Sanjay Kshirsagar

Preparation and characterization of nanocapsules for colon-targeted drug delivery system

Context: Nanoparticles for colon-specific drug delivery system are known for their specific accumulation in the inflamed tissue in the colon and may therefore allow a selective delivery to the site of inflammation for the treatment of inflammatory bowel disease (IBD). Objective: The objective of this study was to formulate and evaluate nanocapsules (NC), an oral system designed to achieve site-specific and instant drug release in colon for effective treatment of IBD. Materials and methods: Prednisolone (PD), a typical glucocorticoid, has been widely used for the treatment of IBD. In this study, nanoprecipitation method was used to prepare polymeric NC of PD with pH responsive polymer Eudragit S100. The effect of several formulation variables such as surfactant, oil, and polymer on the PD-NC properties (average size, drug release rate, and drug entrapment) was investigated. In vitro drug release study was done by changing pH method and an in vivo study on rat was done to ascertain efficiency of PD-NC to release drug specifically in colon. Results and discussion: The optimized formulations lead to the preparation of PD-NC with a mean size of 567.87 nm, high encapsulation efficiency of 90.21%. In vitro studies reveal that NC releases the drug after 4.5-h lag time corresponding to time to reach colonic region, and in vivo studies show that NC release drug after 3-h lag time in rat corresponds to arrival in colon. Conclusion: The above NC formulation of PD is the targeted drug to the colon and may provide effective way of treatment of colonic disease.

Statistical optimization of floating pulsatile drug delivery system for chronotherapy of hypertension

Introduction: A pulsatile drug delivery system is characterized by a lag time that is an interval of no drug release followed by rapid drug release. The purpose of this work was to develop hollow calcium alginate beads for floating pulsatile release of valsartan intended for chronopharmacotherapy. Floating pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. Materials and Methods: To overcome the limitations of various approaches for imparting buoyancy, hollow/porous beads were prepared by simple process of acid-base reaction during ionotropic crosslinking by low viscosity sodium alginate and calcium chloride as a crosslinking agent. In this study, investigation of the functionality of the sodium alginate to predict lag time and drug release was statistically analyzed using the response surface methodology (RSM). RSM was employed for designing of the experiment, generation of mathematical models and optimization study. The chosen independent variables, i.e. sodium alginate and potassium bicarbonate were optimized with a 32 full factorial design. Floating time and cumulative percentage drug release in 6 h were selected as responses. Results: Results revealed that both the independent variables are significant factors affecting drug release profile. A second-order polynomial equation fitted to the data was used to predict the responses in the optimal region. The optimized formulation prepared according to computer-determined levels provided a release profile, which was close to the predicted values. The floating beads obtained were porous (21-28% porosity), hollow with bulk density <1 and had Ft70 of 2–11 h. The floating beads provided expected two-phase release pattern with initial lag time during floating in acidic medium followed by rapid pulse release in phosphate buffer. Conclusion: The proposed mathematical model is found to be robust and accurate for optimization of time-lagged formulations for programmable pulsatile release of valsartan.

Development and evaluation of carvedilol-loaded transdermal drug delivery system: In-vitro and in-vivo characterization study

Context: The transdermal drug delivery system was prepared and the bioavailability of the selected drug was enhanced by reducing first-pass metabolism. Objective: The objective of this study was to enhance the bioavailability of carvedilol through transdermal patches. Materials and methods: To develop a matrix-type transdermal patch containing carvedilol with different ratios of polymer combinations by solvent evaporation technique. Results and discussion: In-vitro permeation studies were performed by Franz diffusion cells. The results followed Higuchi kinetics, and mechanism of release was diffusion mediated. On the basis of the in-vitro and physicochemical parameters of carvedilol patches, the code F-1(PVP: Ethyl Cellulose = 4:1) was chosen for the study of in-vivo, ex-vivo, histocompatibility study, and pharmacological study. The bioavailability studies in rats indicated that the carvedilol-loaded transdermal patches provided steady-state plasma concentration and improved bioavailability of 72% in comparison to oral administration. The ex-vivo permeation study in rat’s skin indicated that the flux and permeability co-efficient of optimized F-1 patch was 30.08 ± 0.7 μg/cm2/h and 0.416 ± 0.05 μg/cm2/h, respectively, which was more as compared to plain carvedilol. The histocompatibility study of the F-1 patch on the rat’s skin after 24 h ex-vivo study gave less pathological changes as compared to other. The antihypertensive activity of the patch in comparison with oral administration was studied using N-nitro-L-arginine methyl ester-induced hypertensive rats. It was observed that the optimized patch (F-1) significantly controlled hypertension (p < 0.05). Conclusion: The developed patch increases the efficacy of carvedilol through enhancement of bioavailability for the therapy of hypertension.

Development of self-microemulsifying drug delivery system of mebendazole by spray drying technology: Characterization, in vitro and in vivo evaluation

ABSTRACT In this study, a novel liquid self-microemulsifying drug delivery system (SMEDDS) containing mebendazole was formulated and further developed into a solid form by a spray drying method using Aerosil 200 as the solid carrier. The optimum liquid SMEDDS consisted of Labrafil 2125 CS, Tween 20, and Maisine 35-1 as the oil phase, the surfactant, and the cosurfactant, respectively. The formulated SMEDDS was completely emulsified or dispersed within a minute. All formulations were dissolved within 1 h using 0.1 N HCl as dissolution medium, whereas pure drug was less significantly dissolved in this time period. The droplet size was found to be within 250 nm for solid forms of SMEDDS. Solid state characterization was performed by scanning electron micrograph, differential scanning calorimetry, and X-ray powder diffraction. After oral administration to Wistar rats, mebendazole in the solid SMEDDS resulted in the significant improvement in bioavailability compared with that of pure drug analyzed by RP-HPLC. The optimized formulation showed 24.87 folds increase in bioavailability as compared to pure drug and 8.39 folds increase in bioavailability in comparison to marketed tablet of mebendazole. The optimized batch has found to be 3.1726 years of shelf life. In conclusion, the solid SMEDDS is a promising solid dosage form for poorly water-soluble and low bioavailability drugs.

Design, development and in vitro-in vivo study of a colon-specific fast disintegrating tablet

Objective: Targeted delivery systems for the treatment of Inflammatory bowel disease (IBD) are designed to increase local tissue concentrations of anti-inflammatory drugs from lower doses compared with systemic administration. The objective of this study was to formulate and evaluate an oral system designed to achieve site-specific and instant drug release in the colon for effective treatment of IBD. Materials and methods: The system consists of a core tablet containing the model drug diclofenac sodium, superdisintegrant sodium starch glycolate, and coated with enteric polymer Eudragit FS 30 D to achieve different total percentage weight gain. Drug release studies were carried out using a changing pH method. A placebo formulation containing barium sulphate in the tablet was administered to human volunteers for in vivo X-ray studies. SEM studies were performed to determine coating thickness and film topography. Results: In vitro studies revealed that the tablet with 10% coating level released the drug after 5 h lag time corresponding to the colonic region. Tablets with 10% coating level could maintain their integrity in human volunteers for 5 h, approximating colon arrival time and release the drug instantaneously. Discussion: Colon-targeting and instant drug release for 10% coating level was due to the dissolution of the Eudragit FS 30 D and the immediate release effect of superdisintegrant. It was observed that as the coating level increased, the lag time also increased. This was because of increased diffusion path length and tortuosity at higher coating levels. Conclusion: An in vivo-in vitro study revealed that not only the sensitivity of the polymer to the pH environment but also the thickness of coating plays an important role in colon delivery and the tablet with 5% superdisintegrant and 10% coating level achieved the desired performance of the colon targeting.

Formulation optimization and in vivo evaluation of mucoadhesive xyloglucan microspheres

Mucoadhesive microspheres of the novel polymer, xyloglucan, have been formulated and their performance characteristics have been systematically evaluated in vitro and in vivo. The mucoadhesive microspheres were obtained by incorporating glipizide as model drug in xyloglucan as a mucoadhesive polymer and sodium alginate as a gel-forming polymer by the orifice-ionic gelation method. A32 factorial design was employed to study the effect of independent variables, xyloglucan concentration (X1) and calcium chloride (CaCl2) concentration (X2), on the dependent variables including drug entrapment efficiency, release time (t80), and percentage mucoadhesion in 1h. The best batch exhibited high drug entrapment efficiency (92.98%) and percentage mucoadhesion (78% after 1h). The drug release was also controlled for more than 8 hours. In vivo testing of the mucoadhesive microspheres revealed significant hypoglycemic effect of glipizide.

In-vivo bioavailability and lymphatic uptake evaluation of lipid nanoparticulates of darunavir

Abstract Darunavir is effective against wild-type and PI-resistant HIV, and has an oral bioavailability of 37%. It needs to be combined with ritonavir, which increases the bioavailability to 82%. The aim of this study was to evaluate the in-vivo efficacy of the darunavir-SLN and demonstrate lymphatic transport as a contributing pathway in increasing the drug bioavailability. The SLN was prepared by hot-homogenization technique using GMS as lipid. In-vitro drug release from SLN at the 12th hour was retarded (80.6%) compared to marketed tablet (92.6%). Ex-vivo apparent permeability of the freeze-dried SLN across everted rat intestine was 24 × 10−6 at 37 °C and 5.6 × 10−6 at 4 °C. The presence of endocytic process inhibitors like chlorpromazine and nystatin reduced it to 18.8 × 10−6 and 20.2 × 10−6, respectively, which established involvement of endocytic mechanism in the uptake of SLN. In-vivo pharmacokinetic studies on rats demonstrated increase in the AUC of SLN (26) as compared to that of marketed tablet (13.22), while the presence of lymphatic uptake inhibitor cycloheximide lowered the AUC of SLN to 17.19 which further led credence to the involvement of lymphatic uptake behind improved bioavailability. The detection of darunavir in the lymphatic fluid of the rats administered with darunavir-SLN further reinforced the conclusion of SLN being taken up by the lymphatic system.

Development of enzyme-controlled colonic drug delivery using amylose and hydroxypropyl methylcellulose: Optimization by factorial design

The aim of the present study is to develop colon-targeted drug delivery systems for diclofenac sodium which release the drug specifically and instantly at target site using amylose as a carrier. Coating formulations were designed based on the full factorial design. The evaluated responses were lag time prior to drug release and T90. Compression-coated tablets of diclofenac sodium containing various proportions of amylose and HPMC were prepared. In vitro drug release studies were done by changing pH method with enzyme. In vivo studies were done to confirm the potential of formulation to release the drug at target site. The dissolution data revealed that the ratio of polymers is very important to achieve optimum formulation. Results showed that the tablet prepared according to the above formulation released drug instantly at pH 6.8 (simulating colonic pH). An in vivo study shows that optimized formulation disintegrated in the target region. The results of this study revealed that factorial design is a suitable tool for optimization of coating formulations to achieve colon delivery. It was shown that coating formulation consisting of amylose 285 mg and HPMC 150 mg coating has the potential for colonic delivery of diclofenac sodium irrespective of change in pH in a patient with IBD.

In vitro drug release and in vivo human X-ray studies of ileo-cecal targeting budesonide fast disintegrating tablet

Crohns disease is a type of inflammatory bowel disease that frequently affects the ileo-cecal region of the gastrointestinal tract. For effective treatment of this disease, a site-targeting drug in the ileo-cecal region is essential. Budesonide (BD) is a synthetic, non-halogenated glucocorticoid and is the drug of choice for the treatment of Crohns disease. The present study is an attempt to develop the dosage form of a BD tablet to achieve targeted drug release in the ileo-cecal region. The BD tablets are coated with Eudragit FS 30 D, which is a polymer that specifically dissolves at and above pH 6.8. The in vitro drug release and in vivo tablet disintegration (using X-ray radiography) were carried out. The coating process was optimized successfully. The in vitro performance of the tablet with coating thickness showed that the tablet did not disintegrate till 4.5 hours, which represents the transit time to the ileo-cecal region. In vivo studies also established that the tablet lasted till 4.5 hours. The tablet containing 0.5% superdisintegrant and 10% coating thickness was able to deliver BD effectively to the ileo-cecal region, thus making it a promising drug delivery system for the treatment of Crohns disease.

Development and Validation of Stability-Indicating Method for Estimation of Chlorthalidone in Bulk and Tablets with the Use of Experimental Design in Forced Degradation Experiments

Chlorthalidone was subjected to various forced degradation conditions. Substantial degradation of chlorthalidone was obtained in acid, alkali, and oxidative conditions. Further full factorial experimental design was applied for acid and alkali forced degradation conditions, in which strength of acid/alkali, temperature, and time of heating were considered as independent variables (factors) and % degradation was considered as dependent variable (response). Factors responsible for acid and alkali degradation were statistically evaluated using Yates analysis and Pareto chart. Furthermore, using surface response curve, optimized 10% degradation was obtained. All chromatographic separation was carried out on Phenomenex HyperClone C 18 column (250 × 4.6 mm, 5 μ), using mobile phase comprising methanol : acetonitrile : phosphate buffer (20 mM) (pH 3.0 adjusted with o-phosphoric acid): 30 : 10 : 60% v/v. The flow rate was kept constant at 1 mL/min and eluent was detected at 241 nm. In calibration curve experiments, linearity was found to be in the range of 2–12 μg/mL. Validation experiments proved good accuracy and precision of the method. Also there was no interference of excipients and degradation products at the retention time of chlorthalidone, indicating specificity of the method.