Quetiapine fumarate is an antipsychotic drug with poor oral bioavailability (9%) due to first-pass metabolism. Present work is an attempt to improve oral bioavailability of quetiapine fumarate by incorporating in solid lipid nanoparticles (SLN). Six quetiapine fumarate SLN formulations were developed using three different lipids by hot homogenisation followed by ultrasonication. The drug excipient compatibility was studied by differential scanning calorimetry (DSC). Stable quetiapine fumarate SLNs having a mean particle size of 200–250 nm with entrapment efficiency varying in between 80% and 92% were developed. The physical stability of optimized formulation F3 was checked at room temperature for 2 months. Comparative bioavailability studies were conducted in male Wistar rats after oral administration of quetiapine fumarate suspension and SLN formulation. The relative bioavailability of quetiapine fumarate from optimized SLN preparation was increased by 3.71 times when compared with the reference quetiapine fumarate suspension. The obtained results are indicative of SLNs as potential lipid carriers for improving the bioavailability of quetiapine fumarate by minimizing first-pass metabolism.
Quetiapine fumarate is an antipsychotic drug with plasma half life of 6 h and poor oral bioavailability (9%) due to extensive first-pass metabolism [
Solid lipid nanoparticles (SLNs) are an alternative nanoparticulate carrier system to polymeric nanoparticles, liposomes, and o/w emulsions [
There are very few reports in literature describing the use of SLNs for bypassing first-pass metabolism. When all-trans-retinoic acid was loaded into SLNs, the oral bioavailability in rats was increased four- to five-fold compared with that of suspension [
In the present study, the quetiapine fumarate loaded SLNs were prepared using glyceryl trimyristate, glyceryl tristearate, and glyceryl monostearate as lipids by hot homogenization followed by ultrasonication method. The prepared SLNs were characterized, and an optimized SLN formulation was used to assess the oral bioavailability improvement of quetiapine fumarate.
Quetiapine fumarate was obtained as a gift sample from Aurobindo Labs, Hyderabad. Dynasan 114 (glyceryl trimyristate), Dynasan 118 (glyceryl tristearate) and Imwitor 900P (glyceryl monostearate) (Sasol, Witten, Germany), egg lecithin (Lipoid, Germany), Poloxamer-188 (Himedia, Mumbai), chloroform (Qualigens, India), methanol (Rankem, India), dialysis membrane (HiMedia, Mumbai) were purchased from the local market. All the other reagents used were of analytical grade.
Quetiapine fumarate loaded SLNs were prepared by hot homogenization followed by the ultrasonication [
Composition of quetiapine fumarate loaded SLN formulations and suspension.
Formulation ingredient | Formulation code | ||||||
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F1 | F2 | F3 | F4 | F5 | F6 | F7 | |
Organic phase | |||||||
Quetiapine fumarate |
10 | 10 | 10 | 10 | 10 | 10 | — |
Dynasan-114 (mg) | 100 | 200 | — | — | — | — | — |
Dynasan-118 (mg) | — | — | 100 | 200 | — | — | — |
Imwitor 900P (mg) | — | — | — | — | 100 | 200 | — |
Egg lecithin (mg) | 100 | 100 | 100 | 100 | 100 | 100 | — |
Chloroform : methanol |
10 | 10 | 10 | 10 | 10 | 10 | — |
Aqueous phase | |||||||
Quetiapine fumarate |
— | — | — | — | — | — | 10 |
Sodium |
— | — | — | — | — | — | 50 |
Poloxamer-188 |
10 | 10 | 10 | 10 | 10 | 10 | — |
Double distilled water |
— | — | — | — | — | — | 10 |
DSC scan was performed by Mettler-Toledo DSC 821e (Columbus, OH, USA) instrument. DSC scans were recorded for the entire drug and lipid combinations at a heating rate of 10°C/min in temperature range of 50–250°C.
The size, PDI, and ZP of quetiapine fumarate SLNs were measured using a Malvern Zetasizer (Nano ZS90, UK). About 100
Entrapment efficiency was determined by measuring the concentration of free drug (unentrapped) in aqueous medium as reported [
About 100
Quetiapine fumarate loaded solid lipid nanoparticles (optimized formulation F3) were stored at room temperature (25°C/60 ± 5% RH) and refrigerated temperature (4°C) for 60 days, and average size, zeta potential, poly dispersity index and EE were determined in triplicate.
A single dose bioavailability study was designed in male Wistar rats under fasting conditions. The oral bioavailabilities of the optimized SLN formulation (F3) and suspension (F7) were estimated by conducting bioavailability studies in male Wistar rats with oral dose of 10 mg/kg body weight. All experimental procedures were reviewed and approved by the institutional animal ethical committee of University College of Pharmaceutical Sciences, Kakatiya University (Warangal, India). Male Wistar rats weighing 200–250 g were taken for study (6 animals per group). Blood samples were withdrawn by retro-orbital venous plexus puncture at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 h after dose. About 1.5 mL of blood samples were withdrawn in eppendorf tubes and centrifuged at 3000 rpm for 30 min. The plasma was transferred to another eppendorf tube and stored at −20°C until analysis.
To 100
Mobile phase: acetonitrile: 0.02 M phosphate buffer pH 5.5 (65 : 35), flow rate: 1 mL/min, column: Lichrospher C-18 (250 mm × 4.6 mm i.d., 5 injection volume: 20 UV detection: 254 nm, retention time: 5.2 min.
The concentrations of quetiapine fumarate in rat serum samples were obtained from the calibration curve prepared. The pharmacokinetic parameters
The relative bioavailability (BA) of quetiapine fumarate SLNs to the oral suspension was calculated as follows:
In the present study, quetiapine fumarate loaded SLNs were prepared by hot homogenisation followed by ultrasonication method using three lipids, each at two different concentrations. The selection and utility of lipids and method of preparation were based on the earlier reports. Dynasan-114, Dynasan-118, and Imwitor-900P were known to produce SLNs. Due to the reports and previous observations, these lipids were tried in our studies as excipients. Egg lecithin and poloxamer were known as surfactants to get the dispersions of SLNs. At first instance, hot homogenization followed by ultrasonication method was tried, which yielded better SLNs. Inspite of availability of other methods of preparation, we used this method only as this resulted in consistent production of smaller size nanoparticles (<250 nm) with narrow size distribution and good entrapment efficiency.
DSC thermograms of pure drug and physical mixtures of drug and different lipids are shown in Figure
DSC thermograms of (a) pure drug, (b) physical mixture of drug and Imwitor-900P, (c) physical mixture of drug and Dynasan-118 and (d) physical mixture of drug and Dynasan-114.
Drug-related peaks are seen at right side of thermograms and lipid-related peaks are on left side of the Figure
All the prepared samples were analyzed in order to determine their particle size distribution, zeta potential, and PDI values. The results are represented in Table
Size, PDI, ZP, total drug content and EE of various formulations.
Formulation code | Size (nm) ± SD | PDI ± SD | ZP (mV) ± SD | Total drug content (mg) ± SD | EE (%) ± SD |
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F1 |
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F2 |
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F3 |
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F4 |
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F5 |
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F6 |
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Entrapment efficiency is an important parameter for characterizing solid lipid nanoparticles. All the formulations were analyzed for entrapment efficiency by HPLC, and the results are shown in Table
All the formulations were analyzed for total drug content by HPLC, and the results are represented in Table
Formulations containing Dynasan-114 (F1 and F2), Dynasan-118 (F3 and F4) and Imwitor-900P (F5 and F6) showed cumulative drug release ranging from 55.24% (F2) to 70.89% (F1), from 58.40% (F4) to 71.24% (F3) and from 55.55% (F6) to 65.32% (F5) respectively in 0.1 N Hydrochloric acid (Figure
Cumulative % drug release from quetiapine fumarate SLNs in 0.1 N Hydrochloric acid.
Formulations containing Dynasan-114 (F1 and F2) showed drug release ranging from 30.20% (F2) to 40.63% (F1) in 6.8 pH phosphate buffer. Formulations containing Dynasan-118 (F3 and F4) showed drug release ranging from 40.26% (F4) to 54.57% (F3) in 6.8 pH phosphate buffer (Figure
Cumulative % drug release from quetiapine fumarate SLNs in pH 6.8 phosphate buffer.
Formulations containing Imwitor-900P (F5 and F6) showed drug release ranging from 36.63% (F6) to 40.80% (F5) in 6.8 pH phosphate buffer. When compared, the cumulative release in 6.8 pH phosphate buffer was less than that of 0.1 N HCl. Formulation (F3) containing Dynasan-118 showed maximum release of 54.47% in 6.8 pH phosphate buffer in 24 hours. In general, the
Quetiapine fumarate loaded solid lipid nanoparticles were stored at room temperature (25°C/60 ± 5%RH) and refrigerated temperature (4°C) for 60 days, and average size, zeta potential, poly dispersity index, and entrapment efficiency (EE) were determined. Stability studies were conducted for optimized formulation (F3) which showed better size, PDI, zeta potential, and EE. The number of samples estimated was in triplicate. The results are shown in Table
Physical parameters of the optimized formulation (F3) when stored at 25°C (RT) and (4°C) for a period of 2 months.
Day | At room temperature | At refrigerated temperature | ||||||
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Size (nm)* | PDI | Zeta potential (mV) | EE (%) | Size (nm)* | PDI | Zeta potential (mV) | EE (%) | |
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The statistical comparison of data was done using unpaired
The drug in the serum samples was estimated by using HPLC method [
Consolidated table showing the pharmacokinetic parameters of quetiapine fumarate in rats—formulation with Dynasan-118 (F3) and suspension (F7)—a comparison (
Pharmacokinetic parameters | Optimized formulation (F3) | Suspension (F7) |
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AUC0–24 (µg/mL) h |
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MRT (h) |
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The statistical comparison of data was done using unpaired
Serum concentration versus time profile of quetiapine fumarate upon oral administration of SLN preparation (F3) and suspension (F7) in rats.
From above results, it was found that
Poorly bioavailable quetiapine fumarate was formulated as SLN using three different lipids after checking the compatibility by DSC studies. The SLN preparation with Dynasan 118 was optimized based on the particle size, PDI, zeta potential, entrapment efficiency, and drug release characteristics. During
The authors declare that they have no conflict of interests.
Arjun Narala thanks the AICTE, New Delhi, for providing financial assistance in the form of scholarship. The authors thank M/s Aurobindo labs, Hyderabad for providing the gift sample of quetiapine fumarate.