Prabhat K. Shrivastava

Dextran Carrier Macromolecule for Colon Specific Delivery of Celecoxib

The colon specific polymeric conjugates of celecoxib were prepared with dextran of different molecular weight Mr approximately 40 000, 70 000, and 100 000 (CSD-40, CSD-70 and CSD-100). Succinic acid was used as linker between the drug and dextran. The prepared conjugates were characterized by UV, IR, 1H NMR and HPLC. The maximum degree of substitution 3.9+/-0.20 % was found with the dextran CSD-100 conjugates. The percent release of drug obtained by in-vitro hydrolysis studies, was found to be 24.37+/- 0.6, 23.0 +/- 0.5 and 20.13+/- 0.8 in simulated colonic fluid (SCF) pH 6.8 while 17.90 +/- 0.4, 16.8+/- 0.75 and 15.47 +/- 0.5 in simulated intestinal fluid (SIF) pH 7.4 for CSD-40, CSD-70 and CSD-100, respectively, in both medium. The drug release from the conjugates was observed for 24 h in 3% w/v rat caecal content and found to be 41.77 +/- 1.2, 39.03 +/- 1.0 and 35.26 +/- 1.09 for CSD-40, CSD-70 and CSD-100 conjugates, respectively. The half life of conjugates was determined and was found to be short in 3% w/v rat caecal content. No amount of drug was released in simulated gastric fluid pH 1.2 and stomach homogenate in 2 h. The amount of drug released from small intestine homogenate was 3.4+/- 0.1 percent in 12 h for the CSD-40. The above result suggests that dextran could be used as a macromolecular carrier for colon specific drug delivery of celecoxib.

Concurrent estimation of clopidogrel bisulfate and aspirin in tablets by validated RP-HPLC method

A simple, rapid, precise RP-HPLC method was developed for simultaneous estimation of aspirin and clopidogrel bisulphate in tablet dosage form used in the treatment of cardiovascular diseases. To achieve the maximum resolution, acetonitrile:50 mM potassium dihydrogen phosphate buffer:methanol, solution pH adjusted to 3, in the ratio 50:30:20; v/v was selected as mobile phase. This mixture was found to be appropriate allowing good separation of both the components at a flow rate of 1.5 ml/min and detection wavelength 240 nm. In these conditions clopidogrel bisulfate and aspirin were eluated at the 7.47 and 2.2 min. The linearity was found in the concentration range 1.5-7.5 and 3.5-15.0 μg/ml, respectively. All the analytical validation parameters were determined and found with in the limit as per ICH guideline, which indicates the validity of method.

Development and validation of a HPLC method for the simultaneous estimation of amlodipin and telmisartan in pharmaceutical dosage form

Abstract Objective To develope and validate a simple and rapid isocratic reversed-phase highperformance liquid chromatographic method (RP-HPLC) for the simultaneous estimation of amlodipin and telmisartan in combined dosage form. Methods The chromatographic separation was achieved by using mobile phase acetonitrile and 0.05M sodium dihydrogen phosphate buffer (60:40) adjusted to pH 6.0, a C-18 column, perfectsil target ODS3 (150 mm × 4.6 mm i.d. , 5 μm). The mobile phase was pumped at a flow rate of 0.8 mL/min and the eluents were monitered at 254 nm. Results Retention times were 4.0 min and 8.2 min for amlodipine and telmisartan respectively. The method was validated in terms of accuracy, precision, linearity, range, specificity, limit of detection and limit of quantitation. Linearity for amlodipine besylate and telmisartan was established in the range of 5-30 and 10-60 μg/mL, respectively. The recoveries for the two compounds were above 96%. Conclusions This method was found to be efficient, accurate, precise, specific and economic and is suitable for routine quality control analyses.

Polyamidoamine dendrimer and dextran conjugates: preparation, characterization, and in vitro and in vivo evaluation

Amide and ester conjugates of aceclofenac with polyamidoamine (PAMAM-G0) dendrimer zero generation and dextran (40 kDa) polymeric carrier, respectively, are presented. The prepared conjugates were characterized by UV, TLC, HPLC, IR, and 1H NMR spectroscopy. The average degrees of substitution of amide and ester conjugates were determined and found to be (12.5 ± 0.24) % and (7.5 ± 0.25) %, respectively. The in vitro hydrolysis studies showed that dextran ester conjugate hydrolyzed faster in a phosphate buffer solution of pH 9.0 as compared to PAMAM dendrimer G0 amide conjugate, and followed the first order kinetics. No amount of the drug was regenerated at pH 1.2 in simulated gastric fluid. The dextran conjugate showed short half-life as compared to the PAMAM dendrimer conjugate. Anti-inflammatory and analgesic activities of the dendrimer conjugate were found to be similar to those of the standard drug. Results of chronic ulceroginic activity showed deep ulceration and high ulcer index for aceclofenac, whereas lower ulcer index was found for the PAMAM dendrimer and dextran (40 kDa) conjugates. Experimental data suggest that PAMAM dendrimer and dextran (40 kDa) can be used as carriers for the sustained delivery of aceclofenac along with a remarkable reduction in gastrointestinal toxicity.

Lamotrigine–dextran conjugates-synthesis, characterization, and biological evaluation

Synthesis of lamotrigine–dextran conjugates is done by oxidation of dextran using sodium periodate (NaIO4), where the aldehyde groups formed were coupled with the amino (–NH2) group of lamotrigine and reduced to secondary imine groups. Characterization of synthesized conjugates was done by using ultraviolet, infrared, nuclear magnetic resonance spectroscopy. Viscometer was used to determine molecular weight, and degree of substitution was estimated by complete hydrolysis of conjugates in borate buffer, which was found to be 8%. Buffer solutions with different pH, i.e., 1.2, 7.4, and 9.0 were used to perform the in vitro hydrolysis study and the amount of conjugates released was estimated by high performance liquid chromatography. The study showed that the rate of hydrolysis increases with increase in pH. The anticonvulsant and hepatotoxicity screening of the synthesized conjugates in different rat models showed that lamotrigine–dextran conjugates proved to be potentially safer than parent lamotrigine formulations.

Dextran successful carrier molecule for the delivery of NSAIDs with reduced gastrointestinal effect

Abstract The dextran ester polymeric prodrug of aceclofenac and mefenamic acid was synthesized through carbonyldiimidazole coupling agent. The prepared polymeric prodrug was characterized by UV, IR, X-RD and 1 H NMR. The in vitro hydrolysis study was performed by HPLC and polymeric conjugate subjected for in vitro hydrolysis showed negligible hydrolysis in simulated gastric fluid pH 1.2 for 3 h. The half-life of the aceclofenac dextran conjugate in simulated intestinal fluid (SIF) pH 7.4 and phosphate buffer solution (PBS) pH 9.0 was found to be 8.51 h and 33.72 min, respectively. The half-life 4.66 h and 25.4 min was found in SIF pH 7.4 and PBS pH 9.0, respectively for mefenamic acid conjugates. The conjugates were screened for biological activity such as anti-inflammatory, analgesic and ulcerogenic activity. The statistical data obtained from the biological experiment suggested that the value was found to be significant with respect to normal control.

Synthesis, characterization and biological evaluation of some glutathione inducing amino acid conjugates of valproic acid with reduced hepatotoxicity

Abstract Objective To synthesis and evaluate three glutathione inducing amino acid conjugates of valproic acid (VPA) and compare with the same VPA to diminish its hepatotoxicity. Methods Purified synthesised prodrugs were subjected to thin layer chromatography, melting point, solubility studies and characterised by UV, FTIR, 1H, 13C NMR and elemental analysis. The synthesised prodrugs were subjected to in vitro hydrolysis in various buffer solution (pH 1.2, 7.4, 9.0) and in vivo anticonvulsant, hepatotoxic activity studies. Result Three synthesized conjugates were assumed to be in agreement with the anticipated structures. All the three conjugates were also able to prevent seizures in experimental rats with a comparable activity as the parent drug, VPA. Among the three conjugates, the glycine conjugate showed better anticonvulasant activity compared to glutamic acid and cystine conjugates. Conclusions Significant reduction in hepatotoxicity and comparable anticonvulsant activities were obtained in all synthesised prodrugs as compared to VPA.

Synthesis, characterisation, and biological activity of three new amide prodrugs of lamotrigine with reduced hepatotoxicity

Lamotrigine (LTG) is an antiepileptic drug used for the prevention of convulsions. Except several known side effects, hepatic dysfunction is also reported. Hepatotoxic side effects occur due to the dichlorophenyl moiety which develops an abnormally low level of glutathione. Depletion of glutathione causes oxidative stress and hepatic cell damage. The goal of the present study was to test the action and side effects of the three compounds synthesised and compared to LTG. Three amide prodrugs of LTG were synthesised by its reaction with N-acetylamino acids, viz, glycine, glutamic acid, and methionine. Purified synthesised prodrugs were subjected to thin layer chromatography, melting point, solubility and partition coefficients determination and characterised by UV, FTIR, 1H and 13C NMR spectroscopy. The synthesised prodrugs were subjected to in vitro hydrolysis and to anticonvulsant and hepatotoxic activity studies. Significant reduction in hepatotoxicity and comparable anticonvulsant activities were obtained in all synthesised prodrugs as compared to LTG.