Indra K. Reddy

Atenolol gastrointestinal therapeutic system: optimization of formulation variables using response surface methodology

Abstract Osmotically controlled drug delivery systems are of interest for the maintenance of constant drug levels in essential hypertension. The objective of this study was to prepare and evaluate an optimized, osmotically controlled formulation of a model drug, atenolol. Preparation involved the fabrication of biconvex, bilayered tablets containing drug, an osmotic agent and other additives. Earlier studies on the screening of several variables have revealed that orifice size, coating level and the amount of Carbopol® 934P have pronounced effects on the in-vitro release kinetics of atenolol. Therefore, for formulation optimization, a three-factor, three level Box-Behnken design was employed with independent variables of orifice size (X1), coating level (X2), and the amount of Carbopol® 934P (X3). The response variable was cumulative percent of atenolol released with constraints on time for 10, 25, 50 and 75% release. Mathematical equations and response surface plots were used to relate independent variables with percent released in 24 h (Y5). The regression equation generated was Y5=19.38+2875.60X1+26.96X2+0.52X3−2410.0X1X2+49.68X1X3+0.11X2X3−130 729X12+2.24X22−0.01X32. The optimization model predicted >90% drug release with X1, X2 and X3 levels of 0.017, 2 and 163.3 respectively. Preparation and testing of the optimized formulation showed a good correlation between predicted and observed values.

Permeability of Chemical Delivery Systems Across Rabbit Corneal (SIRC) Cell Line and Isolated Corneas: A Comparative Study

The purpose of this study was to investigate the corneal permeability of phenylephrone chemical delivery systems (CDS) across isolated cornea and to evaluate the utility of the SIRC cell line (epithelial cells originating from rabbit cornea) as an in vitro model for predicting the ocular permeability. The effect of benzalkonium chloride (BAC) on the drug permeability through SIRC cell layers was also studied. The transport of phenylephrone CDS across the isolated cornea of the albino rabbit was measured at various pH values using a two-chamber glass diffusion cell, and the results were compared with the reported permeability values across SIRC cells of rabbit origin. Corneal membranes showed lower flux values for compounds, especially for hydrophilic compounds, than the SIRC cell line. A significant correlation was observed between the permeability coefficients through corneal membranes and SIRC cells. When the pH of the transport medium was increased, the permeability coefficients increased and lag times decreased in both in vitro models. Furthermore, both in vitro models showed significant correlation between permeability coefficients and lipophilicities of the drugs. The three esters, having higher lipophilic characteristics, showed higher permeability than phenylephrine HCl. The phenylacetyl ester of phenylephrone showed a three-fold increase in penetration across SIRC cell layers in the presence of 0.01% BAC. These results suggest that the use of SIRC cell layers can reasonably predict the permeability of ophthalmic drugs across corneal membranes.

Captopril gastrointestinal therapeutic system coated with cellulose acetate pseudolatex: evaluation of main effects of several formulation variables.

Maintenance of constant drug levels in the body for those drugs that are used in management of hypertension is extremely beneficial. This can be successfully achieved by delivering the antihypertensives as osmotically-controlled drug-delivery system that essentially eliminates the influence of pH on the drug release. The main objective of this study was to evaluate the main effects of the formulation variables on the release of captopril from osmotically-controlled drug-delivery system coated with a custom-made cellulose acetate (CA) pseudolatex reported earlier. A secondary objective was to identify a suitable antioxidant for incorporating in the formulation as the drug undergoes metal-catalyzed oxidative degradation. The drug showed good stability (> or = 90% intact captopril) in solution in the presence of ascorbic acid for a period of 48 h. A seven-factor, 12-run Plackett-Burman screening design was employed to study the main effects of amounts of Polyox(R) N10 and N80, Carbopol(R) 934P and 974P, sodium chloride, orifice size, and % coating weight gain. The response variable was cumulative percent of drug released in 12 h, Y(3), with constraints on lag time Y(1) and time for 50% drug released Y(2)amount of sodium chloride (1.97).

Stability characterization of controlled release coprecipitates and solid dispersions

The present study was conducted to determine the effects of ageing at exaggerated storage conditions on controlled release tablets prepared with indomethacin-Eudragit((R)) coprecipitates (CPs) and solid dispersions (SDs). CPs and SDs compressed as tablets were stored at -20, 4, 37, 45, 55, 37 degrees C/11% RH, 37 degrees C/51% RH and 37 degrees C/91% RH. The samples were analyzed over a period of six months for their dissolution, crystalline reversion and thermal changes. Samples stored at extremely low temperatures, higher temperatures and humidity conditions exhibited a significant decrease in dissolution rates. However, no significant change in the release rates was observed for samples stored at 4 degrees C. The degree of crystallinity increased over a period of time as confirmed by X-ray diffractometry. DSC data demonstrated that indomethacin exists in two polymorphic forms, Form I (mp 160-161 degrees C) and Form II (mp 153-154 degrees C). CPs showed an endotherm of Form I, whereas SDs showed a mixture of Form I and II.

Effect of chiral enhancers on the permeability of optically active and racemic metoprolol across hairless mouse skin

The stratum corneum, the rate-limiting barrier in transdermal drug delivery, is chiral in nature and enantiomers behave differently with respect to their transport across the skin, resulting in enantioselective permeation. The permeation characteristics of individual enantiomers of metoprolol free base (MB) were investigated using hairless mouse skin. The influence of chiral permeation enhancers, l-menthol and (+/-)-linalool, on the permeation of MB was also investigated. In the absence of enhancers, the permeation profiles of R- and S-MB from donor solutions containing either RS-MB or pure enantiomers are comparable (p < 0. 05). In presence of enhancers, l-menthol and (+/-)-linalool, the flux values were increased 2.4- to 3.0-fold, respectively, and the permeation profiles of R- and S-MB from donor solutions containing RS-MB are comparable (p < 0.05). However, when donor vehicle contains pure enantiomers, the permeation enhancing effect of l-menthol on S-MB was significantly higher (by 25%) than on R-MB (p < 0.05). Further, in presence of l-menthol, the flux of S-MB from donor solution containing pure S-MB was 35% higher than the flux of RS-MB from racemate. No such effect was seen with (+/-)-linalool. In all the investigations, no enantiomeric inversion was observed during the permeation process. The lag times were shorter in the case of l-menthol compared with (+/-)-linalool.

Solid-state stability assessment of controlled release tablets containing Carbopol® 971P

A tablet formulation containing dyphylline, Carbomer, magnesium stearate, talc and lactose was prepared by the direct compression method. The objective of the study was to assess the stability of these tablets after subjecting them to exaggerated conditions of temperature (4, 25, 37, 45 and 55 degrees C) and humidity (37 degrees/11%RH, 37 degrees/51%RH and 37 degrees C/91%RH). The samples were analyzed for crystalline, thermal and dissolution changes with time for a period of 12 months using X-ray diffractometry (XRD), differential scanning calorimetry (DSC) and U.S.P. Dissolution Apparatus 2. Moisture sorption studies of all tablets indicated sorption of large amounts of moisture at 37 degrees C/91%RH. The fit factors, f1 andf2, were calculated and used to compare the dissolution profiles. The results showed increased f1 and decreased f2 values at higher humidity, while the samples were fairly stable at lower humidity and at all temperatures studied. Powder XRD patterns of tablets showed a change in crystallinity at higher humidity. The thermal and crystalline data indicated that the change in dissolution behavior at higher humidity may be due to the conversion of dyphylline to its hydrate form.

Aqueous-based polymeric dispersion: preparation and characterization of cellulose acetate pseudolatex

Abstract The objective of the present study was to prepare and characterize the cellulose acetate (CA) pseudolatex as a semipermeable membrane provider for atenolol gastrointestinal therapeutic system (GITS). For the polymer film coating, it is important to relate the macroscopic properties such as tensile strength and toughness to the atomic-scale property, free-volume. Using ethyl acetate as the solvent, CA pseudolatex was prepared by a phase inversion emulsification technique. The particle size of the pseudolatex was reduced to nanometer size range by passing through a microfluidizer. Diacetin was used as the plasticizer. Mechanical properties showed a considerable decrease in their values except % elongation as the plasticizer concentration increased from 90 to 150%. Glass transition temperatures of the CA pseudolatex membranes were 160°C (unplasticized pseudolatex), 63°C (90% plasticizer), 17.6°C (110% plasticizer), −60°C (160% plasticizer), and 20.1°C (actual film from tablet surface). Approximate F v (free-volume fraction), as a function of diacetin concentration, was estimated by positron annihilation spectroscopy (PAS). There was an increase in F v from 5.800 to 6.082 as the diacetin concentration increased from 90 to 170%. Tritium tracer diffusion experiments revealed that the permeability of the pseudolatex films increased as the diacetin concentration increased. The CA pseudolatex provided a mechanically strong film on bilayered osmotically controlled tablet dosage forms.

Growth Pattern of Sirc Rabbit Corneal Cells in Microwell Inserts

AbstractThe SIRC rabbit corneal cell line (ATCC CCL 60) has been used in a number of in vitro studies. However, the growth pattern of SIRC rabbit corneal cells on microwell inserts has not been established. Microwell inserts were seeded with SIRC rabbit corneal cells, suspended in growth medium. Cultures were maintained in a humidified incubator (5% CO237°C) for 21 days, with the growth medium replaced in the wells and inserts every seventh day of culture. Light microscopy was performed on hematoxylin and eosin-stained cross sections. The SIRC rabbit corneal cells formed multiple epithelioid cell layers. Maximum cell layer growth occurred at day 10 (4.54 cell layers ± 0.32). Although decreased slightly, the number of cell layers remained stable with an average of more than 4 cell layers observed for days 12-14. On the 21st day of culture, the average number of cell layers decreased to 3.87 (± 0.09) and exfoliation of the surface cells was evident. Microscopy of the cross sections indicates that new cell l...

Cataplasm-Based Controlled Drug Delivery: Development and Optimization of a Novel Formulation

The objective of the present study was to study the formulation variables involved in the development of a novel plasterlike preparation (cataplasm) and to optimize important formulation variables with an aim to maximize the in vitro release of the drug with minimum lag time. Cataplasm was prepared by dispersing a model drug (ibuprofen), humectant (glycerol), adhesive (Indopol H100), polymer (Carbopol C934P) with other formulation ingredients in a beaker with an open-blade impeller. The paste was cast on a nonocclusive backing membrane and dried overnight. The diffusion of the model drug was studied across a cellulosic membrane using Franzs diffusion cells. The amounts of three formulation variables, carbopol (X1), glycerol (X2), and indopol (X3) were studied at three levels, and a face-centered cubic design was used to maximize the flux. An optimization procedure for maximum flux and minimum lag time predicted a flux of 97.22 mcg/cm2/hr at X1 (2% w/w), X2 (11.75% w/w), and X3 (6%, w/w). An experimental patch prepared with the above concentrations yielded a flux of 90.7 mcg/cm2/hr.

Permeability of Pure Enantiomers of Timolol Across SIRC Rabbit Corneal Cells

The permeability characteristics of S- and R-isomers of timolol maleate across SIRC rabbit corneal cells in the presence and absence of benzalkonium chloride were evaluated. The barrier properties of the cell line were assessed by measuring transepithelial electrical resistance (TEER) and the permeability of a hydrophilic marker, mannitol. The permeability of S-timolol maleate across the SIRC layers was slightly higher than the reported value across the corneal membrane. There was no significant difference between the permeability of S- and R-isomers, indicating that there was no stereoselective transport across the cell line. The permeability of the low molecular weight isomers was greater than the permeability of mannitol suggesting that both paracellular and transcellular pathways contribute to the transport of these enantiomers across the cell line. The permeability of S- and R-isomers of timolol maleate and mannitol increased 2.8- and 5.2-times, respectively, in the presence of benzalkonium chloride. However, the cell layers showed a significant decrease in TEER after 2 h in the presence of 0.01% benzalkonium chloride. These findings suggest the possible use of the SIRC rabbit corneal cell line model to assess the permeability characteristics of enantiomers of timolol maleate.