Bioavailability Study In Rabbits Research Articles

BIOAVAILABILITY STUDY OF ONDANSETRON GEL IN RABBITS AND HUMAN VOLUNTEERS APPLING UPLC AS ANALYTICAL TOOL AND EVALUATION OF THE ANTIEMETIC EFFECT OF ONDANSETRON GEL IN CISPLATIN-INDUCED EMESIS IN RATS

Objective: This study was undertaken to determine the bioavailability of ondansetron gel in experimental animals and humans applying UPLC as an analytical tool and evaluation of the antiemetic effect of ondansetron gel in cisplatin-induced emesis in rats.
 Methods: Ondansetron gel (F13: sodium alginate 7% w/w) was used, marketed I. V. ondansetron (Zofran) ® was chosen as reference. The bioavailability study in rabbits was selected as a parallel design using nine healthy rabbits divided into three groups whereas, bioavailability study in humans was an open-label, wherein 6 healthy subjects administered ondansetron gel. The potential effect of ondansetron gel was evaluated for the prevention of different phases of emesis motivated by exposure to antineoplastic drugs (cisplatin) by determination of body weight loss, water and food intake applying kaolin-pica model in rats using seventy-two rats divided into six groups.
 Results: Ondansetron gel (0.5%) showed detectable plasma concentration 22.833±2.17 ng/m1 after ¼ h and 419.55±2.17 ng/ml after 1-h post-treatment in rabbits and human respectively and concentration was maintained above-reported minimum effective concentration for more than 2.5 h for rabbits and 7 h for humans compared to 1.75 h after I. V. administration.
 The ondansetron gel significantly reduces all phases of cisplatin-induced emesis and a decrease in body weight, water, and food consumption was significantly attenuated.
 Conclusion: Based on the high efficacy of gel on emesis induced by cisplatin, and its high bioavailability, transdermal ondansetron gel could be a promising convenient system to prevent nausea and vomiting following administration of antineoplastic drugs.

Formulation and Characterization of Eplerenone Nanoemulsion Liquisolids, An Oral Delivery System with Higher Release Rate and Improved Bioavailability.

Because Eplerenone (EPL) is a Biopharmaceutical Classification System (BCS) class-II drug and is prone to extensive liver degradation, it suffers from poor bioavailability after oral administration. This work aimed to prepare liquisolids loaded with EPL-nanoemulsions (EPL-NEs) that have a higher drug release rate and improved bioavailability by the oral route. Based on solubility studies, mixtures of Triacetin (oil) and Kolliphor EL/PEG 400 surfactant/co-surfactant (Smix) in different ratios were used to prepare EPL-NE systems, which were characterized and optimized for droplet size, zeta potential, polydispersity index (PDI), and drug content. Systems were then loaded onto liquisolid formulations and fully evaluated. A liquisolid formulation with better drug release and tableting properties was selected and compared to EPL-NEs and conventional EPL oral tablets in solid-state characterization studies and bioavailability studies in rabbits. Only five NEs prepared at 1:3, 1:2, and 3:1 Smix met the specified optimization criteria. The drug release rate from liquisolids was significantly increased (90% within 45 minutes). EPL-NE also showed significantly improved drug release but with a sustained pattern for four hours. Liquisolid bioavailability reached 2.1 and 1.2 relative to conventional tablets and EPL-NE. This suggests that the EPL-NE liquisolid is a promising oral delivery system with a higher drug release rate, enhanced absorption, decreased liver degradation, and improved bioavailability.

Thermally reversible xyloglucan gels as vehicles for nasal drug delivery

The aim of this study was to investigate the potential application of thermosensitive gels formed by a xyloglucan polysaccharide derived from tamarind seed for nasal drug delivery. Xyloglucan that had been partially degraded by β-galactosidase to eliminate 45% of galactose residues formed gels at concentrations of 2.5% w/w at gelation temperatures decreasing over the range 27–28°C. The in vitro release of ondansetron hydrochloride from the enzyme-degraded xyloglucan gels followed higuchi kinetics over a period of 5 h at 34°C by anomalous transport mechanism. The ex vivo permeation of ondansetron hydrochloride from the gels was sustained. Histological examination of nasal mucosa following a single administration of the gels showed no evidence of mucosal damage. Finally, the bioavailability study in rabbits revealed that the absolute bioavailability of ondansetron hydrochloride was significantly increased from 28.64% in the case of the oral drug solution to 52.79% in the case of the nasal in situ gel. The results of this study suggest the potential of the enzyme-degraded xyloglucan gels as vehicles for nasal delivery of drugs.

Bilayered transmucosal drug delivery system of pravastatin sodium: Statistical optimization, in vitro, ex vivo, in vivo and stability assessment

The objective of the present study was to develop a mucoadhesive sustained release bilayered buccal patch of pravastatin sodium using Eudragit S100 as the base matrix so as to surmount hepatic first pass metabolism and gastric instability of the drug. A 32 full factorial design was employed to study the effect of independent variables viz. levels of HPMC K4M and carbopol 934P on % cumulative drug release, mucoadhesion time and mucoadhesive force. Amount of carbopol 934P and HPMC K4M significantly influenced characteristics like swelling index, in vitro mucoadhesive force, drug release, and mucoadhesion time. In vitro evaluation revealed that formulations exhibited satisfactory technological parameters. The mechanism of drug release was found to be non-Fickian diffusion. Different permeation enhancers were investigated to improve the permeation of drug from the optimized patches (F9) across the buccal mucosa. Formulation [F9 (P3)] containing 4% (v/v) dimethyl sulfoxide exhibited desirable permeation of drug. Histopathological studies performed using goat buccal mucosa revealed no mucosal damage. Bioavailability studies in rabbits demonstrated that [F9 (P3)] significantly higher Cmax (67.34 ± 3.58 ng/ml) and AUC0-∞ (350.27 ± 9.59 ng/ml×h) (p < 0.05) of pravastatin sodium from optimized patch than IR tablet (Cmax 58.73 ± 4.63 ng/ml and AUC0-∞ 133.80 ± 8.25 ng/ml×h). Formulation [F9 (P3)] showed sustained drug plasma concentration over a period of 10 h which was significantly longer than oral tablet (p < 0.05). Stability studies as per ICH guidelines established physical stability of the patch and chemical stability drug. The present study established potential of the optimized mucoadhesive buccal patches to circumvent the hepatic first-pass metabolism, gastric instability and to improve bioavailability of pravastatin sodium.

Enhanced bioavailability of buspirone from reservoir-based transdermal therapeutic system, optimization of formulation employing Box-Behnken statistical design.

The purpose of the present study was to develop and optimize reservoir-based transdermal therapeutic system (TTS) for buspirone (BUSP), a low bioavailable drug. A three-factor, three-level Box-Behnken design was employed to optimize the TTS. Hydroxypropyl methylcellulose, D: -limonene and propylene glycol were varied as independent variables; cumulative amount permeated across rat abdominal skin in 24 h, flux and lag time were selected as dependent variables. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The statistical validity of polynomials was established, and optimized formulation factors were selected by feasibility and grid search. Validation of the optimization study with seven confirmatory runs indicated high degree of prognostic ability of response surface methodology. BUSP-OPT (optimized formulation) showed a flux 104.6 microg cm(-2) h(-1), which could meet target flux. The bioavailability studies in rabbits showed that about 2.65 times improvement (p < 0.05) in bioavailability, after transdermal administration of BUSP-OPT compared to oral solution. The ex vivo-in vivo correlation was found to have biphasic pattern and followed type A correlation. Reservoir-based TTS for BUSP was developed and optimized using Box-Behnken statistical design and could provide an effective treatment in the management of anxiety.

In Vitro Release Kinetics and Bioavailability of Gastroretentive Cinnarizine Hydrochloride Tablet

An oral sustained release dosage form of cinnarizine HCl (CNZ) based on gastric floating matrix tablets was studied. The release of CNZ from different floating matrix formulations containing four viscosity grades of hydroxypropyl methylcellulose, sodium alginate or polyethylene oxide, and gas-forming agent (sodium bicarbonate or calcium carbonate) was studied in simulated gastric fluid (pH 1.2). CNZ release data from the matrix tablets were analyzed kinetically using Higuchi, Peppas, Weibull, and Vergnaud models. From water uptake, matrix erosion studies, and drug release data, the overall release mechanism can be explained as a result of rapid hydration of polymer on the surface of the floating tablet and formation of a gel layer surrounding the matrix that controls water penetration into its center. On the basis of in vitro release data, batch HP1 (CNZ, HPMC-K100LV, SBC, LTS, and MgS) was subjected to bioavailability studies in rabbits and was compared with CNZ suspension. It was concluded that the greater bioavailability of HP1 was due to its longer retention in the gastric environment of the test animal. Batch no. HP1 of floating tablet in rabbits demonstrated that the floating tablet CNZ could be a 24-h sustained release formulation.

Enhanced bioavailability of lacidipine via microemulsion based transdermal gels: Formulation optimization, ex vivo and in vivo characterization

The purpose of the present study was to develop and optimize the microemulsion based transdermal therapeutic system for lacidipine (LCDP), a poorly water soluble and low bioavailable drug. The pseudo-ternary phase diagrams were developed for various microemulsion formulations composed of isopropyl myristate, Tween 80 and Labrasol. The microemulsion was optimized using a three-factor, three-level Box–Behnken design, the independent variables selected were isopropyl myristate, surfactant mixture (Tween 80 and Labrasol) and water; dependent variables (responses) were cumulative amount permeated across rat abdominal skin in 24 h ( Q 24; Y 1), flux ( Y 2), and lag time ( Y 3). Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equations were generated for responses Y 1, Y 2 and Y 3. The statistical validity of the polynomials was established, and optimized formulation factors were selected by feasibility and grid search. Validation of the optimization study with 10 confirmatory runs indicated high degree of prognostic ability of response surface methodology. The gel of optimized formulation (ME-OPT) showed a flux of 43.7 μg cm −2 h −1, which could meet the target flux (12.16 μg cm −2 h −1). The bioavailability studies in rabbits showed that about 3.5 times statistically significant ( p < 0.05) improvement in bioavailability, after transdermal administration of microemulsion gel compared to oral suspension. The ex vivo– in vivo correlation was found to have biphasic pattern and followed type A correlation. Microemulsion based transdermal therapeutic system of LCDP was developed and optimized using Box–Behnken statistical design and could provide an effective treatment in the management of hypertension.

In situ gels of Metoclopramide Hydrochloride for intranasal delivery: In vitro evaluation and in vivo pharmacokinetic study in rabbits

Intranasal (IN) administration is a promising approach for rapid-onset delivery of medications and to circumvent their first-pass elimination when taken orally. Metoclopramide Hydrochloride (MET HCl) is a potent antiemetic, effective even for preventing emesis induced by cancer chemotherapy. The feasibility of developing an efficacious intranasal formulation of metoclopramide has been undertaken in this study. Formulations were modulated so as to have gelation at physiological ion content after intranasal administration. Gelation was determined by physical appearance. The mucoadhesive force in terms of detachment stress, determined using sheep nasal mucosal membrane, increased with increasing concentration of carbopol. The results of in vitro drug permeation studies across sheep nasal mucosa indicate that effective permeation could be significantly increased by using in situ gelling formulation with carbopol concentration 0.15% or greater. Histological examination did not detect any damage during in vitro permeation studies. Finally, the bioavailability study in rabbits revealed that the absolute bioavailability of MET HCl was significantly increased from 40.67% in the case of the oral drug solution to 54.61% in the case of the nasal in situ gel. This study points to the potential of mucoadhesive nasal in situ gel in terms of ease of administration, accuracy of dosing, prolonged nasal residence and improved drug bioavailability.

Synthesis of a new mPEG-dexamethasone conjugate and preliminary bioavailability studies in rabbits

Poly(ethylene glycol) esters have been proposed as a potential oral-controlled drug delivery system for dexamethasone (DXM). The drug was covalently attached to monomethoxypolyethylene glycol amine (mPEG-NH 2 ) (Mw = 10,000 Da) using a succinate linker. A new PEG-based prodrug system was designed using ester derivatives. The drug-polymer conjugate (mPEG-DXM) was freely water soluble at room temperature. First of all, the adduct hydrolytic stability was assessed at physiological pH. Then, the bioavailability was evaluated by orally administering the mPEG-DXM conjugate in rabbits and comparing to that obtained by the intravenous route. The area under the concentration-time curve (AUC) of PEGylated drug was twice as large as that of the parent drug after oral administration. In conclusion, PEGylated DXM was useful for maintaining the DXM concentration in the blood after oral administration.

Oral Bioavailability of Flutamide from 1‐O‐Alkylglycerol Stabilized o/w Nanoemulsions

Size of oil globule and emulsifier film covering it are the key factors modifying oral absorption of drugs dissolved/dispersed in oil globules of o/w emulsions. Since oral bioavailability of flutamide (FTM) is poor, nanoemulsions incorporating FTM in oil phase and globules stabilized by a novel lipophilic emulsifier, 1‐O‐alkylglycerol were developed and characterized. All nanoemulsions had a size around 200 nm. They exhibited considerable release retardation in vitro. Flutamide nanoemulsions were evaluated for oral bioavailability in rabbits and in situ intestinal absorption in rats. Serum level data of flutamide obtained in the in situ experiments indicate higher FTM absorption from nanoemulsions than the aqueous FTM suspension. Among the nanoemulsions, 1‐O‐alkylglycerol stabilized systems showed higher absorption. The results of bioavailability studies in rabbits indicate increased absorption and decreased elimination of FTM from nanoemulsions, thus improving the bioavailability. Increased rate of absorption of flutamide in the in situ experiments can be attributed to the permeation enhancement effect of 1‐O‐alkylglycerols. However, size of the oil droplet seems to be the major factor in improving oral bioavailability in rabbits.

Enhanced bioavailability of metoclopramide HCl by intranasal administration of a mucoadhesive in situ gel with modulated rheological and mucociliary transport properties

The prolonged residence of drug formulation in the nasal cavity is of utmost importance for intranasal drug delivery. The objective of the present investigation was to develop a mucoadhesive in situ gel with reduced nasal mucociliary clearance in order to improve the bioavailability of the antiemetic drug, metoclopramide hydrochloride (MCP HCl). The in situ gelation upon contact with nasal mucosa was conferred via the use of the thermogelling poloxamer 407 whereas mucoadhesion and drug release enhancement were modulated via the use of mucoadhesive and polyethylene glycol (PEG) polymers respectively. The results revealed that the different mucoadhesives augmented the gel viscosity but reduced its sol–gel transition temperatures ( T sol–gel) and the drug release. The inclusion of PEG counteracted the effect of the mucoadhesive polymers whereby it decreased the gel consistency and increased the T sol–gel as well as the in vitro drug release. The formulations with favorable sol–gel transition temperatures (25–32 °C) and high in vitro drug release (100% release in 60 min) were also rheologically stable upon storage. The mucoadhesiveness test was performed in vivo in rats, results showed that the carbopol-containing in situ gel prolonged the mucociliary transport time from 10 min (control solution) to 52 min (mucoadhesive gel) and maintained nasal mucosal integrity after 14-days application. The bioavailability study in rabbits revealed that the absolute bioavailability of MCP HCl was significantly increased from 51.7% in case of the oral drug solution to 69.1% in case of the nasal in situ gel. The study point to the potential of mucoadhesive nasal in situ gel in terms of ease of administration, accuracy of dosing, prolonged nasal residence and improved drug bioavailability.

Improvement in vitamin A status with consumption of dark-green vegetables–a bioavailability study in rabbits

The bioavailability of synthetic β-carotene and β-carotene from a natural source in rabbits in the presence of citric pectin were determined. Thirty animals were divided into three groups which received the following diets for 30 days: vegetable group (VG): 6mg/day natural β-carotene (kale) + 12% citric pectin; positive control group (PCG): 6mg/day synthetic β-carotene (oil + β-carotene) + 12% citric pectin; negative control group (NCG): 12% citric pectin only. Plasma retinol and β-carotene did not differ significantly ( p > 0.05) between VG and PCG. Liver retinol (VG: 35.54 μg/g; PCG: 54.19 μg/g; NCG: 2.01 μg/g), β-carotene (VG: 0.65 μg/g; PCG: 0.68 μg/g; NCG: not detected) and retinyl palmitate (VG: 57.67 μg/g; PCG: 66.09 μg/g; NCG: 0.84 μg/g) also did not differ ( p > 0.05) between the VG and PCG groups. We conclude that the bioavailability of natural β-carotene is the same as that of synthetic β-carotene.

Hydrophilic and hydrophobic cyclodextrins in a new sustained release oral formulation of nicardipine: in vitro evaluation and bioavailability studies in rabbits

The feasibility of using complexes with cyclodextrins (CDs) in nicardipine (NC) controlled delivery has been examined, with a view to extending the pharmaceutical applications spectrum of these carriers. For a fast release fraction, a hydrophilic β-cyclodextrin derivative (hydroxypropyl-β-cyclodextrin) was employed to form a water-soluble complex. For the sustained-releasing portion, triacetyl-β-cyclodextrin (TAβCD) was used to provide complexes with appropriate hydrophobicity. An optimal formulation was designed by the combination of each fraction in different mixing ratios. The release behaviour of the complexes, as well as of their mixtures, was examined in simulated gastric (pH 1.2) and intestinal (pH 6.8) fluids. The formulations released the drug rapidly at the initial stage, followed by a slow release. The drug release rate was markedly retarded in the increasing order of the amount of NC/TAβCD complex. When NC was administered to rabbits, its absorption was very rapid with a short elimination half-life, while a prolonged maintenance of the plasma levels was obtained for the two selected formulations. The drug bioavailability was considerably improved especially after the administration of the mixture of hydrophilic and hydrophobic complexes, when compared with the NC/TAβCD complex. The results suggested that the critical combination of hydrophilic and hydrophobic CDs complexes, in appropriate ratios, could be a promising drug delivery system with a prolonged therapeutic effect coupled with a more balanced bioavailability.

High-performance liquid chromatographic analysis of melatonin in human plasma and rabbit serum with on-line column enrichment

This paper describes the development of a simple and sensitive analytical method for the quantification of melatonin in human plasma and rabbit serum, using standard analytical equipment and on-line column enrichment without prior extraction, clean-up or derivatization. The analytical procedure was found to be accurate, precise and linear. For human plasma, the accuracy was 101% (range 89–106%), and the mean precision was 5% (range 2–9%) for all concentrations (0, 2, 10, 50 and 200 ng/ml) tested ( n=6). The accuracy in rabbit serum was 101% (range 90–112%), and the mean precision was 13% (range 8–19%) for all concentrations (0, 2, 10, 50, 200 and 500 ng/ml) tested ( n=6). The retention time of melatonin was about 8 min and the total recoveries were found to be approximately 65 and 85%, respectively, for human plasma and rabbit serum. The limit of detection was found to be lower than 1 ng/ml for human plasma and around 2 ng/ml for rabbit serum. The method is, therefore, found to be suitable for melatonin bioavailability studies in rabbits and presumably also in humans.