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Background: The drug cinnarizine is used in the treatment of vertigo and migraine. The main drawback is its very low water solubility which causes unpredictable bioavailability. Solubility is better in acidic pH. Therefore, gastro-retentive formulation would be beneficial to improve the bioavailability of the drug. Objective: The objective of the study was to prepare floating microballoons of cinnarizine which would float in the gastric fluid and release the drug in a sustained manner. Methods: Microballoons were prepared by diffusion solvent evaporation technique using polymers (Eudragit® S100, Eudragit® RLPO, Eudragit RL®100), characterised by FTIR, XRD, DSC and optimized by sequential simplex design. For optimization, formulations were graded with respect to formulation efficiency (percentages of yield, sphericity and drug content) and performance index (buoyancy and dissolution efficiency), from which the overall response of the formulations was determined. Finally, the optimized formulation was radiolabelled with 99mTc-MIBI and fed to Wistar albino rats and was evaluated for gastric retention by gamma scintigraphic study. Results: FTIR studies indicated drug and polymers were compatible. DSC and XRD analysis confirmed that the drug was in amorphous state in the formulation. SEM studies confirmed the sphericity of the microballoons. Formulation N7 showed the best overall response (65.61) which was the nearest to the target. Gamma scintigraphic study confirmed that the formulation was retained in the stomach for more than 5 h. Conclusion: The results indicated that floating microballoons of cinnarizine would stay in the stomach for prolonged period and thereby improve the bioavailability of the drug.

Background: Monitoring of plasma concentrations is a necessity for narrow therapeutic index potent drugs. Development of non-invasive methods can save the patients from the trauma of needles and hence is considered as a research priority. Introduction: Gabapentin, an anti-epileptic drug requires therapeutic monitoring because of its narrow therapeutic index. The objective of the study was to develop a suitable method for the non-invasive extraction of gabapentin for the same. Methods: Transdermal reverse iontophoresis was performed using pig ear skin as a barrier membrane. Three compartment iontophoretic cells were used for the extraction study. Extractions were carried out under low intensity electric field (current intensity- 0.5 mA/cm2, electrical field approximately 5 V). The donor compartment was charged with aqueous gabapentin (10 µg/ml in phosphate buffer of pH 7.4). For studying the effect of receiving vehicle (pH, ionic strength, and enhancer) on the extraction efficiency of gabapentin, the two receiver chambers were charged with media having varying concentration of these factors. Drug content was determined by HPLC. Results: Compared to other pHs, cumulative extraction of gabapentin at pH 5 was significantly higher at both anode and cathode (p Conclusion: Extraction flux can be optimized by manipulation of the receiver media.

Objective: Rheumatoid arthritis is a dreaded disease, characterized by pain, inflammation and stiffness of joints, leading to severe immobility problems. The disease shows circadian variation and usually gets aggravated in early morning hours. Aceclofenac, a BCS Class II compound is routinely used in the treatment of pain and inflammation associated with rheumatoid arthritis. The objective of this study was to develop an osmotic delivery system of Aceclofenac that after administration at bedtime would deliver the drug in the morning hours. Methods: A series of osmotically controlled systems of aceclofenac was developed by using lactose, sodium chloride and hydroxypropyl methylcellulose K100M as osmogens. Cellulose acetate (2% w/v in acetone) with varying concentrations of polyethylene glycol-400 was used as the coating polymer to create semi permeable membrane and dissolution was carried out in 290 mOsm phosphate buffer. Formulation optimization was done from four considerations: cumulative release at the end of 6 hours (lag time), cumulative release at the end of 7 hours (burst time), steady state release rate and completeness of drug release. Results: A formulation having swelling polymer hydroxypropyl methylcellulose in the core and lactose and sodium chloride as osmogens, polyethylene glycol-400 (16.39 %) as pore former, with a coating weight of 5% was a close fit to the target release profile and was chosen as the optimum formulation. Conclusion: Aceclofenac tablets containing lactose, HPMC and sodium chloride in the core, given a coating of cellulose acetate and PEG-400 (5% wt gain), generated a release profile for optimum management of rheumatoid arthritic pain.

Recently, transdermal reverse iontophoresis across the skin has been investigated as a novel technology for the purpose of diagnosis as well as therapeutic drug monitoring. Accordingly, the objective of this study was to investigate ex vivo and in vivo transdermal extraction of levetiracetam, an antiepileptic drug, across the pig ear skin by reverse iontophoresis. Reverse iontophoresis experiments were performed using three chambered diffusion cells. Extractions profiles were generated in phosphate buffers at different current intensities, pH and ionic strength as well donor drug concentrations. This was followed by ex vivo extraction in gels and in vivo extractions using New Zealand rabbits. Results indicate that levetiracetam was extracted at both anode and cathode. Flux values were unaffected by increase in current intensities (0.5 mA and 0.6 mA) but affected by pH and ionic strength. Neither in cathodal nor in anodal extraction, flux values did show a proportional relationship with the donor drug concentration. At low and medium concentration levels, flux values did not show any major change but the extraction flux at high donor concentration was much higher. In contrast, in vivo experiment with rabbits resulted in wide variation of fluxes with very high fluxes recorded at the cathodal end. Reasons attributed to this difference may include lower current intensity, and species variation. The most significant finding of this study is that measurable amounts of the levetiracetam were extracted at both the ends indicating its feasibility for non-invasive drug monitoring.

BACKGROUND For the narrow therapeutic index anti-epileptic drugs, monitoring of plasma concentration is a necessity for avoiding complications related to fluctuation of plasma level. OBJECTIVE The work was aimed at extracting gabapentin by transdermal reverse iontophoresis to investigate its feasibility for noninvasive therapeutic drug monitoring. METHODS Gabapentin was delivered in phosphate buffer (pH 7.4) at a therapeutic concentration range of 2-10 µg/ml. The same media was also used in receiver compartment. Extractions were carried out under an electric field of 5 V (current intensity range 0.3 -0.5 mA/cm2), provided by a custom-made power source for a period of 4 h. Samples were withdrawn at hourly intervals and drug content was analyzed by HPLC. RESULTS Results indicated that gabapentin extraction occurred at both anode and cathode with cathodal extractions showing higher value at all concentrations. Extraction rates at both the chambers were affected by time, the first hour extraction was notably higher than the later hours. Highest extraction rate was noted at pH 5. Surprisingly, anodal extraction was found to show greater positive correlation with current intensity compared to cathodal extraction. CONCLUSIONS As gabapentin carried no net charge at pH 7.4, orientation mediated electromigration was suggested to be the cause.

Objective: Formulations were developed for targeted controlled delivery of 5-fluorouracil at the colonic site. Methods: Probable dose for drug loading in the tablets and duration of drug release at the colon was determined. Core tablets were formulated with an aim to deliver the drug at a constant rate following zero order kinetics throughout the duration of release. Hydroxypropyl methylcellulose E15 and potassium chloride were incorporated as hydrophilic agents in the core matrix for drug release at the desired level and the formulation with the best release profile was chosen for coating with a coating solution containing Eudragit S100, polyethylene glycol 400 and talc. The amounts of Eudragit S100 and weight gain of the tablet were optimized using sequential simplex optimization method. Results: The optimized coated formulation (0.6875 g of Eudragit S100; 7.5% weight gain) was able to provide minimum drug release in the 5 hr lag time (5.9% of cumulative release) and an average release rate of 19.8% per hr thereafter. Conclusion: The optimized formulation for 5-Fluorouracil delivery at the colonic site was able to achieve a sufficient lag time and controlled drug release and can be highly beneficial for optimum therapeutic activity and negligible side effects when administered orally. Key words: Colonic delivery, Eudragit S100, Hydroxypropyl methylcellulose E15, Potassium chloride, Sequential optimization, Zero order release.

Application of transdermal reverse iontophoresis for diagnostic purpose is a relatively new concept but its short span of research is full of ups and downs. In early nineties, when the idea was floated, it received a dubious welcome by the scientific community. Yet to the disbelief of many, 2001 saw the launching of GlucoWatch® G2 Biographer, the first device that could measure the blood sugar level noninvasively. Unfortunately, the device failed to match the expectation and was withdrawn in 2007. However, the concept stayed on. Research on reverse iontophoresis has diversified in many fields. Numerous in vitro and in vivo experiments confirmed the prospect of reverse iontophoresis as a noninvasive tool in therapeutic drug monitoring and clinical chemistry. This review provides an overview about the recent developments in reverse iontophoresis in the field of therapeutic drug monitoring.

The high rate homogenisation techniques was used for preparing glyburide loaded glyceryl monostearate solid lipid nanoparticles (Glb-SLNs) to improve the drug's solubility and oral bioavailability. It was mediated through pseudo-ternary phase diagrams to optimize the surfactant/co-surfactant ratio. The optimized Glb-SLNs were characterized by FT-IR spectroscopy, DSC, powder X-ray diffraction study and SEM analysis. In rat skeletal muscle cells (L6 myocytes) and in streptozotocin and high-fat diet-induced diabetic rats, anti-diabetic activity was evaluated. Flow cytometry analysis has accessed the effects of glucose uptake performed by the 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2- deoxyglucose (2-NBDG) in L6 myotubes. In normal rats and diabetic rats, parameters such as the blood glucose level, serum insulin, serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), lipid peroxidase, catalase, glutathione, and HbA1c levels were assessed. Glb-SLNs at a dose of 50 μM showed a relative increase in relative fluorescence intensity of 92.5% to represent the glucose uptake potentiality. In vivo results revealed that the treatment with SLNs of glyburide (Glb-SLNs) normalized blood-glucose levels and serum biochemical parameters as compared with those of STZ controls. The protective effect was further confirmed by histopathological examination of the liver. These animals showed a comparable histopathological regeneration on Glb-SLNs treatment. These positive results demonstrated the success of the proposed SLNs approach in enhancing glyburide oral bioavailability and confirmed its potential as an effective system for diabetes treatment.

Type 1 diabetes is a complex disease involving a combination of factors, such as genetic susceptibility, immunologic dysregulation and exposure to environmental triggers. Animal models serve an important function both in elucidating the pathophysiology and preliminary screening of antidiabetic molecules. Hence, the development of models for type 1 diabetes can be broadly divided into 3 categories, namely: identification of spontaneously developing type 1 diabetes mellitus strains, creating diabetes-prone species through gene transfer techniques and forced destruction of islet cells through chemical or surgical means. This review discusses the models used to study type 1 diabetes with special emphasis on genetics.

The purpose of the present work was to formulate and evaluate skin permeability of a glipizide gel to assess its suitability for transdermal delivery. A polymer gel was prepared by soaking hydroxypropyl methyl cellulose (5 g) overnight in phosphate buffer: ethanol (50:50, v/v) and mixing it with separately prepared glipizide solution in the same vehicle to bring the concentration to 2 mg /ml. In vitro skin permeability was assessed in full thickness skin of rabbits and pigs. For in vivo studies New Zealand rabbits were used. In vitro passive permeation was carried out in Franz diffusion cell but for iontophoresis, diffusion cell was modified according to Glikfield design. Iontophoresis was performed at a current density of 0.5 mA/cm2 via silver/silver chloride electrodes with the passive controls but for in vivo study current density was reduced to 0.125 mA/cm2. Blood samples were analyzed for drug content by HPLC and blood sugar levels were also recorded periodically during in vivo permeation. Results of the in vitro study indicated that iontophoresis considerably increased the permeation rate of glipizide compared to passive controls in both the skin types (P0.05). For in vivo studies current densities and drug concentration had to be lowered to 0.125 mA/cm2 as excessive permeation resulting in hypoglycemic shocks were noted when study was carried out at a current density of 0.5 mA/cm2. The low intensity current was well tolerated. The plasma concentration of glipizide was significantly higher (P0.05) than that obtained in the passive controls. The study indicated even at very low current density, iontophoresis could enhance the permeation of glipizide significantly.

In vitro iontophoretic delivery of glipizide across the pigskin was investigated. The experiment was carried out at three different donor drug concentrations using cathodal iontophoresis (current density 0.5 mA cm(-2)) with corresponding passive controls. At all concentration levels, iontophoresis showed enhanced permeation rate compared to passive controls (P0.01). For passive permeation, the steady-state flux significantly increased with the increase in donor drug concentration (P0.01). Passive process followed zero-order profile while the profile was nonlinear in iontophoresis. Competition by chloride ions released in the cathode compartment could be the reason. Flux enhancement was highest at the lowest drug load and lowest at the highest drug load. The target flux of glipizide was calculated to be 0. 4147 micromol h(-1). As the highest flux obtained was 0.2727 micromol cm(-2) h(-1), it can be said that glipizide is a promising candidate for iontophoretic delivery.

beta-Carotene, when supplemented in diet, has been found to increase the survival period of mice bearing a transplantable tumor, Dalton's lymphoma. Tumor cell-count, body weight pattern, hematological parameters like total count showed marked alterations in a dose-responsive manner with beta-carotene administration when compared to their untreated counterparts. Decreased tumor cell proliferation is also reflected by increased hemoglobin levels of the host.

Purpose: To assess iontophoretic transdermal delivery of glibenclamide across pigskin for its transdermal development. Methods: In vitro iontophoretic transdermal delivery of glibenclamide across the pigskin was investigated at three different drug concentrations in the donor cell of the diffusion apparatus, using cathodal iontophoresis (current density 0.5 mA cm-2) along with the passive controls. Results: For passive permeation, the steady state flux significantly increased with the donor drug concentration. At all concentration levels, iontophoresis considerably increased the permeation rate compared to passive controls. Flux enhancement was highest at the lowest drug load and lowest at the highest drug load. The highest flux value obtained was 0.0603 μmol cm-2 h-1 and the target flux for glibenclamide was 0.3933 μmol h-1. Required permeation rate was achieved by iontophoresis using a much smaller application area. Conclusion: Permeation rate of drugs across the pigskin can be considerably enhanced by the use of Iontophoresis. Keywords: Glibenclamide; Iontophoresis; Pigskin; Transdermal drug delivery.

Inadequate skin permeability is the main challenge encountered in the transdermal drug delivery and to solve this crisis physical and chemical enhancement techniques are being developed. The aim of the present investigation was to study the combined effect of two such techniques, iontophoresis and esterification, on the transdermal delivery of atenolol. A series of ester prodrugs of atenolol were synthesized, characterized and studied for physicochemical properties and stability. In vitro permeation studies were carried out for atenolol and prodrugs at different donor concentrations (5, 10, and 20 mM) by passive process and iontophoresis (0.5 mA/cm(2)). Evaluation of the physicochemical parameters showed significant increase in lipophilicity and slight reduction in pK value in the ester prodrugs compared to parent drug. Stability studies revealed higher stability at pH 4 than pH 6. Prodrugs significantly enhanced the transdermal flux of atenolol in passive process while in iontophoresis the enhancement ranged from 1.4 to 2.7 fold compared to atenolol. In the prodrug series, permeation rate increased with increase in the length of alkyl side chain up to the addition of 5 carbon units, but thereafter no specific pattern was recorded in both passive and iontophoretic process. The steady state flux was highest in atenolol valerate (1.48 micromol/cm(2) h), which shows the promise of meeting the desired permeation rate (3.0- 31.0 micromol/ h) for maintenance of the therapeutic level in a 70 kg human.

Clinical benefits, industry interest, regulatory precedence, and strong market potential have made transdermal research the fastest growth area in drug delivery. As most drugs permeate poorly through skin, a major challenge is achieving the therapeutic level by enhancement of permeation rate. Iontophoresis, utilizing a minimal amount of current, is found to affect the skin permeation process drastically. Ideally suited for protein drugs, attempts have been made to utilize the technology for accelerating the low-molecular-weight drugs for chronic administration. However, because of the difficulty associated with the energy supply, commercialization was not feasible until recent times. Fortunately, the unprecedented growth of microelectronics has bridged this lacuna and brought the technology right into limelight. This article analyses the advantages of electrically assisted drug delivery in relation to passive permeation, with special reference to some cardiovascular drugs, for which there is already a demand in the market.

The differential levels of induction of hepatic microsomal cytochrome P-450 (cyt. P-450), UDP-glucuronyl transferase (UDPGT) and cytosolic glutathione-S-transferase (GST) activities were evaluated over various periods of time, following tumor transplantation in male Swiss albino mice in the presence and absence of beta-carotene supplementation in their basal diet (100 mg/kg). An increase in the total hepatic microsomal cytochrome P-450 and UDP-glucuronyl transferase and cytosolic GSH-transferase activities (1.5 to 2 fold) occurred during the later stage of tumor progression (22 +/- 2 days onwards). However, beta-carotene supplementation throughout the study increased or decreased the random activity trends of the above markers significantly (P0.05-0.01). Finally, beta-carotene supplementation could enhance the survival of the host bearing lymphoma by almost 2-fold (50-60 days) over and above the lymphoma controls (30-35 days).

Transdermal dosage forms, though a costly alternative to the conventional formulations, are becoming popular because of some unique advantages. Controlled zero-order absorption, simple administration mode and the option of easy removal in case of adverse manifestations make them particularly desirable in cardiovascular therapy. Nitroglycerin and isosorbide dinitrate, the two antiischaemic drugs; and clonidine, an antihypertensive molecule, are being extensively used in the transdermal form. Studies that compared these patches with the established dosage forms had shown that though patches were costlier than conventional prescription products, they reduced the occurrence of hospitalization and diagnostic costs. Currently a number of antihypertensive drugs are being developed for transdermal administration. This article reviews the research on cardiovascular patches as well as the marketed products.

The prodrug approach is one of the methods which have been evaluated for improving the systemic delivery of pharmacologically active compounds. ln the present study, we have synthesized ester prodrugs of atenolol and propranolol by adding alkyl side chains to the β-hydroxy function of the drug with the objective of enhancing their lipophilicity. In vitro skin permeability study in excised mice skin showed that the prodrugs permeate freely through the skin than the respective drug moieties and significant flux enhancement (6.2-fold) was observed in both cases. In the case of atenolol, the highest permeability coefficient was shown by capriate (C 10 side chain) where as in propranolol the highest permeability was recorded with caproate ester (C 6 side chain). The difference in permeability may be attributed to their difference in the intrinsic lipophilicities.