Controlled in vivo release of nicorandil from a carvone-based transdermal therapeutic system in human volunteers.

The aim of our present study was to prepare and evaluate a carvone-based transdermal therapeutic system (TTS) of nicorandil to find its ability in providing the desired in vivo controlled release profile on dermal application to human volunteers. The effect of EVA 2825, and adhesive-coated EVA 2825, and adhesive-coated EVA 2825-rat skin composite on the in vitro permeation of nicorandil from a carvone-based HPMC gel drug reservoir was studied against a control (rat abdominal skin alone). The carvone-based drug reservoir system was sandwiched between adhesive-coated EVA 2825-release liner composite and a backing membrane. The resultant drug reservoir sandwich was heat-sealed to produce a circle-shaped TTS (20 cm(2)) that was subjected to in vivo evaluation on dermal application to human volunteers against oral administration of immediate-release tablets of nicorandil. The carvone-based TTS provided a steady-state plasma concentration of 20.5 ng/ml for approximately 24 hr in human volunteers. We concluded that the carvone-based TTS of nicorandil provided the desired in vivo controlled-release profile of the drug for the predetermined period of time.

Effect of nerodilol, carvone and anethole on the in vitro transdermal delivery of selegiline hydrochloride.

The aim of the study was to investigate the effect of terpene enhancers (nerodilol, carvone or anethole) on the in vitro transdermal delivery of selegiline hydrochloride with a broad objective of developing a membrane-moderated transdermal therapeutic system (TTS). The in vitro permeation studies were carried across the rat epidermis from hydroxypropyl methylcellulose (HPMC) gel drug reservoir containing selected concentrations of nerodilol, carvone or anethole and selegiline hydrochloride. The amount of selegiline hydrochloride permeated during the 24 h of the study (Q24) from HPMC gel drug reservoir without terpene enhancer was 2169 +/- 50 microg/cm2 and the corresponding flux of the drug was 92 +/- 1 microg/cm2 x h. The amount of drug permeated and its flux increased with an increase in terpne concentration in HPMC gel drug reservoir. Nerodilol provided an approximately 3.2-fold increase in the flux of selegiline hydrochloride followed by carvone with a 2.8-fold increase, and anethole with a 2.6-fold increase. It is concluded that the terpene nerodilol, carvone and anethole produced a marked penetration enhancing effect on the in vitro transdermal delivery of selegiline hydrochloride that could possibly be used in the formulation of membrane-moderated TTS.

Bioavailability of nerodilol-based transdermal therapeutic system of nicorandil in human volunteers.

The objective of the present investigation was to design and evaluate a nerodilol-based transdermal therapeutic system (TTS) for finding its ability in providing the desired steady-state plasma concentration of nicorandil in human volunteers. The influence of EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825-rat skin composite on the in vitro permeation of nicorandil from a nerodilol-based HPMC gel drug reservoir was studied against a control (excised rat skin alone). The flux of nicorandil from the nerodilol-based HMPC drug reservoir across excised rat skin (control) was 384.0+/-4.6 microg/cm2 h and this decreased to 222.7+/-7.1 microg/cm2 h when studied across EVA2825 membrane indicating that EVA2825 membrane was effective as rate controlling membrane. The flux of the drug decreased to 183.8+/-5.7 microg/cm2 h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat to EVA2825 membrane. However, the flux of nicorandil across adhesive-coated EVA2825-membrane-rat-skin composite was 164.8+/-1.8 microg/cm2 h, which was 1.74-times of the required flux that prompted for preparation of TTS. The nerodilol-based drug reservoir system was sandwiched between a composite of adhesive-coated EVA2825 membrane-release liner and a backing membrane. The resultant sandwich was heat-sealed to produce circle-shaped TTS (20 cm2) that were subjected to bioavailability study in human volunteers against immediate release nicorandil tablet. The nerodilol-based TTS provided a steady-state plasma concentration of 25.5 ng/ml for 24 h in human volunteers. It was concluded that the nerodilol-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations.

In vitro and in vivo evaluation of guar gum-based matrix tablets of rofecoxib for colonic drug delivery.

The present study was carried out to develop and evaluate guar gum-based matrix tablets of rofecoxib for their intended use in the chemoprevention of colorectal cancer. Matrix tablets containing 40% (RXL-40), 50% (RXL-50), 60% (RXL-60) or 70% (RXL-70) of guar gum were prepared by wet granulation technique, and were subjected to in vitro drug release studies. Guar gum matrix tablets released only 5 to 12% of rofecoxib in the physiological environment of stomach and small intestine. The matrix tablets RXL-40 disintegrated completely within 10 h in a dissolution medium without rat caecal contents (control study), and hence not studied further. When the dissolution study was continued in simulated colonic fluids (rat caecal content medium), the matrix tablets RXL-50 were acted upon by colonic bacterial enzymes releasing the entire quantity of drug wherein there was no appreciable difference when compared to that released in control study. The matrix tablets RXL-60 released another 88% of rofecoxib whereas matrix tablets RXL-70 released only 57% of rofecoxib in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The guar gum matrix tablets RXL-70 were subjected to in vivo evaluation in human volunteers to find their ability of targeting rofecoxib to colon. The delayed Tmax, prolonged absorption time (ta), decreased Cmax and decreased ka indicated that rofecoxib was not released significantly in stomach and small intestine, but was delivered to colon resulting in a slow absorption of the drug and making it available for local action in human colon.

In vitro evaluation of guar gum as a carrier for colon-specific drug delivery.

A novel tablet formulation for oral administration using guar gum as the carrier and indomethacin as a model drug has been investigated for colon-specific drug delivery using in vitro methods. Drug release studies under conditions mimicking mouth to colon transit have shown that guar gum protects the drug from being released completely in the physiological environment of stomach and small intestine. Studies in pH 6.8 phosphate buffered saline (PBS) containing rat caecal contents have demonstrated the susceptibility of guar gum to the colonic bacterial enzyme action with consequent drug release. The pre-treatment of rats orally with 1 ml of 2% w/v aqueous dispersion of guar gum for 3 days induced enzymes specifically acting on guar gum thereby increasing drug release. A further increase in drug release was observed with rat caecal contents obtained after 7 days of pre-treatment. The presence of 4% w/v of caecal contents obtained after 3 days and 7 days of enzyme induction showed biphasic drug release curves. The results illustrate the usefulness of guar gum as a potential carrier for colon-specific drug delivery. The study also reveals that the use of 4% w/v of rat caecal contents in PBS, obtained after 7 days of enzyme induction provide the best conditions for in vitro evaluation of guar gum.

Bioavailability studies on guar gum-based three-layer matrix tablets of trimetazidine dihydrochloride in human volunteers.

Guar gum-based three-layer matrix tablets of a highly water-soluble drug, trimetazidine dihydrochloride, were evaluated for their in vivo release in healthy volunteers in comparison with commercially available conventional immediate release tablets. Six healthy volunteers participated in the study and a two-way crossover design was followed. The plasma concentration of trimetazidine dihydrochloride was estimated by reverse-phase HPLC. The pharmacokinetic parameters were calculated from the plasma concentration of trimetazidine dihydrochloride versus time data. The delayed T(max), decreased C(max) and K(a), unaltered bioavailability, and prolonged t(1/2) and MRT indicated a slow and prolonged release of trimetazidine dihydrochloride from guar gum three-layer matrix tablets in comparison with the immediate release tablet dosage form. The guar gum three-layer matrix tablets of trimetazidine dihydrochloride may be useful in providing constant drug delivery with minimum fluctuations.

Three-layer guar gum matrix tablet formulations for oral controlled delivery of highly soluble trimetazidine dihydrochloride.

The present study is carried out to design oral controlled drug delivery systems for highly water-soluble drugs using guar gum as a carrier in the form of three-layer matrix tablets. Trimetazidine dihydrochloride was chosen as a model drug because of its high water solubility. Matrix tablet granules containing 30% (M1), 40% (M2) or 50% (M3) of guar gum were prepared by the wet granulation technique using starch paste as a binder. Three-layer matrix tablets of trimetazidine dihydrochloride were prepared by compressing on either side of guar gum matrix tablet granules of trimetazidine dihydrochloride M1, M2 or M3 with 200 mg of guar gum granules containing either 65% of guar gum (T1M1, T1M2 or T1M3), 75% of guar gum (T2M1, T2M2 or T2M3) or 85% of guar gum (T3M1, T3M2 or T3M3) as release retardant layers. The three-layer matrix tablets were evaluated for hardness, thickness, drug content uniformity, and were subjected to in vitro drug release studies. The amount of trimetazidine dihydrochloride released from the matrix and three-layer matrix tablets at different time intervals was estimated using a HPLC method. The three-layer guar gum matrix tablet (T3M3) provided the required release rate on par with the theoretical release rate for guar gum formulations meant for twice daily administration. The three-layer guar gum matrix tablet (T3M3) showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/RH 75% for 6 months. The DSC study did not show any possibility of interaction between trimetazidine dihydrochloride and guar gum/other formulation excipients used in the study. The results indicated that guar gum, in the form of three-layer matrix tablets, is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs such as trimetazidine dihydrochloride.

Gamma scintigraphic studies on guar gum matrix tablets for colonic drug delivery in healthy human volunteers.

A novel colon-specific drug delivery system based on a polysaccharide, guar gum, was evaluated by conducting gamma scintigraphic studies using technetium-99m-DTPA as tracer, in six healthy male human volunteers. Scintigraphs taken at regular intervals have shown that some amount of tracer present on the surface of the tablets was released in stomach and small intestine and the bulk of the tracer present in the tablet mass was delivered to the colon. The colonic arrival time of the tablets was found to be 2 to 4 h. On entering the colon, the tablets were found to be degraded in five out of six volunteers thereby releasing a larger amount of the tracer. The study clearly demonstrates that guar gum, in the form of directly compressed matrix tablets, is a potential carrier for colon-specific drug delivery.

Development of colon targeted drug delivery systems for mebendazole.

The objective of the present study is to develop colon targeted drug delivery systems for mebendazole using guar gum as a carrier. Matrix tablets containing various proportions of guar gum were prepared by wet granulation technique using starch paste as a binder. The tablets were evaluated for drug content uniformity, and were subjected to in vitro drug release studies. The amount of mebendazole released from the matrix tablets at different time intervals was estimated by a high-performance liquid chromatography method. Guar gum matrix tablets released 8-15% of the mebendazole in the physiological environment of stomach and small intestine depending on the proportion of guar gum used in the formulation. When the dissolution study was continued in simulated colonic fluids the matrix tablets containing 20% of guar gum released another 83% of mebendazole after degradation into 2-3 pieces. The matrix tablets containing 30% of guar gum also released about 50% of mebendazole in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that matrix tablets containing either 20% or 30% of guar gum are most likely to provide targeting of mebendazole for local action in the colon. The mebendazole matrix tablets containing either 20% or 30% of guar gum showed no change either in physical appearance, drug content or dissolution pattern after storage at 45 degrees C/75% relative humidity for 3 months. Differential scanning calorimetry indicated no possibility of interaction between mebendazole and guar gum.

Pharmacokinetic evaluation of guar gum-based colon-targeted drug delivery systems of mebendazole in healthy volunteers.

The pharmacokinetic evaluation of guar gum-based colon-targeted tablets of mebendazole against an immediate release tablet was carried out in human volunteers. Six healthy volunteers participated in the study and a crossover design was followed. Mebendazole was administered at a dose of 50 mg both in immediate release tablet and colon-targeted tablets. On oral administration of colon-targeted tablets, mebendazole started appearing in the plasma at 5 h, and reached the peak concentration (C(max) of 25.7+/-2.6 ng/ml) at 9.4+/-1.7 h (T(max)) whereas the immediate release tablets produced peak plasma concentration (C(max) of 37.2+/-6.8 ng/ml) at 3.4+/-0.9 h (T(max)). Colon-targeted tablets showed delayed t(max) and absorption time, and decreased C(max) and absorption rate constant when compared to the immediate release tablets. The results of the study indicated that the guar gum-based colon-targeted tablets of mebendazole did not release the drug in stomach and small intestine, but delivered the drug to the colon resulting in a slow absorption of the drug and making the drug available for local action in the colon.

Influence of menthol and pressure-sensitive adhesives on the in vivo performance of membrane-moderated transdermal therapeutic system of nicardipine hydrochloride in human volunteers.

A membrane-moderated transdermal therapeutic system of nicardipine hydrochloride was developed using 2% w/w hydroxypropylcellulose (HPC) gel as a reservoir system containing 5% w/w of menthol as a penetration enhancer. The permeability flux of nicardipine hydrochloride through the ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38 or TACKWHITE A 4MED on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28% w/w vinyl acetate) or EVA 2825 membrane/skin composite was also studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new transdermal therapeutic system for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED, and 2% w/w HPC gel as reservoir containing 5% w/w of menthol as a penetration enhancer. In vivo studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 26h with improved bioavailability in comparison with the immediate release capsule dosage form.

Pharmacokinetic evaluation of guar gum-based three-layer matrix tablets for oral controlled delivery of highly soluble metoprolol tartrate as a model drug.

The objective of the present study is to carry out pharmacokinetic evaluation of oral controlled release formulation (guar gum-based three-layer matrix tablets) containing highly soluble metoprolol tartrate as a model drug. Six healthy volunteers participated in the study, and a two-way crossover design was followed. The plasma concentration of metoprolol tartrate was estimated by reverse-phase HPLC. The pharmacokinetic parameters were calculated from the plasma concentration of metoprolol tartrate versus time data. The delayed T(max) lower C(max) decreased K(a) unaltered bioavailability and prolonged t(1/2) indicated a slow and prolonged release of metoprolol tartrate from guar gum three-layer matrix tablets in comparison with the immediate release tablet dosage form. The results of the study indicated that guar gum three-layer matrix tablets were able to provide oral controlled delivery of highly water-soluble drug such as metoprolol tartrate in humans.

In vivo evaluation of guar gum-based colon-targeted drug delivery systems of ornidazole in healthy human volunteers.

The aim of the present study was to find the in vivo performance of guar gum-based colon-targeted tablets of ornidazole (dose 250 mg) in comparison with an immediate release tablet of ornidazole (250 mg) in human volunteers. Six healthy volunteers participated in the study, and a cross over design was followed. The plasma concentration of ornidazole was estimated by HPLC. The immediate release tablets of ornidazole produced peak plasma concentration (Cmax of 2171.33+/-278.15 ng/ml) at 2.91+/-0.14 h (Tmax) whereas colon-targeted tablets produced peak plasma concentration (Cmax of 1716.66+/-125.83 ng/ml) at 11.91+/-0.14 h. The delayed Tmax, decreased Cmax, and decreased ka of ornidazole from guar gum-based colon-targeted ornidazole tablets, in comparison with the immediate tablets, indicated that the drug was not released in stomach and small intestine, but targeted to colon. Slow absorption of ornidazole from the less absorptive colon might result in the availability of drug for local action in the colon.

Studies on the development of colon-targeted delivery systems for celecoxib in the prevention of colorectal cancer.

The nonsteroidal anti-inflammatory drugs (NSAIDs) are found to be potential chemopreventive agents of colorectal cancer. Celecoxib, an NSAID with selective cyclooxygenase-2 inhibition, was proved to be effective for the prevention of colon cancer in patients with familial adenomatous polyposis (FAP) and sporadic polyps. In the light of this information, the present study was carried out to develop oral colon-targeting drug delivery systems for celecoxib using guar gum as a carrier. Matrix tablets containing various proportions of guar gum were prepared by wet granulation technique using starch paste as a binder. The tablets were evaluated for hardness, drug content and were subjected to in vitro drug release studies. The amount of celecoxib released from the matrix tablets at different time intervals was estimated by a HPLC method. Guar gum matrix tablets released only 2-4% of celecoxib in the physiological environment of stomach and small intestine depending on the proportion of guar gum used in the formulation. When the dissolution study was continued in simulated colonic fluids (rat caecal content medium), the matrix tablets containing 20% of guar gum released another 37% of celecoxib after degradation by the colonic bacterial action. The matrix tablets containing 30% of guar gum released about 24% of celecoxib in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that the matrix tablets containing either 20 or 30% of guar gum are most likely to target celecoxib for local action in the colon. The guar gum matrix tablets of celecoxib showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/RH 75% for 6 months. Differential scanning calorimetry (DSC) studies indicated no possibility of interaction between celecoxib and guar gum/other formulation excipients.

Design and in vitro evaluation of oral colon targeted drug delivery systems for tinidazole.

The aim of the present investigation is to develop colon targeted drag delivery sytems for tinidazole using guar gum as a carrier in the treatment of amoebiasis. Fast-disintegrating tinidazole core tablets were compression-coated with 55, 65 and 75% of guar gum. All the formulations were evaluated for the hardness, drug content uniformity, and subjected to in vitro drug release studies. The amount of tinidazole released from tablets at different time intervals was estimated by HPLC method. The compression-coated formulations released < 0.5% of tinidazole in the physiological environment of stomach and small intestine. When the dissolution study was continued in simulated colonic fluids, the compression coated tablet with 55% of guar gum coat released 99% of tinidazole after degradation by colonic bacteria at the end of 24 h of the dissolution study. The compression coated tablets with 65 and 75% of guar gum coat released about 67 and 20% of tinidazole, respectively in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that compression coated tinidazole tablets with either 55 or 65% of guar gum coat is most likely to provide targeting of tinidazole for local action in the colon owing to its minimal release of the drug in the first 5 h of physiological environment of stomach and small intestine. The tinidazole compression coated tablets showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/75% RH for 6 months.

Effect of the solvent system on the in vitro permeability of nicardipine hydrochloride through excised rat epidermis.

PURPOSE: The present investigation was carried out to study the effect of the solvent system on the permeation of nicardipine hydrochloride across excised rat epidermis in order to select a suitable solvent system for use in the development of a transdermal therapeutic system. METHODS: The solubility of nicardipine hydrochloride in pure and mixed solvent systems was determined. The solvents used were water, propylene glycol, ethanol or various proportions of ethanol and water. The effect of these pure or mixed solvent systems on the skin permeation of nicardipine hydrochloride was also studied using in vitro permeation studies through excised rat epidermis mounted in modified Keshary-Chien diffusion cells. Fourier Transform Infrared Spectroscopy (FT-IR) and Differential Scanning Calorimetry (DSC) studies were carried out to study the effect of these solvents on the biophysical properties of rat' stratum corneum. RESULTS: Although the solubility of nicardipine hydrochloride in propylene glycol (51.23 mg/mL) was higher than that in water (7.90 mg/mL) and ethanol (20.01 mg/mL), the flux of the drug from propylene glycol was as low (7.25+/-0.13 microg/cm(2)/h) as that from water (7.05+/-0.15 microg/cm(2)/h) and lower than that from ethanol (21.51+/-0.81 microg/cm(2)/h). The solubility of nicardipine hydrochloride in binary ethanol-water solvent systems in various proportions was higher than in pure solvents. The highest permeability was observed from an ethanol-water (70:30 v/v) solvent system (56.10+/-1.23 micro g/cm(2)/h) which showed the highest solubility (224.21 mg/mL). The DSC and FT-IR data indicated that the binary solvent system containing ethanol-water in the ratio of 70:30 v/v increased the drug permeability through the skin by disrupting the highly ordered intercellular lipid structure of the stratum corneum in comparison with the untreated stratum corneum. CONCLUSIONS: The results of the study indicate that the use of a binary solvent system, ethanol and water in the ratio of 70:30 v/v, is an effective vehicle for the development of a transdermal therapeutic system for nicardipine hydrochloride.

In vivo evaluation of 99mTc-DTPA and 99mTc-sulphur colloid as tracers in colonic drug delivery systems using gamma scintigraphy in volunteers.

PURPOSE: The suitability of 99mTc-diethylenetriaminepenta- acetic acid (DTPA) and 99mTc-sulphur colloid (99mTc-SC) as tracers in gamma scintigraphy for the evaluation of colon-specific drug delivery systems was assessed in healthy volunteers. METHOD: Sodium chloride core tablets containing either 99mTc-DTPA or 99mTc-SC were prepared and compression coated with two different quantities of guar gum. The compression-coated tablets were subjected to gamma scintigraphic studies for colonic drug delivery in healthy human volunteers. RESULTS: The tablets containing 99mTc-DTPA did not release the tracer in stomach and small intestine, and on entering the colon disintegrated completely whereas the tablets containing 99mTc-SC remained intact in stomach, small intestine and in colon as well. The study showed that DTPA is a suitable tagging agent for 99mTc in the evaluation of guar gum based colonic drug delivery systems containing water-soluble drugs. CONCLUSION: In the present investigation guar gum was applied externally as a compression coat over the radiolabelled core. Since the core consisted of water-soluble material (sodium chloride), it is possible that the release of the tracer from the 99mTc-DTPA containing formulations is a combined effect of enzymatic action and diffusion of the salt. The failure of disintegration of 99mTc-SC containing formulations might be due to its interference with the disintegration or the part diffusion observed with 99mTc-DTPA cores. The results of the study showed that DTPA is a suitable tagging agent for 99mTc in the evaluation of colonic drug delivery systems containing water-soluble drugs by gamma scintigraphy.

Guar gum as a carrier for colon specific delivery; influence of metronidazole and tinidazole on in vitro release of albendazole from guar gum matrix tablets.

PURPOSE: The present investigation is to study the influence of metronidazole and tinidazole on the usefulness of guar gum, a colon-specific drug carrier based on the metabolic activity of colonic bacteria, using matrix tablets of albendazole (containing 20% of guar gum) as a model formulation. METHODS: The matrix tablets of albendazole were subjected to in vitro drug release studies in simulated colonic fluids (4%w/v of rat caecal contents) obtained after oral treatment of rats for 7 days either with varying doses of metronidazole/ tinidazole and 1 mL of 2%w/v of guar gum or with 1 mL of 2%w/v of guar gum alone (control study) after completing the dissolution study in 0.1 M HCl (2 h) and pH 7.4 Sorensen's phosphate buffer (3 h). RESULTS: The guar gum matrix tablets of albendazole were found degraded by colonic bacteria of rat caecal contents and released about 44% of albendazole in simulated colonic fluids (control study) at the end of 24 h indicating the susceptibility of the guar gum formulations to the rat caecal contents. However, the release of albendazole decreased when the drug release studies were carried out in caecal contents of rats treated for 7 days with either metronidazole (10-50 mg/ kg once daily) or tinidazole (10-30 mg/ kg once daily), and the release of albendazole from the matrix tablets was found to be dose dependent. The release of the drug from guar gum formulations was found to increase with a decrease in the dose of metronidazole/tinidazole administered. The antimicrobial activity of metronidazole/ tinidazole against the anaerobic bacteria of the rat"s GI flora might have been inhibited to a varying degree depending on the dose of metronidazole/tinidazole administered. CONCLUSIONS: The results of the study showed that concomitant administration of either metronidazole or tinidazole with guar gum based colon-specific drug delivery systems may interfere with the targeting of drugs to colon.

In vivo pharmacokinetics in human volunteers: oral administered guar gum-based colon-targeted 5-fluorouracil tablets.

The objective of the present study is to compare the guar gum-based colon-targeted tablets of 5-fluorouracil against an immediate release tablet by in vitro dissolution and in vivo pharmacokinetic studies in human volunteers. Twelve healthy volunteers participated in the study. 5-Fluorouracil was administered at a dose of 50 mg both in immediate release tablet and colon-targeted tablet. On oral administration of colon-targeted tablets, 5-fluorouracil started appearing in the plasma at 6 h, and reached the peak concentration (C(max) of 216+/-15 ng/ml) at 7.6+/-0.1 h (T(max)), whereas the immediate release tablets produced peak plasma concentration (C(max) of 278+/-21 ng/ml) at 0.6+/-0.01 h (T(max)). The AUC(0- infinity ) for 5-fluorouracil from colon-targeted tablet and immediate release tablet were found to be 617+/-39 and 205+/-21 ng/ml/h, respectively. Colon-targeted tablets showed delayed t(max), delayed absorption time (t(a)), decreased C(max) and decreased absorption rate constant when compared to the immediate release tablets. The results of the study indicated that the guar gum-based colon-targeted formulation did not release the drug in stomach and small intestine, but delivered it to the colon resulting in a slow absorption of the drug and making it available for local action in colon.

In vitro drug release studies on guar gum-based colon targeted oral drug delivery systems of 5-fluorouracil.

Intravenous administration of 5-fluorouracil for colon cancer therapy produces severe systemic side-effects due to its cytotoxic effect on normal cells. The broad objective of the present study was to develop novel tablet formulations for site-specific delivery of 5-fluorouracil to the colon without the drug being released in the stomach or small intestine using guar gum as a carrier. Fast-disintegrating 5-fluorouracil core tablets were compression coated with 60% (FHV-60), 70% (FHV-70) and 80% (FHV-80) of guar gum, and were subjected to in vitro drug release studies. The amount of 5-fluorouracil released from the compression-coated tablets in the dissolution medium at different time intervals was estimated by a HPLC method. Guar gum compression-coated tablets released only 2.5-4% of the 5-fluorouracil in simulated GI fluids. When the dissolution study was continued in simulated colonic fluids (4% w/v rat caecal content medium) the compression-coated FHV-60, FHV-70 and FHV-80 tablets released another 70, 55 and 41% of the 5-fluorouracil respectively. The results of the study show that compression-coated tablets containing 80% (FHV-80) of guar gum are most likely to provide targeting of 5-fluorouracil for local action in the colon, since they released only 2.38% of the drug in the physiological environment of the stomach and small intestine. The FHV-80 formulation showed no change either in physical appearance, drug content or dissolution pattern after storage at 40 degrees C/RH 75% for 6 months. The differential scanning calorimetric study showed that 5-fluorouracil did not interact with the formulation excipients used in the study.