Y. S. R. Krishnaiah

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.

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.

Evaluation of guar gum as a compression coat for drug targeting to colon

Abstract Colon-specific drug delivery systems based on a polysaccharide, guar gum, were evaluated using in vitro and in vivo methods. In vitro drug release studies have shown that guar gum in the form of compression coat applied over indomethacin core tablets protects the drug from being released under conditions mimicking mouth to colon transit. Studies in pH 6.8 phosphate buffered saline (PBS) containing 4% w/v rat caecal contents have demonstrated the susceptibility of guar gum to the colonic bacterial enzyme action with consequent drug release. gamma-scintigraphic studies in human volunteers with technetium-99m-DTPA as a tracer in sodium chloride core tablets compression coated with guar gum have shown that the gum coat protect the drug (tracer in the present study) from being released in the stomach and small intestine. On entering the ascending colon, the tablets commenced to release the tracer indicating the breakdown of the gum coat by the enzymatic action of colonic bacteria. The tablets disintegrated in the ascending colon of all the volunteers, except one, resulting in the distribution of released tracer across the entire colon. The study clearly established that guar gum, in the form of compression coat, is a potential carrier for drug targeting to colon.

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.

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.

Studies on the development of oral colon targeted drug delivery systems for metronidazole in the treatment of amoebiasis.

The aim of the present study is to develop colon targeted drug delivery systems for metronidazole using guar gum as a carrier. Matrix, multilayer and compression coated tablets of metronidazole containing various proportions of guar gum were prepared. All the formulations were evaluated for the hardness, drug content uniformity, and were subjected to in vitro drug release studies. The amount of metronidazole released from tablets at different time intervals was estimated by high performance liquid chromatography method. Matrix tablets and multilayer tablets of metronidazole released 43-52% and 25-44% of the metronidazole, respectively, in the physiological environment of stomach and small intestine depending on the proportion of guar gum used in the formulation. Both the formulations failed to control the drug release within 5 h of the dissolution study in the physiological environment of stomach and small intestine. The compression coated formulations released less than 1% of metronidazole in the physiological environment of stomach and small intestine. When the dissolution study was continued in simulated colonic fluids, the compression coated tablet with 275 mg of guar gum coat released another 61% of metronidazole after degradation by colonic bacteria at the end of 24 h of the dissolution study. The compression coated tablets with 350 and 435 mg of guar gum coat released about 45 and 20% of metronidazole, 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 metronidazole tablets with either 275 or 350 mg of guar gum coat is most likely to provide targeting of metronidazole for local action in the colon owing to its minimal release of the drug in the first 5 h. The metronidazole 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.

A three-layer guar gum matrix tablet for oral controlled delivery of highly soluble metoprolol tartrate.

The objective of the study is to design oral controlled drug delivery systems for highly water-soluble drugs using guar gum as a carrier in the form of a three-layer matrix tablet. Metoprolol tartrate was chosen as a model drug because of its high water solubility. Matrix tablets containing either 30 (M1), 40 (M2) or 50% (M3) of guar gum were prepared by wet granulation technique using starch paste as a binder. Three-layer matrix tablets of metoprolol tartrate were prepared by compressing on both sides of guar gum matrix tablet granules of metoprolol tartrate M1, M2 or M3 with either 50 (TL1M1, TL1M2 or TL1M3) or 75 mg (TL2M1, TL2M2 or TL2M3) of guar gum granules as release retardant layers. Both the matrix and three-layer matrix tablets were evaluated for hardness, thickness, drug content uniformity, and subjected to in vitro drug release studies. The amount of metoprolol tartrate released from the matrix and three-layer matrix tablets at different time intervals was estimated by using a HPLC method. Matrix tablets of metoprolol tartrate were unable to provide the required drug release rate. However, the three-layer guar gum matrix tablets (TL2M3) provided the required release rate on par with the theoretical release rate for metoprolol tartrate formulations meant for twice daily administration. The three-layer guar gum matrix tablet (TL2M3) showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/75% RH for 6 months. The FT-IR study did not show any possibility of metoprolol tartrate/guar gum interaction with the 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 metoprolol tartrate.

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.

Studies of guar gum compression-coated 5-aminosalicylic acid tablets for colon-specific drug delivery.

The aim of this study was to develop colon-specific delivery systems for 5-aminosalicylic acid (5-ASA) using guar gum as a carrier. Core tablets containing 5-ASA were prepared by wet granulation with starch paste and were compression coated with coating formulations containing different quantities of guar gum (300, 200, 150, and 125 mg). In vitro drug release studies were carried out in simulated gastric and intestinal fluids and in pH 6.8 buffer containing rat cecal contents. The application of 175 mg of coating formulation containing 150 mg of guar gum over 5-ASA core tablets resulted in the release of less than 2% drug in simulated gastric and intestinal fluids and about 93% of 5-ASA in pH 6.8 buffer containing rat cecal contents. Differential scanning calorimetric (DSC) studies showed the absence of any interaction between 5-ASA and the excipients on storage at 45 degrees C for 12 weeks. The study confirmed that selective delivery of 5-ASA to the colon can be achieved using guar gum as a carrier in the form of a compression coating over the drug core.

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.