Pharmacokinetics of itraconazole after intravenous and oral dosing of itraconazole-cyclodextrin formulations

The current research evaluated and compared the efficacy of hydroxybutenyl-beta-cyclodextrin (HBenBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) as enhancers of itraconazole solubility and oral bioavailability. At 10 wt% cyclodextrin, 17-fold and 3.8-fold increases in itraconazole aqueous solubility were observed in the presence of HBenBCD and HPBCD, respectively. Significant differences in the dissolution of itraconazole in the presence of these two cyclodextrins were also observed. Itraconazole pharmacokinetics is known to exhibit a significant food effect. However, testing in biorelevant media indicated that no food effects should be observed after oral administration of itraconazole:HBenBCD complexes. Formulations of itraconazole with HBenBCD were prepared and these complexes, along with the commercial forms of itraconazole with and without HPBCD (Sporanox) were administered to male Sprague-Dawley rats by oral and intravenous routes. Intravenous administration of itraconazole formulated with HBenBCD resulted in a higher AUC relative to Sporanox. When administered as oral solutions, the itraconazole:HBenBCD formulation provided higher oral bioavailability than the Sporanox oral solution. When administered as solid formulations, the itraconazole:HBenBCD solid formulation provided a 2x increase in oral bioavailability relative to the Sporanox solid formulation. No food effects were observed with the itraconazole:HBenBCD solid dosage forms. Drug/metabolite ratios were dependent upon the dosage form.     

Flurbiprofen-loaded nanoparticles prepared with polyvinylpyrrolidone using Shirasu porous glass membranes and a spray-drying technique: nano-sized formation and improved bioavailability

A unique flurbiprofen-loaded nanoemulsion was listed earlier using a Shirasu porous glass (SPG) membrane emulsification technique, which gave constant emulsion droplets with a thin size distribution. In this study, a flurbiprofen-loaded nanoemulsion was developed further into a solid form using polyvinylpyrrolidone (PVP) as a carrier by a spray-drying technique. The flurbiprofen-loaded nanoparticles with a weight ratio of flurbiprofen/PVP/surfactant mixture of 1/8/2 were connected with about 130?000-fold enhanced drug solubility and had a mean size of about 70?nm. In these nanoparticles, flurbiprofen was found in an altered amorphous state. Additionally, the nanoparticles gave significantly shorter T_max, and greater AUC and C_max compared to the commercially available product. Specially, the AUC of the drug from the nanoparticles was about 10-fold greater compared to the commercially available product. Therefore, these flurbiprofen-loaded nanoparticles can be convenient for distributing a poorly water-soluble flurbiprofen with improved bioavailability using uniform nano-sized particles.     

Microencapsulation of menthol by crosslinked chitosan via porous glass membrane emulsification technique and their controlled release properties

Chitosan-encapsulated menthol microcapsules were successfully prepared in an oil-in-water (o/w) emulsion using the Shirasu Porous Glass (SPG) membrane emulsification technique and high-speed dispersion technique for preparing a mixed o/w emulsion. The size of the menthol-loaded chitosan microcapsules was strongly depended on the average pore size of the SPG membrane and the amount of menthol loading in the dispersed phase. The membrane pore size of 5.2?µm was suitable for a viscous dispersed phase containing light mineral oil. The average diameter of emulsion droplets of 28.3?µm was obtained. Increasing the menthol loading in the dispersion phase from 5% to 10% w/w of chitosan decreased the emulsion droplet size with a broad size distribution. The crosslinked microcapsule size and size distribution of mixed emulsion droplets decreased with the increasing crosslinking time. The menthol release was a diffusion control which depended on the proportion of amino group in chitosan-to-tripolyphosphate molar ratio and crosslinking time. This work also demonstrated that hydrophilicity/hydrophobicity of the continuous phase and dispersion phase controlled SPG membrane emulsification efficiency and quality of the resulting emulsion droplets.     

Development of raloxifene-solid dispersion with improved oral bioavailability via spray-drying technique

The purpose of this study was to develop a raloxifene-loaded solid dispersion with enhanced dissolution rate and bioavailability via spray-drying technique. Solid dispersions of raloxifene (RXF) were prepared with PVP K30 at weight ratios of 1:4, 1:6 and 1:8 using a spray-drying method, and characterized by differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and solubility and dissolution tests. The bioavailability of the solid dispersion in rats was also evaluated compared to those of RXF powder and commercial product. Results showed that the RXF-loaded solid dispersion was in amorphous form with increased solubility and dissolution rate. The absorption of RXF from solid dispersion resulted in approximately 2.6-fold enhanced bioavailability compared to pure drug. Moreover, RXF-loaded solid dispersion gave similar AUC, C_max and T_max values to the commercial product, suggesting that it was bioequivalent to the commercial product in rats. These findings suggest that an amorphous solid dispersion of RXF could be a viable option for enhancing the oral bioavailability of RXF.     

Development of novel flurbiprofen-loaded solid self-microemulsifying drug delivery system using gelatin as solid carrier

To develop a novel flurbiprofen-loaded solid self-microemulsifying drug delivery system (solid SMEDDS) with improved oral bioavailability using gelatin as a solid carrier, the solid SMEDDS formulation was prepared by spray-drying the solutions containing liquid SMEDDS and gelatin. The liquid SMEDDS, composed of Labrafil M 1944 CS/Labrasol/Transcutol HP (12.5/80/7.5%) with 2% w/v flurbiprofen, gave a z-average diameter of about 100?nm. The flurbiprofen-loaded solid SMEDDS formulation gave a larger emulsion droplet size compared to liquid SMEDDS. Unlike conventional solid SMEDDS, it produced a kind of microcapsule in which liquid SMEDDS was not absorbed onto the surfaces of carrier but formed together with carrier in it. However, the drug was in an amorphous state in it like conventional solid SMEDDS. It greatly improved the oral bioavailability of flurbiprofen in rats. Thus, gelatin could be used as a carrier in the development of solid SMEDDS with improved oral bioavailability of poorly water-soluble drug.     

Spray-dried redispersible oil-in-water emulsion to improve oral bioavailability of poorly soluble drugs.

A physically stabilized dry emulsion dosage form reforming the original emulsion after rehydration was developed by spray-drying a liquid oil-in-water emulsion containing maltodextrin as carrier and sodium caseinate as emulsifying agent. Several oil:water as well as maltodextrin:water ratios were tested, the homogenization and spray-drying processes and the reconstitution properties were investigated and an optimum formulation was selected for poorly soluble drug incorporation, having an identical oil:water and carrier:water ratio of 10% (w/w) and a load of solid material of 20% (w/w). Lipophilic 5-phenyl-1,2-dithiole-3-thione (5-PDTT) was selected as a model drug. 5-PDTT release from the solid state emulsion was studied using an in vitro two-phase stirred model and the relative bioavailability of 5-PDTT in the dry emulsion was obtained in the rabbit after oral administration of the reconstituted emulsion, compared to a 5-PDTT-sulfobutyl ether 7 beta-cyclodextrin complex in solution. Incorporation of 5-PDTT in the oil phase neither affects the surface morphology of the powder nor the reconstitution, the droplet size or the drug releasing properties and, furthermore, allows a 3-fold improvement of 5-PDTT relative bioavailability in rabbit after oral administration. These results indicate that dry emulsions may be considered as relevant dosage forms to improve bioavailability of poorly absorbable lipophilic drugs.     

Fabrication of a uniformly sized fenofibrate microemulsion by membrane emulsification

Fenofibrate-loaded microemulsions composed of Labrafil M 1944 CS, Capryol PGMC and fenofibrate as the dispersed phase and Labrasol in demineralised water as the continuous phase were prepared by utilising a Shirasu-porous-glass (SPG) membrane emulsification technique. The process parameters were optimised by adjusting the feed pressure (15–45?kPa), agitator speed (250–800?rpm) and temperature of the continuous phase (25–45°C). As a result, narrowly distributed microemulsions were obtained via SPG membrane emulsification at an agitator speed of 250?rpm, a feed pressure of 30?kPa and a continuous phase temperature of 25°C. Furthermore, TEM images clearly showed that the microemulsion prepared by SPG membrane emulsification had a uniform, spherical morphology with a narrow size distribution. Our results indicated that the SPG membrane emulsification technique is highly efficient for the preparation of narrowly distributed microemulsions with relatively smaller particle sizes compared with the common stirring method.     

Improvement of bioavailability and photostability of amlodipine using redispersible dry emulsion

To improve the bioavailability and photostability of poorly water-soluble and photosensitive amlodipine, dry emulsion (DE) was prepared by spray-drying the oil-in-water emulsion of amlodipine. Labrafil M 1944 CS and dextrin were employed as oil phase and matrix material, respectively. Dispersing DE in distilled water formed an emulsion with a mean droplet size 1.4-fold larger than that of the homogenized amlodipine emulsion before spray-drying (0.24 ± 0.30 μm versus 0.17 ± 0.02 μm). The mean droplet size of DE remained unchanged during 6-month storage at room temperature. 94.4% versus 33.1% of amlodipine remained intact after 24-h UV irradiation of amlodipine as DE formulation or as powder. These data suggest that DE formulation greatly improved the photostability of amlodipine, as well as increasing the physical stability of emulsion systems. In vitro release of DE was higher than that of amlodipine powder (66% versus 48% release at 60 min). Consequently, DE formulation resulted in 2.6- and 2.9-fold higher C_max and AUC_0–24 h of amlodipine compared after oral administration of amlodipine powder in rats. Our data suggest that the DE may be a potential oral dosage form for amlodipine to improve its bioavailability.     

Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: Itraconazole

The aim of the present series of experiments was to improve the solubility and dissolution/precipitation behaviour of a poorly soluble, weakly basic drug, using itraconazole as a case example. Binary inclusion complexes of itraconazole with two commonly used cyclodextrin derivatives and a recently introduced cyclodextrin derivative were prepared. Their solubility and dissolution behaviour was compared with that of the pure drug and the marketed formulation Sporanox®. Ternary complexes were prepared by addition of Soluplus®, a new highly water soluble polymer, during the formation of the itraconazole/cyclodextrin complex. A solid dispersion made of itraconazole and Soluplus® was also studied as a control. Solid state analysis was performed for all formulations and for pure itraconazole using powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicated that with all formulation approaches, the aqueous solubility of itraconazole formed with hydroxypropyl-β-cyclodextrin (HP-β-CD) or hydroxybutenyl-β-cyclodextrin (HBen-β-CD) and Soluplus® proved to be the most favourable formulation approaches. Whereas the marketed formulation and the pure drug showed very poor dissolution, both of these ternary inclusion complexes resulted in fast and extensive release of itraconazole in all test media. Using the results of the dissolution experiments, a newly developed physiologically based pharmacokinetic (PBPK) in silico model was applied to compare the in vivo behaviour of Sporanox® with the predicted performance of the most promising ternary complexes from the in vitro studies. The PBPK modelling predicted that the bioavailability of itraconazole is likely to be increased after oral administration of ternary complex formulations, especially when itraconazole is formulated as a ternary complex comprising HP-β-CD or HBen-β-CD and Soluplus®.     

Preparation and characterization of solid dispersions of itraconazole by using aerosol solvent extraction system for improvement in drug solubility and bioavailability

The objective of this study was to elucidate the feasibility to improve the solubility and bioavailability of poorly water-soluble itraconazole via solid dispersions by using supercritical fluid (SCF). Solid dispersions of itraconazole with hydrophilic polymer, HPMC 2910, were prepared by the aerosol solvent extraction system (ASES) under different process conditions of temperature/pressure. The particle size of solid dispersions ranged from 100 to 500 nm. The equilibrium solubility increased with decrease (15 to 10 MPa) in pressure and increase (40 to 60 degrees C) in temperature. The solid dispersions prepared at 45 degrees C/15 MPa showed a slight increase in equilibrium solubility (approximately 27-fold increase) when compared to pure itraconazole, while those prepared at 60 degrees C/10 MPa showed approximately 610-fold increase and no endothermic peaks corresponding to pure itraconazole were observed, indicating that itraconazole might be molecularly dispersed in HPMC 2910 in the amorphous form. The amorphous state of itraconazole was confirmed by DSC/XRD data. The pharmacokinetic parameters of the ASES-processed solid dispersions, such as Tmax, Cmax, and AUC(o-24 h) were almost similar to Sporanox capsule which shows high bioavailability. Hence, it was concluded that the ASES process could be a promising technique to reduce particle size and/or prepare amorphous solid dispersion of drugs in order to improve the solubility and bioavailability of poorly water-soluble drugs.     

Influence of cryogenic grinding on properties of a self-emulsifying formulation

Recently, self-emulsifying drug delivery systems (SEDDS) have been developed as a method to deliver lipophilic drugs. Gelucire 44/14 is an excipient, from the lauroyl macrogolglycerides family, producing a fine oil-in-water emulsion when introduced into an aqueous phase under gentle agitation as SEDDS, improving thereby solubility of poorly water-soluble drugs and their bioavailability. The aims of this study were to process Gelucire 44/14 into a powder by cryogenic grinding to produce solid oral dosage forms and to investigate influence of this process on different properties of a formulation made of Gelucire 44/14 and ketoprofen (90/10). Cryogenic grinding produced Gelucire 44/14 in a powder form and this process did not change its physical properties, emulsification capacities and dissolution performances of the formulation tested. However, interactions took place between ketoprofen and Gelucire 44/14 with a decrease of the melting peak and a reduction of the droplet size of the formed emulsion. The influence of drug-Gelucire 44/14 interactions must be investigated case by case in any formulations.     

Uniform titanium dioxide (TiO(2)) microcapsules prepared by glass membrane emulsification with subsequent solvent evaporation

Anatase-type titanium dioxide (TiO(2)) was encapsulated using an Shirasu porous glass (SPG) membrane emulsification technique and followed by solvent evaporation. The oil phase, consisting of fine#10; powder of anatase TiO(2), Disperbyk-180, the hydrophobic oil phase additive, and polymer wall solution, was pushed through the membrane pores into the aqueous phase of poly(vinyl alcohol) and sodium dodecyl sulfate to form the solid-in-oil-in water, (S/O)/W, emulsion droplets. Three types of styrene-based copolymer poly(styrene-co-acrylic acid) (PS-AA), poly(styrene-co-2-ethyl hexyl acrylate) (PS-2EHA) and poly(styrene-co-dimethyl aminoethylmethacrylate) (PS-DMAEMA) were used as an encapsulating shell. Uniform droplets were successfully obtained by modifying the oil phase using methyl laurate or hexadecanol as the oil phase additive, together with carefully monitoring the emulsification flow rate during the emulsification. The (S/O)/W emulsion was gently stirred in a sealed reactor, and evacuation of solvent started under moderate heating with increasing a vacuum intensity. Those uniform-sized TiO(2) microcapsules revealed fine porous morphologies on their surfaces as a result of a mild phase separation induced from the addition of the oil phase additive. The encapsulation efficiency was influenced by the stability of TiO(2) in the oil phase, the polymer wall employed, and the operational control of the glass membrane emulsification process. The membrane emulsification process could prepare the TiO(2) microcapsules with about approximately 6-8.5 wt% of encapsulation loadings. PS-AA and PS-2EHA copolymers provided better encapsulation efficiency compared to PS-DMAEMA. SPG membranes with 1.42, 2.8, 5.25, 7.0, or 9.5 microm were employed and 2-20 microm microcapsules were subsequently obtained.     

Self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble grapefruit flavonoid Naringenin: design,characterization, in vitro and in vivo evaluation

Abstract

Naringenin (NRG), predominant flavanone in grapefruits, possesses anti-inflammatory, anti-carcinogenic, hepato-protective and anti-lipid peroxidation effects. Slow dissolution after oral ingestion due to its poor solubility in water, as well as low bioavailability following oral administration, restricts its therapeutic application. The study is an attempt to improve the solubility and bioavailability of NRG by employing self-nanoemulsifying drug delivery technique. Preliminary screening was carried out to select oil, surfactant and co-surfactant, based on solubilization and emulsification efficiency of the components. Pseudo ternary phase diagrams were constructed to identify the area of nanoemulsification. The developed self-nanoemulsifying drug delivery systems (SNEDDS) were evaluated in term of goluble size, globule size distribution, zeta potential, and surface morphology of nanoemulsions so obtained. The TEM analysis proves that nanoemulsion shows a droplet size less than 50?nm. Freeze thaw cycling and centrifugation studies were carried out to confirm the stability of the developed SNEDDS. In vitro drug release from SNEDDS was significantly higher (p?<?0.005) than pure drug. Furthermore, area under the drug concentration time-curve (AUC_0–24) of NRG from SNEDDS formulation revealed a significant increase (p?<?0.005) in NRG absorption compared to NRG alone. The increase in drug release and bioavailability as compared to drug suspension from SNEDDS formulation may be attributed to the nanosized droplets and enhanced solubility of NRG in the SNEDDS.     

Development of novel ibuprofen-loaded solid dispersion with enhanced bioavailability using cycloamylose

To develop a novel ibuprofen-loaded solid dispersion with enhanced bioavailability using cycloamylose, it was prepared using spray-drying techniques with cycloamylose at a weight ratio of 1:1. The effect of cycloamylose on aqueous solubility of ibuprofen was investigated. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared with ibuprofen powder. This ibuprofen-loaded solid dispersion improved about 14-fold drug solubility. Ibuprofen was present in an unchanged crystalline state, and cycloamylose played the simple role of a solubilizing agent in this solid dispersion. Moreover, the dispersion gave 2-fold higher AUC (area under the drug concentration-time curve) value compared with a ibuprofen powder, indicating that it improved the oral bioavailability of ibuprofen in rats. Thus, the solid dispersion may be useful to deliver ibuprofen with enhanced bioavailability without crystalline change.     

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.     

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.     

Cogrinding enhances the oral bioavailability of EMD 57033, a poorly water soluble drug, in dogs.

The oral bioavailability of EMD 57033, a calcium sensitizing agent with poor solubility, was compared in dogs using four solid dosage form formulation approaches: a physical blend of the drug with excipients, micronization of the drug, preparation of coground mixtures and spray-drying of the drug from a nanocrystalline suspension. The formulations contained generally accepted excipients such as lactose, hydroxypropylmethyl cellulose and sodium lauryl sulphate in usual quantities. Drug micronization and cogrinding was realized by a jet-milling technique. Nanoparticles were created by media milling using a bead mill. All formulations were administered orally as dry powders in hard gelatine capsules. While micronization increased the absolute bioavailability of the solid drug significantly compared to crude material (from nondetectable to 20%), cogrinding with specific excipients was able to almost double this improvement (up to 39%). With an absolute bioavailability of 26%, spray-dried nanoparticular EMD 57033 failed to show the superior bioavailability that had been anticipated from in vitro data. The control solution prepared with cyclodextrin was shown to have an absolute bioavailability of 57% (vs. i.v. infusion). It was concluded that cogrinding can be a useful tool to improve the bioavailability of poorly soluble drugs from a solid dosage form format.     

Pharmacokinetics of raloxifene in male Wistar-Hannover rats: influence of complexation with hydroxybutenyl-beta-cyclodextrin

Raloxifene is a highly insoluble, highly metabolized serum estrogen receptor modulator approved for use in the treatment of osteoporosis. Hydroxybutenyl-beta-cyclodextrin (HBenBCD) is a novel solubility enhancer previously demonstrated to increase the oral bioavailability of tamoxifen, letrozole, and itraconazole. The current study evaluated the pharmacokinetics of raloxifene in oral and intravenous formulations with HBenBCD in male Wistar-Hannover rats. Analytical methodology to measure raloxifene and its metabolites was developed by measuring raloxifene metabolism in vitro. Formulation with HBenBCD significantly increased raloxifene oral bioavailability. Mean+/-S.D. oral bioavailabilities were 2.6+/-0.4% for raloxifene formulated with microcrystalline cellulose, 7.7+/-2.1% for a solid capsule formulation of raloxifene:HBenBCD complex, and 5.7+/-1.3% for a liquid-filled capsule formulation containing raloxifene:HBenBCD/PEG400/H(2)O. Relative to raloxifene/microcrystalline filled capsules, the presence of HBenBCD in the solid capsule formulation afforded: (i) a decrease in raloxifene T(max) (2.5+/-0.5h versus 4.0+/-0.5h); (ii) a two-fold increase in raloxifene C(max) and a three-fold increase in raloxifene AUC; and (iii) a 12-fold increase in raloxifene glucuronide C(max) and a 6.5-fold increase in raloxifene glucuronide AUC. Hence, these studies demonstrate that raloxifene formulations containing HBenBCD significantly increased the oral bioavailability in rats relative to formulations that did not contain HBenBCD.     

Preparation and in vivo evaluation of piroxicam-loaded gelatin microcapsule by spray drying technique

To develop a piroxicam-loaded gelatin microcapsule with enhanced bioavailability, a gelatin microcapsule encapsulated ethanol and piroxicam has been formulated by using gelatin as a water-soluble polymer shell. The aqueous solubility and bioavailability of piroxicam in piroxicam-loaded microcapsule in rats were then evaluated compared to piroxicam powder. The piroxicam-loaded gelatin microcapsule spherical in shape with smooth surface showed the geometric mean diameter of about 19 microm. It had the piroxicam solubility of about 1.87 mg/ml and the amount of ethanol of about 4.37 microg/mg. Furthermore, it gave significantly higher total plasma concentrations, Cmax and area under the blood concentration-time curve (AUC) of piroxicam in rats than did piroxicam powder, indicating that the drug from gelatin microcapsule could be more orally absorbed in rats. In particular, the AUC of piroxicam in gelatin microcapsule was significantly about 2 fold increased compared to piroxicam powder. This enhanced oral relative bioavailability of piroxicam in gelatin microcapsule was contributed by the marked increase in the absorption rate of piroxicam due to the improved solubility of piroxicam. Thus, the piroxicam-loaded gelatin microcapsule developed using spray-drying technique with gelatin, sodium lauryl sulfate and ethanol would be useful to deliver piroxicam in a pattern that allows fast absorption in the initial phase, leading to better absorption.     

Formulation and Development of CoQ10-Loaded s-SNEDDS for Enhancement of Oral Bioavailability

Purpose

Coenzyme (CoQ10) is a poorly soluble drug strategically selected to enrich oral bioavailability by incorporating in solid self-nanoemulsifying drug delivery system (s-SNEDDS) comprised of oil, surfactant, and cosurfactant. The conventional self-emulsifying drug delivery system (SEDDS) and liquid SNEDDS (l-SNEDDS) usually have the problem of drug instability and precipitation.

Methods

The selected oils, surfactant, and cosurfactant with maximum drug solubility were Lauroglycol FCC, Labrasol, and Transcutol P. The ternary phase diagrams were constructed, and selected formulations from ternary phase diagrams were subjected to thermodynamic stability and self-dispersibility test and characterized for emulsion droplet size and droplet size distribution. The optimized formulation was comprised of Lauroglycol FCC 20 % (w/w), Labrasol 10 % (w/w), and Transcutol P 20 % (w/w) as oil, surfactant, and cosurfactant.

Results

The transmission electron microscopy (TEM) study of optimized l-SNEDDS reported mean globule size of 34 nm was transformed into s-SNEDDS by spray-drying technique using solid carrier. The s-SNEDDS was characterized for differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), and X-ray diffraction (X RD). The in vitro release profile of s-SNEDDS showed drug release (97.5?±?4.5 %), marketed formulation (57.96?±?0.54 %), and CoQ10 powder (0.36?±?0.06 %) in 1 hour. The pharmacokinetic study of optimized s-SNEDDS in male Wistar rats revealed the improved maximum concentration (C _max) (3.4-fold vs CoQ10 powder; 1.4-fold vs marketed formulation) and area under the curve (AUC) (5-fold vs CoQ10 powder; 2-fold vs marketed formulation). With this result, s-SNEDDS could be of potential to enhance the oral bioavailability of CoQ10.

Conclusion

Thus, s-SNEDDS in addition to enhancing the dissolution and oral bioavailability often results in low production cost, easy processing, and better patient compliance.