In vitro and in vivo evaluation of a novel capsule for colon-specific drug delivery

The aim of this study was to estimate colon-specific drug delivery of a novel capsule (CS capsule). Theophylline was used as model drug and little was released from the CS capsules in the release medium mimicking physiological environment of stomach to small intestine. However, 66.7 ± 8.8% theophylline was released from the capsules in the phosphate buffer (pH 6.8) mimicking the physiological environment of colon in the next 4 h, while the addition of galactomannanase (39.3 U/L) accelerated the disintegration of the CS capsule and enhanced the release rate to 92.6 ± 6.0%. Rats in vivo pharmacokinetics demonstrated that the relative bioavailability of theophylline after intragastric administration of CS capsules was 76.72% with delayed T_max of 8 h comparing to that of theophylline solution with T_max of 1.5 h. Radiolabeled with technetium-99m, the CS capsule could keep intact from stomach to small intestine while disintegration of the CS capsule was observed in the proximal colon or the joint between the distal small intestine and right colon. A great quantity of radiolabeled marker was released as well as distributed in the whole colon at 10 h after administration. As a whole, the CS capsule prepared could provide an alternative carrier for the colon-specific drug delivery. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2626–2635, 2009     

Bioavailability of sustained release indomethacin suppositories containing polycarbophil

The bioavailability of indomethacin from polyethylene glycol base, commercial suppositories Indocid¹, MSD and from polyethylene glycol base containing 5, 6 and 8% of polycarbophil, with the purpose of obtaining a controlled release suppositories, was determined in dogs. The results show that polycarbophil as a bioadhesive increased absorption and improved the bioavailability of indomethacin where the areas under the curves for the commercial suppositories and those containing 0, 5, 6 and 8% polycarbophil were 19.5, 14.9, 31.2, 21.4 and 21.2 μ h ml⁻¹, respectively. The maximum plasma concentration (C_max) and the time to reach C_max (t_max) were 4.76, 2.98, 4.50, 2.36 and 1.29 μg/ml and 1, 1, 1, 1 and 12 h for the commercial suppositories and those containing 0, 5, 6 and 8% polycarbophil, respectively. The data indicate that as the polycarbophil concentration increased from 0 to 5% in the polyethylene glycol suppositories, the plasma levels and bioavailability improved significantly (p < 0.1, Student's t-test), whereas on increasing from 5 to 6 and 8% the plasma levels and bioavailability decreased significantly (p < 0.05). At 8% polycarbophil concentration, sustained release suppositories were produced but a decrease in plasma levels was observed.     

A novel lipid-based solid dispersion for enhancing oral bioavailability of Lycopene – In vivo evaluation using a pig model

Lycopene is a potent anti-oxidant, which has been widely reported for its potential benefits at reducing the risks of certain types of cancer e.g. prostate cancer. The oral bioavailability of this highly lipophilic carotenoid is low and highly influenced by the extent of intestinal lymphatic uptake. The aim of this study was to develop an optimised formulation, which allows for efficient absorption following oral administration. A self-emulsifying drug delivery system (SEDDS) and solid dispersion of Lycopene were developed initially. Subsequently, a novel lipid based solid dispersion (LBSD) was designed. Processing via a solid dispersion approach was found to alter the solid state characteristics of Lycopene, as determined by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The bioavailability of Lycopene was significantly increased after oral administration of LBSD to fasted pigs, relative to the commercial product (Lycovit^®). A clear distinction in terms of C_max and AUC was observed between Lycovit^® and LBSD. In conclusion, a novel LBSD formulation was developed to enhance the oral bioavailability of the model lipophilic compound, Lycopene, by enhancing dissolution in the gastrointestinal tract and promoting intestinal lymphatic uptake utilising digestible lipid excipients.     

The Preparation and Evaluation of a Tablet Dosage Form of Cyclosporine in Dogs

Cyclosporine (CsA) is commercially available for oral administration as a solution in olive oil with alcohol and an emulsifier. To improve its variable absorption and low patient acceptability, several oral formulations were prepared and tested in vitro and in vivo in dogs. A tablet formulation prepared by direct compression was then selected for comparison with the commercial oil solution placed into soft gelatin capsules. The study involved a randomized crossover design in six dogs. In order to determine absolute bioavailability and to compensate for any time-dependent changes in clearance, an intravenous tracer dose of ³H-CsA was administered along with each oral test product on each of two occasions. Absolute bioavailability (mean ± SD) was 46.0 ± 11.1 and 45.4 ± 9.9% for the capsules and tablets, respectively. C _max, t _max, and mean absorption time were not significantly different between the two products. No differences were observed in the pharmacokinetics of the intravenously administered CsA in the two experiments, which were separated by 8–13 days. We conclude that the proposed tablet formulation for CsA is equivalent in dogs to the commercial dosage form placed into soft gelatin capsules.     

Encapsulation of poorly soluble basic drugs into enteric microparticles: a novel approach to enhance their oral bioavailability

Poorly water soluble basic drugs are very sensitive to pH changes and following dissolution in the acidic stomach environment tend to precipitate upon gastric emptying, which leads to compromised or erratic oral bioavailability. In this work, we show that the oral bioavailability of a model poorly soluble basic drug (cinnarizine) can be improved by drug encapsulation within highly pH-responsive microparticles (Eudragit L). The latter was prepared by emulsion solvent evaporation which yielded discrete spherical microparticles (diameter of 56.4 ± 6.8 μm and a span of 1.2 ± 0.3). These Eudragit L (dissolution threshold pH 6.0) microparticles are expected to dissolve and release their drug load at intestinal conditions. Thus, the enteric microparticles inhibited the in vitro release of drug under gastric conditions, despite high cinnarizine solubility in the acidic medium. At intestinal conditions, the particles dissolved rapidly and released the drug which precipitated out in the dissolution vessel. In contrast, cinnarizine powder showed rapid drug dissolution at low pH, followed by precipitation upon pH change. Oral dosing in rats resulted in a greater than double bioavailability of Eudragit L microparticles compared to the drug powder suspension, although C_max and T_max were similar. The higher bioavailability with microparticles contradicts the in vitro results. Such an example highlights that although in vitro results are an indispensable tool for formulation development, an early in vivo assessment of formulation behaviour can provide better prediction for oral bioavailability.     

Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems: in vitro,in vivo and in situ intestinal permeability studies

Abstract

The main purpose of this work was to develop and evaluate a self-emulsifying drug delivery system (SEDDS) of piperine to enhance its solubility and bioavailability. The formulation was optimized by solubility test and ternary phase diagrams. Then physiochemical properties and in vitro release of SEDDS were characterized. In vivo pharmacokinetics study and in situ single-pass intestinal perfusion were performed to investigate the effects of SEDDS on the bioavailability and intestinal absorption of piperine. The optimized formulation was composed of ethyl oleate, Tween 80 and Transcutol P (3:5.5:1.5, w/w), with the level of the piperine reached 2.5% (w/w). The in vitro dissolution rates of piperine SEDDS were significantly higher than the self-prepared capsules. In vivo pharmacokinetic study showed C_max1, C_max2 and area under the curve of piperine after oral administration of SEDDS in rats were 3.8-, 7.2- and 5.2-fold higher than the self-prepared capsules, respectively, and the relative bioavailability of SEDDS was 625.74%. The in situ intestinal absorption study revealed that the effective permeability and the effective absorption rate values of piperine for SEDDS were significantly improved comparing to solutions (p?<?0.01). So SEDDS formulation could improve the oral bioavailability and intestinal absorption of piperine effectively.     

Formulation Optimization and Bioavailability After Oral and Nasal Administration in Rabbits of Puerarin-Loaded Microemulsion

The main objective of the study was to investigate the efficacy of microemulsion (ME) to facilitate bioavailability of puerarin (PUE) after oral and nasal administration. The pseudo-ternary phase diagrams were constructed to screen the ME components and optimize the ME formulation. The optimized formulation for bioavailability assessment consisted of 20% Tween 80, 20% glycerin, and 1.6% ethyl oleate. The solubility (27.8 mg/mL) of PUE in ME was significantly improved compared to that (4.58 mg/mL) of crude PUE in water. The ME droplets were spherical with a mean particle diameter of 23.4 nm. After nasal (5 mg/kg) and oral (20 mg/kg) administration of a single dose of PUE as ME to fasted rabbits, the absolute bioavailability was 34.58% and 13.54%, respectively. It showed a shorter T_max (0.75 h) for nasal administration than that (1.0 h) for oral administration of PUE-loaded ME. The C_max of PUE-loaded ME was 0.55 μg/mL after nasal administration and 0.64 μg/mL after oral administration, respectively. The results showed that nasal administration might be a promising route to enhance the absorption of PUE in the form of ME.     

Andrographolide Liquisolid using Porous-Starch as the Adsorbent with Enhanced Oral Bioavailability in Rats

Andrographolide (AGL) is the major component of Andrographispaniculata. The poor water solubility and low dissolution strongly affect its oral absorption. Liquisolid technology has been used to improve its dissolution and oral bioavailability. Liquisolid powders of AGL (AGL-LS-PSG) were obtained by firstly dissolving AGL in the mixture of NMP, PEG 6000 and Soluplus®, and solidified by absorption of the blend in porous starch. Angle of repose, Carr index and Hauser ratio presented good powder fluidity and compressibility characteristics of AGL-LS-PSG. The results of optical microscopic observation, PXRD and DSC analysis indicated that AGL has been completely adsorbed in porous starch granules and existed in an amorphous or molecularly dispersing state. AGL-LS-PSG can obviously increase the drug dissolution rate compared to commercial guttate pills and raw drug. In vivo pharmacokinetic behavior of AGL-LS-PSG was investigated following a single oral administration to rats. The C_max (0.37 ± 0.06 μg mL^?1) and AUC_0?2h (13.55 ± 2.67 μg h mL^?1) of AGL-LS-PSG were evidently increased compared to commercial guttate pills (C_max = 0.30 ± 0.21 μg mL^?1, AUC_0–2h = 9.88 ± 3.57 μg h mL^?1). This study indicated great potential of liquisolid technology in effectively improving the dissolution and bioavailability of AGL.     

Formulation development of an oral dosage form for an hiv protease inhibitor,AG1284

Several preformulation characteristics of a series of novel HIV protease inhibitors were examined as a prelude to expedient oral dosage form development. Initial studies indicated that these compounds were orally bioavailable in rats (≤ 39%), but chemically unstable at low pH. AG1284 was selected as the lead compound from the series for further preclinical development based on its relatively high oral bioavailability and stability. The pH-rate profiles of AG1284 indicated a first-order degradative loss of a dimethylbenzyl group under acidic conditions. Concentrated solutions of an amorphous form prepared in various pharmaceutical solvents exhibited precipitation on standing. The precipitate was identified as crystalline AG1284 by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and polarized light/hot stage microscopy, and its solubility in water proved to be much lower than that of the amorphous form. Oral administration in dogs of a solid blend of AG1284 with polyethylene glycol 3350 (PEG 3350) in enteric-coated hard gelatin capsules did not yield any detectable AG1284 levels in plasma. When dosed in a propylene glycol/water (60/40) solution at 50 mg/kg to rats, oral bioavailability and C_max were 39% and 2.8 μg/ml, respectively. When delivered in a lyophilizable emulsion to rats at 100 mg/kg, oral bioavailability and C_max were 31% and 3.0 μg/ml, respectively. The lyophilized product could be reconstituted with WFI to regenerate an emulsion.     

Preparation and evaluation of sustained-release azithromycin tablets in vitro and in vivo

The objective of this study was to prepare azithromycin (AZI) sustained-release products in order to allow for a high dose to be administered, reduce gastrointestinal side-effects and increase the compliance of patients. AZI sustained-release tablets with different release performance (F-I: T_100% = 3 h and F-II: T_100% = 8 h in pH 6.0 phosphate buffer) were successfully prepared by wet granulation. The in vitro release rate and drug release mechanism were studied. The release rate of F-I was affected by dissolution media with different pH, but not for F-II. Hixson–Crowell model was the best regression fitting model for F-I and F-II. Additionally, F-I and F-II both belonged to non-Fick diffusion. Oral pharmacokinetics of the two tablets and one AZI dispersible tablet as reference were studied in six healthy beagle dogs after oral administration. Compared with the reference, the C_max of F-I and F-II were decreased, and the T_max were prolonged, in that case which meet the requirement of sustained-release tablets. The relative bioavailability of F-I and F-II were 79.12% and 64.09%. T-test of AUC_0–144, and AUC_0–∞ for F-I and F-II indicated there was no significant difference between F-I and F-II. These mean that the extended release rate did not induce different pharmacokinetics in vivo.     

Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake

Huperzine A (Hup-A) is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS) was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion (SPIP) technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration–time curve (AUC) of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension (P<0.01). The absorption rate constant (K_a) and the apparent permeability coefficient (P_app) for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values of K_a and P_app of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration (C_max) of the blocking model were significantly lower than those of the control model (P<0.05). The proportion of lymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%, respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.     

Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite,norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin

This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5–64.8%, and the peak plasma concentration (C_max) of verapamil by 34.1–65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (T_max) and the terminal half-life (t_1/2) of verapamil in the presence of lovastatin. The AUC and C_max of norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.     

Differences in the bioavailability of dihydrotachysterol preparations

The bioavailability of four preparations containing dihydrotachysterol (DHT₂) was tested in two separate trials with administration of single, oral doses of 1 mg per individual. The relative bioavailability of corresponding preparations (capsules vs capsules and oral solution vs oral solution) was tested in a randomised, crossover pattern within the same group of volunteers. Two different groups of 24 healthy volunteers took part in each trial. Solution and capsule bioavailability was also compared inter-individually. A new sensitive HPLC-method (quantification limit 0.5 ng · ml^-1) was used for the measurement of DHT₂ concentration in serum.Three of the preparations tested had a similar bioavailability (mean AUC values of 195.5–223 ng · h · ml^-1); the bioavailability of the fourth preparation (A.T.10 oral solution) was considerably lower (mean AUC value 111.5 ng · h · ml^-1). The present dosage recommendations of all four preparations are identical.A new dosage recommendation is thus required for the oral solution with low bioavailability (A.T.10).     

Formulation and optimization of duloxetine hydrochloride buccal films: in vitro and in vivo evaluation

Duloxetine hydrochloride (DH) is a serotonin–norepinephrine reuptake inhibitor (SSNRI) indicated for the treatment of depression. Duloxetine suffers from reduced oral bioavailability (≈50%) due to hepatic metabolism. This study aims to develop DH buccoadhesive films to improve its bioavailability. DH buccoadhesive films were prepared adopting the solvent casting method using hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA). The prepared films were evaluated for weight uniformity, drug content, surface pH, swelling index, mucoadhesion strength and drug release percentages. Accelerated stability and bioavailability studies in healthy human volunteers were also performed for the selected films. Results of the evaluation tests showed that the optimum physicochemical characters were obtained by the films prepared with 2% HPMC using 10% propylene glycol (F2 films). Accelerated stability studies revealed that DH showed proved stability throughout the experiment time. DH bioavailability from F2 films was determined and compared with that of the marketed oral capsules (Cymbalta^® 30?mg). The pharmacokinetic results showed that C_max for F2 was higher than the market product. In addition, ANOVA analysis showed that a T_max of F2 film was significantly lower, while, the AUC_0–72 of F2 was significantly higher than that of Cymbalta capsules. The percentage relative bioavailability of DH from F2 was found to be 296.39%. Therefore, the prepared buccal films offer an alternative route for the administration of DH with the possibility of improving its bioavailability.     

The effects of differing pharmaceutical preparations of indomethacin on night pain and morning stiffness in patients with rheumatoid arthritis

Summary

A study was carried out in 18 patients with rheumatoid arthritis to compare the effects of two different preparations of indomethacin with placebo on night pain, sleep and duration of morning stiffness. Patients were treated for I night each, in random order, with identical capsules containing 75?mg indomethacin, either as Indomod' (all sustained-release form) or ‘Indocid’ R (25?mg normal, 50?mg sustained-release form), or placebo as a substitute for their usual night-time medication. The results of visual analogue scale scores and a standard sleep assessment questionnaire score indicated the same order of effectiveness for each of the three parameters, with ‘Indomod’ best, ‘Indocid’ R intermediate and placebo worst, but only the difference in sleep was statistically significant. ‘Indomod’, therefore, might offer a slight advantage over the same dose of indomethacin as ‘Indocid’ R given at night. Less side-effects were produced by active treatment than by placebo and none was severe.     

In Vitro-In Vivo Evaluation of a Controlled Release Buccal Bioadhesive Device for Oral Drug Delivery

Purpose. To investigate the use of buccal bioadhesive device in targeting controlled drug delivery to the gastrointestinal tract. Methods. A three-leg crossover study was designed to evaluate the application of buccal bioadhesive device for providing controlled drug delivery to the gastrointestinal tract of a model drug cyanocobalamin in four healthy adult male beagle dogs. Results. In vitro dissolution studies using deionized water as the medium indicated that 100% of the drug was released within 15 min from a immediate release oral capsule formulation, whereas 90% of the drug was released within a period of 18 hrs from a buccal bioadhesive device formulation. Drug release from the buccal bioadhesive devices appeared to follow Higuchi's square root of time dependent model. The terminal half-life of the drug following I.V. administration in four dogs was found to be 16.4 ± 2.4 hrs. Following immediate release oral capsule administration of the drug C_max, t_max and bioavailability were 2333 ± 1469 ng/L, 2.5± 1.0 hrs and 14.1 ± 7.9%, respectively. Following buccal bioadhesive device administration of the drug C_max, t_max and bioavailability were 4154 ± 1096 ng/L, 11 ± 1.2 hrs and 35.8 ± 4.1%, respectively. Significantly higher bioavailability of the drug was observed with the buccal bioadhesive device administration when compared to the immediate release oral capsule. Conclusions. The buccal bioadhesive device appears to improve the oral bioavailability of cyanocobalamin by providing controlled delivery of the drug to the gastrointestinal tract.     

Improved dosage form of the combined alendronate and calcitriol (Maxmarvil®) on the absorption of alendronate in Korean postmenopausal women

Alendronate is one of the most potent anti-osteoporotic agents for postmenopausal osteoporosis. However, high doses of alendronate cause esophageal irritation, myalgia, gastrointestinal discomfort and decrease of serum calcium level. Recently, Maxmarvil^® was developed as an enteric-coated tablet containing alendronate (5 mg) and calcitriol (0.5 μg) to minimize these side effects of alendronate. In the present study, we evaluated the pharmacokinetic profile and examined the incidence of unfavorable effects after oral administration of Maxmarvil^® in Korean healthy postmenopausal women without a previous history of fracture. In the in vitro dissolution test, alendronate was not released from Maxmarvil^® in pH 1.2 phosphate buffer solution but released in pH 6.0 and 6.8 phosphate buffer solutions and completely dissolved in 30 min. After oral administration of Maxmarvil^®, three out of 18 (16.7 %) women showed mild adverse effects; two myalgia and one upper gastrointestinal discomfort without heartburn. Most of these complaints disappeared during the study without additional treatment. The peak (U _max) and the average (U _ave) urinary excretion rate of alendronate and the time to reach U _max (T _max) were 2.94 μg/h, 0.901 μg/h and 6.77 h, respectively. The total cumulative urinary excretion of alendronate (Ae_0–24 h) was 21.6 μg (0.432 % of oral alendornate), which was similar to the reported values. Taken together, enteric-coated Maxmarvil^® is less harmful for the esophagus and gastrointestinal mucosa, shows the same pharmacokinetic profile to conventional alendronate (70 mg) and improves the tolerability of medication in clinical practice.     

Development of udenafil-loaded microemulsions for intranasal delivery: in vitro and in vivo evaluations

To achieve rapid onset of action and improved bioavailability of udenafil, a microemulsion system was developed for its intranasal delivery. Phase behavior, particle size, transmission electron microscope (TEM) images, and the drug solubilization capacity of the microemulsion were investigated. A single isotropic region was found in pseudo-ternary phase diagrams developed at various ratios with CapMul MCM L8 as an oil, Labrasol as a surfactant, and Transcutol or its mixture with ethanol (1:0.25, v/v) as a cosurfactant. Optimized microemulsion formulations with a mean diameter of 120-154 nm achieved enhanced solubility of udenafil (>10 mg/ml) compared with its aqueous solubility (0.02 mg/ml). An in vitro permeation study was performed in human nasal epithelial (HNE) cell monolayers cultured by the air-liquid interface (ALI) method, and the permeated amounts of udenafil increased up to 3.41-fold versus that of pure udenafil. According to the results of an in vivo pharmacokinetic study in rats, intranasal administration of udenafil-loaded microemulsion had a shorter T_max value (1 min) compared with oral administration and improved bioavailability (85.71%) compared with oral and intranasal (solution) administration. The microemulsion system developed for intranasal administration may be a promising delivery system of udenafil, with a rapid onset of action and improved bioavailability.     

The effect of antacid,metoclopramide, and propantheline on the bioavailability of metoprolol and atenolol

Concomitant administration of antacid increased the maximum concentration (Cp_max) and the area under the plasma concentration-time curve (AUC) of 100 mg oral dose of metoprolol by 25 per cent (p< 0.05) and 11 per cent (p < 0.1) respectively. For atenolol the opposite effect was observed and Cp_max and AUC were decreased by 37 and 33 per cent respectively (p< 0.02). In both cases the antacid did not affect the time-course of the drug in the plasma. Pretreatment with metoclopramide did not affect the time-course of atenolol in the plasma or its bioavailability. Propantheline prolonged the absorption phase of atenolol and the time of peaking (t_max) was shifted from 2.1 to 4.5 h. Cp_max of atenolol was essentially unchanged by propantheline pretreatment while the AUC was increased by 36 per cent. It is concluded that the negative effect of the antacid on the bioavailability of atenolol is caused by a reduction in the in vivo dissolution rate due to increased gastric pH. The positive effect of propantheline might be due either to more efficient absorption of atenolol in the upper part of the intestine or more extensive dissolution of the drug as a result of prolonged contact with gastric juice or a combination of these factors.     

Influence of Indomethacin Amphoteric Gel on Gastric Ulcerogenicity and Absorption of Indomethacin in Rats

Indomethacin is a potent and efficacious antiinflammatory agent. However, a limiting side effect is its ability to cause gastric ulceration. This study was designed to investigate the effects of an amphoteric gel on the gastric ulcerogenicity and pharmacokinetics of indomethacin. Oral administration (5 mg/kg) in a suspension and a gel formulation were compared to an intravenous (iv) formulation of indomethacin in rats. The iv formulation administered to rats produced large severe ulcers in some rats but not in others. In contrast, the oral suspension produced small ulcers in all rats. The difference in toxicities is attributed to a centrally mediated action as a result of high plasma levels of indomethacin following iv administration, compared to locally mediated action with the suspension, resulting from local high concentrations of indomethacin on the apical epithelial surface because of the presence of indomethacin crystals. Oral administration of the gel formulation did not result in any gastric ulceration and improved the bioavailability of indomethacin to 115.5%, compared with 68.2% for the suspension. The reduced gastrointestinal toxicity of indomethacin in the gel was attributed to the gel's ability to dissolve indomethacin, preventing the localized high concentration observed with the suspension and possibly providing a gastric protectant phospholipid. The gel formulation doubled the oral bioavailability and the t _max of indomethacin compared to the suspension but did not affect the half-life. The results indicate that the local irritant effect of indomethacin, in rats, can be reduced by appropriate formulation design and suggest that the ulcerogenicity index for indomethacin can be improved by the use of an amphoteric gel formulation.