Sajeev Chandran

Brimonidine Tartrate–Eudragit Long-Acting Nanoparticles: Formulation, Optimization, In Vitro and In Vivo Evaluation

In the present study, an effort was made to design prolonged release Eudragit nanoparticles of brimonidine tartrate by double emulsion–solvent evaporation technique for the treatment of open-angle glaucoma. The effect of various formulation variables like initial drug amount, lecithin proportion, phase volume and pH, secondary emulsifier and polymer proportion were studied. Various process variables like energy and duration of emulsification, lyophilization on the characteristics of nanoparticles and in vitro drug release profile were studied. The selected formulations were subjected to in vivo intraocular pressure-lowering efficacy studies by administering aqueous dispersion of nanoparticles into the lower cul de sac of glaucomatous rabbits. The prepared Eudragit-based nanoparticles were found to have narrow particle size range and improved drug loading. The investigated process and formulation variables found to have significant effect on the particle size, drug loading and entrapment efficiency, and in vitro drug release profile of nanoparticles. The selected formulations upon in vivo ocular irritability and tolerability tests were found to be well tolerated with no signs of irritation. In vivo pharmacodynamic efficacy studies revealed that the selected nanoparticle formulations significantly improved the therapy as area under the ∆IOP vs. time curve [AUC(∆IOP vs.t)] showed several fold increase in intensity and duration of intraocular pressure (IOP) decrease. All the selected nanoparticle formulations were found to prolong the drug release in vitro and prolong IOP reduction efficacy in vivo, thus rendering them as a potential carrier in developing improved drug delivery systems for the treatment of glaucoma.

Design and Evaluation of Ethyl Cellulose Based Matrix Tablets of Ibuprofen with pH Modulated Release Kinetics.

Controlled release preparations have been reported to reduce the gastro irritant and ulcerogenic effects of non steroidal antiinflammatory drugs. In the present study, an attempt was made to develop matrix tablet-based controlled release formulations of ibuprofen, using ethyl cellulose as the rate-controlling polymer. In order to prevent initial release of the drug in the acidic environment of the stomach, cellulose acetate phthalate was incorporated in the matrix in varying amounts. It was found that with increasing the proportion of ethyl cellulose in the matrix, the drug release was extended for 14-16 h. Incorporation of cellulose acetate phthalate in ethyl cellulose matrix provided very low initial release of the drug in the first 2-3 h followed by enhanced release rate in alkaline medium owing to the high solubility of cellulose acetate phthalate at basic pH which led to creation of a porous matrix. It was concluded that combination of cellulose acetate phthalate with ethyl cellulose in the matrix base can be an effective means of developing a controlled release formulation of ibuprofen with very low initial release followed with controlled release up to 14-16 h.

Microspheres with pH modulated release: Design and characterization of formulation variables for colonic delivery

Abstract The aim of this study was to design and develop microspheres of indomethacin with pH and transit time dependent release properties for achieving targeted delivery to the colon. Microspheres containing varying proportions of ethyl cellulose and Eudragit (L100 or S100) either alone or in combination were prepared using an oil-in-oil emulsion-based solvent evaporation technique. System comprising of acetone (internal phase) and liquid paraffin (external phase) in the ratio of 1 : 1 and 1 : 9 yielded microspheres with good physical properties (spherical and discrete), high drug loading (70–80%) and entrapment efficiency (70–85%). The lag time in the initial release depended on the proportion of pH-sensitive polymer Eudragit, while the duration of indomethacin release from microspheres was found to be directly proportional to proportion of the total polymer. Thus, a pH- and time-modulated sigmoidal release pattern could be observed in optimized formulations with less than 10% drug release in 4–6 h followed by controlled release extending up to 14–16 h.

Design and evaluation of matrices of Eudragit with polycarbophil and carbopol for colon-specific delivery

The purpose of the present study was to investigate the effect of incorporating pH-responsive polymers Eudragit (L100 or S100) in matrix bases composed of hydrophilic polymers polycarbophil and carbopol to design oral controlled release formulations with sigmoidal release profile for colon-specific delivery. Matrix tablets were prepared by wet granulation technique using indomethacin as model drug and were characterized for physical parameters, in vitro drug release, release kinetics, and stability on storage. The gastrointestinal (GI) transit of selected formulations was also investigated in human subjects using gamma scintigraphy. In vitro release studies indicated that the presence of pH-sensitive polymers in hydrophilic polymer base retarded the initial release significantly (10–15% release in 6 h) followed with controlled release for the next 8–10 h in simulated GI fluid pH (without enzymes). The presence of Eudragit in hydrophilic matrix base retarded the swelling of the matrix base in acidic to weakly acidic pH, but in alkaline pH, enhancement in drug release rate was observed due to the dissolution of Eudragit from the base resulting in a porous matrix structure, resulting in around 80–90% release in 14 h of study. In vivo gamma scintigraphy studies in healthy human subjects proved that the formulations had acceptable matrix strength to withstand gastric and colonic transit. The mean colonic residence time of selected designed formulations varied between 15 and 19 h. Such a matrix design could have potential application as colon-specific drug delivery systems with pH- and time-dependent drug release profile.

New Ultraviolet Spectrophotometric Method for the Estimation of Nimesulide

Two simple and accurate ultraviolet (UV) spectrophotometric methods with better detection range for estimation of nimesulide in pure form and in solid dosage form were developed in the present studies using 50% v/v and 100% v/v acetonitrile as the solvent system. The linearity range of nimesulide in both the methods was found to be 10–50 μg/ml at a λmax of 300 nm. The linear regression equations obtained by the least-square regression method are Abs = 1.33 × 10−1. Conc + 1.89 × 10−1 in 50% v/v acetonitrile and Abs = 1.05 × 10−1. Conc + 1.14 × 10−1 in 100% v/v acetonitrile. The detection limit as per the error propagation theory was found to be 0.46 μg/ml and 1.04 μg/ml, respectively, in 50% v/v and 100% v/v acetonitrile. The developed methods were employed with high degree of precision and accuracy for the estimation of total drug content in three commercial tablet formulations of nimesulide. The results of the analysis were validated statistically and by recovery studies.

Rapid and sensitive spectrofluorimetric method for the estimation of celecoxib and flurbiprofen

In this study new, rapid and sensitive spectrofluorimetric methods for the quantitative estimation of celecoxib and flurbiprofen in pure form and in their pharmaceutical dosage forms were developed. The solvent systems, wavelengths of detection (excitation and emission) were optimized in order to maximize the sensitivity and minimize the cost of analysis for both the drugs. No extraction procedure was employed for analysis of these compounds in their formulation matrix, which reduced the time of sample preparation. The excitation and emission wavelengths were found to be 256 nm and 403 nm respectively for celecoxib in water and 250 nm and 314 nm respectively for flurbiprofen in 1:1 mixture of methanol and 0.1N sulphuric acid. The linear regression equations obtained by least square regression method for fluorescence intensity (FI) and concentration in ng/ml (conc) were FI=1.2874´conc+22.647, for celecoxib; and FI=27.7970´conc+46.049, for flurbiprofen. The limit of detection as per the error propagation theory was found to be 4.97 ng/ml and 0.99 ng/ml for celecoxib and flurbiprofen respectively. The developed methods were successfully employed with high degree of precision and accuracy for the estimation of total drug content in two commercial capsule formulations of celecoxib and two ophthalmic drops of flurbiprofen. The results of analysis were treated statistically, as per International Conference on Harmonization guidelines for validation of analytical procedures, and by recovery studies. It was concluded that developed methods are simple, accurate, sensitive, precise and reproducible and could be applied directly and easily to the pharmaceutical preparations of celecoxib and flurbiprofen.

Sustained release ocular inserts of brimonidine tartrate for better treatment in open-angle glaucoma

Pathology of eye, especially in the case of glaucoma, requires optimal therapeutically effective concentration of the drug in the ocular tissues for prolonged period of time with decreased dosing frequency and improved patient compliance. In the present study, brimonidine tartrate (BRT) ocular inserts were designed based on hydrophilic and/or inert/zwitterionic polymer matrix to design mucoadhesive and extended release ocular inserts. Designed inserts were evaluated for their physicochemical properties such as crushing strength/hardness, friability, drug content and mucoadhesion, and erosion and in vitro drug release characteristics. The selected optimised formulations were compared with marketed preparation for in vivo ocular irritation in healthy rabbits and for in vivo pharmacodynamic efficacy on alpha-chymotrypsin-induced glaucomatous rabbits. The developed formulations showed good physicochemical properties and mucoadhesive strength, and a good correlation was seen between rate of erosion or swelling with drug release rate in case of formulations with higher proportion of polyethylene oxide (PEO). Modulation of drug release was achieved by incorporating Eudragit in PEO matrix. Addition of Eudragit resulted in shifting of drug release mechanism from erosion-controlled to diffusion-controlled mechanism. In vivo ocular irritation studies confirmed the absence of any irritation upon administration in rabbits. Intraocular pressure (IOP) measurement studies showed an improved IOP-lowering ability of ocular insert of BRT in comparison to eye drops.

Design and in vitro evaluation of formulations with pH and transit time controlled sigmoidal release profile for colon-specific delivery

The primary objective of the study was to develop a pH and transit time controlled sigmoidal release polymeric matrix for colon-specific delivery of indomethacin. Tablet matrices were prepared using a combination of hydrophilic polymers (polycarbophil or carbopol) having pH sensitive swelling properties with hydrophobic polymer ethyl cellulose. The prepared matrices were characterized for physical properties and in vitro release kinetics. The presence of ethyl cellulose in a hydrophilic polymer matrix resulted in a sigmoidal in vitro drug release pattern with negligible to very low drug release in the initial phase (0–6 h) followed by controlled release for 14–16 h. The retardation in initial release can be attributed to the presence of ethyl cellulose that reduced swelling of hydrophilic polymer(s) while in the later portion, polymer relaxation at alkaline pH due to the ionization of acrylic acid units on carbopol and polycarbophil resulted in enhanced drug release. Thus, a sigmoidal release pattern was obtained that could be ideal for colonic delivery of indomethacin in the potential treatment of colon cancer.

Simple Rapid Validated RP-LC Method for the Estimation of Flurbiprofen in Rabbit Serum and Aqueous Humor

Abstract New reversed-phase liquid chromatographic methods, with UV detection, were developed for the quantitative estimation of flurbiprofen in rabbit blood serum and aqueous humor. The mobile phase and other chromatographic conditions were optimized to minimize interference from biological matrix and at the same time provide sufficient sensitivity for the method to be adopted for in vivo studies of ophthalmic formulations of flurbiprofen. Acetonitrile was used to precipitate proteins from serum or aqueous humor during sample preparation. A mobile phase of methanol: acetonitrile: phosphate buffer pH 5.6 (40:20:40) was employed with UV detection at 248 nm for estimation of drug in both the biological matrix. The retention time and asymmetry factor for the proposed method of estimation in serum and aqueous humor was found to be 3.1312±0.0101 min and 1.1310±0.0091 respectively. The linear regression equations obtained by least square regression method, were Area (µV sec) = 52.27 × Conc. (in ng/ml)–1618.70 in serum and Area (µV sec) = 61.79 × Conc. (in ng/ml) − 783.24 in aqueous humor. The results of analysis were treated statistically, as per ICH guidelines for validation of analytical procedures, USP-2003, and by recovery studies. The results were found to be accurate, reproducible and free from interference. The developed methods were further used for estimation of flurbiprofen in rabbit serum and aqueous humor following single topical administration of in-house aqueous drop and market formulation to rabbit eye.

A Simple, Rapid, and Validated LC Method for the Estimation of Nimesulide in Human Serum and Its Application in Bioavailability Studies

Abstract A new, simple, and rapid, sensitive reversed phase liquid chromatographic method was developed for the estimation of nimesulide in blood serum using a 60:40 mixture of acetonitrile and orthophosphoric acid (pH 3.0) as the mobile phase at 230 nm. The mobile phase and other chromatographic conditions were optimized to minimize interference from the serum matrix and at the same time provide sufficient sensitivity for the method to be adopted for in vivo studies of oral formulations of nimesulide. Acetonitrile was used to precipitate proteins from serum during sample preparation. Detector response was found to be linear in the region of 100–1000 ng/ml. The detection and quantitation limit, as per the error propagation theory, was found to be 50 ng/ml and 100 ng/ml, respectively. The linear equation obtained by the least square regression method was Area = 37.29 × Conc.(ng/ml)−1699.89 with a retention time of 3.97 ± 0.04 min. The results of the analysis were treated statistically, as per ICH guidelines for validation of analytical procedures, USP-2000. and by recovery studies. An internal standard was not employed in the method, as sample recoveries were in good agreement with their label claims. The results were found to be accurate, reproducible, and free from interference. The developed methods were further used for estimation of nimesulide for oral bioavailability of designed sustained release formulations of nimesulide.