* |
| Tmax (h) | 1.0±0.5 | 0.9±0.4 | 1.0±0.3 | 0.9±0.6 |
| AUC (0-t) (ng/ml h) | 2128±142 | 1414±91# | 2272±154* | 2085±133* |
| AUC (0-∞) (ng/ml h) | 2180±166 | 1505±101# | 2376±155* | 2155±120* |
| Relative bioavailability (%) | 100 | 69.0 | 109.0 | 98.8 |
P<0.05 compared with Commercial product (fed).
P>0.05 compared with Commercial product (fed).
Conclusions
In this research, LUR was poorly soluble in water but was successfully developed to be a novel oral formulation with diminished food effect. The mole ratio of LUR and SBE-β-CD was determined by phase solubility studies. The preparing conditions of the saturated water solution method were successfully optimized by the single-factor test and CCD. Characterization studies proved the formation of LUR-SBE-β-CD. The dissolution test revealed that variational gastroenteric environments and different release mediums almost did not affect the release behaviors of the LUR-SBE-β-CD inclusion complex in comparison with the commercial product. Compared with the commercial product, the bioavailability of inclusion complex exhibited an important enhancement and the food effect on drug absorption could be ignored. Therefore LUR-SBE-β-CD was a developed formulation that could improve the bioavailability of the water-insoluble drugs in the fasted state.
Acknowledgements
This work was supported by the National Science and Technology Major Project (No: 2019zx09301057).
Disclosure of conflict of interest
None.
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