The present study was aimed to develop generic formulation of extended release tablets of Nevirapine anhydrous using hydrophilic polymer. Nevirapine NVP tablets were prepared by wet granulation method by employing hydrophilic polymer (HPMC K4M and K15M).The matrix granules were prepared by mixing drug along with polymer and diluents in different polymer ratio from 20% (F1 and F5), 25%(F2), 30%(F3) to 35% (F4) ratio using water as a granulating fluid. The prepared granules were evaluated for various physicochemical parameters by official procedure and compressed in tablets. In-vitro release profiles of NVP from ER tablets were determined using USP apparatus type I (Basket), 50rpm and bath temperature 37°C. Tablets dissolution was carried out in 900 ml of media (0.04M sodium phosphate buffer pH 6.8 containing 2% SLS). Samples were withdrawn at predetermined time intervals up to 24 Hrs and analysed using HPLC with UV detector at a wavelength of 282 nm. Stress stability studies showed formulation is stable and Invitro release profile study showed that formulation F2 was comparable with innovator product.
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Srikanth thota et al., The present study outlines a systematic approach for Formulation and Evaluation of Immediate release Tablets of lamivudine and Zidovudine , Nevirapine- HAART triple therapy. The objective of this regimen is, To delay disease progression, To increase the duration of survival by achieving maximal and prolonged suppression of HIV replication, To rest orate and preserve immunological function. Combination therapy is more effective and has less chances of developing resistance than mono therapy. To achieve this goal various prototype formulation trials were taken and evaluated with respect to the various quality control tests such as Thickness, hardness, weight variation, dissolution, disintegration, hardness and assay. The formula was finalized by comparing the Invitro dissolution profile with that of the Marketed Tablets. The in vitro release study was performed in 0.1N HCl up to 60 min. Among all the formulations, formulation F7 release profile was good as compared to the marketed products. Stability studies (40±2°C/75±5%RH) for 2 months indicated that no characteristics changes in formulation. There was no chemical interaction between drug and excipients.
Dushant DG et al., The present study was aimed to develop generic formulation of extended release (ER) tablets of Nevirapine anhydrous (NVP) using hydrophilic polymer. Nevirapine NVP(ER) tablets were prepared by different manufacturing technology i.e. direct compression, roller compaction, and wet granulation method by employing hydrophilic polymer (HPMC K4M and K15M).The matrix granules were prepared by mixing drug along with polymer and diluents in different polymer ratio from 20% (F1, F2, F3 and F7), 25%(F4), 30%(F5) to 35% (F6) ratio and in wet granulation technology used water as a granulating fluid. The prepared granules were evaluated for various physicochemical parameters by official procedure and compressed in tablets. The In-vitro release profile of various batches was prepared by different technologies and has been compared with the innovator product. In-vitro release profiles of NVP from ER tablets were determined using USP apparatus type I (Basket), 50 rpm and bath temperature 37°C. Dissolution of tablets was carried out in 900 ml of media (0.04M sodium phosphate buffer pH 6.8 containing 2% SLS). Samples were withdrawn at predetermined time intervals up to 24 hrs. and analyzed using HPLC with UV detector at a wavelength of 282 nm. Stress stability studies indicated that the formulation is stable and In-vitro release profile study showed that formulation using wet granulation technology F4 was comparable with innovator product.
Vishal S. Narang et al., Generic fixed-dose combinations of anti retrovirals are frequently prescribed for the treatment of human immunodeficiency virus infection. A randomized, 2-way study was conducted in 24 fasting, healthy, Indian male subjects to assess bioequivalence between a single combination tablet containing lamivudine, stavudine, and nevirapine (treatmentA)with respect to separate marketed tablets administered simultaneously (treatment B). Each subject received treatments A and B separated by 19 days of a drug-free washout period. Plasma concentrations of anti retroviral, determined by a validated liquid chromatography/tandem mass spectrometry assay, were used to assess pharmacokinetic parameters such as maximum observed plasma concentration and area under the plasma concentration curve. Pharmacokinetic parameters were comparable for either treatment. As geometric mean ratios (%treatment A/treatment B) of log-transformed parameters of area under the plasma concentration curve and plasma concentration, as well as their resultant 90% confidence intervals, were within 80% to 125% and 75% to 133%, respectively, 2 treatments were considered bioequivalent
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in the extent and rate of absorption. Both treatments exhibited similar tolerability under fasting conditions.
Basavaraj.k Nanjwade et al., To develop and characterize an oral extended-release matrix tablet of metformin hydrochloride using a combination of a hydrophobic carrier and hydrophilic polymer ,and two types of formulation techniques. Melt granulation and direct compression, the influence of the carrier, polymer and preparation method ion metformin release form the formulations in invitro as well as other physicochemical properties were studied. The release data were are subjected to various release kinetics models and also compared with the commercial brand. The kinetic analysis showed that the formula containing 30w/w of polymer exhibited release similar to that of the commercial brand .Melt granulation was the more effective in extending drug release than direct compression .the use of hydrophobic carrier along with a hydrophilic polymer effectively controls the initial rapid release of highly water soluble drug such as metformin HCL. Hot melt granulation method was especially more effective in achieving this then the direct compression method.
Uttam Mandal et al., He is mainly focused on design an oral sustained release matrix tablets of metformin HCL and optimize the drug release profile using response surface methodology .Tablets were prepared by non aqueous wet granulation method using HPMC K15M as matrix forming polymer .A central composite design for 2 factor at levels each was employed to systematically optimize drug release profile .HPMC-K15M and PVP-K30 were taken as the independent variables. The polymer and bonder had significant effect on the drug release from tablets. The study helped in the finding the optimum formulation with the sustained release.
Sunil Kumar et al., In the present work, extended release metformin tablet were designed for non-insulin depended diabetes for better patient compliance by wet granulation method. HPMC K100M was used as polymer ,stearic acid and IPA as binder agent .Estimation of extended release metformin tablet in the prepared tablet formulations was carried out at 233 nm in phosphate buffer pH 6.8 . The prepared formations were further evaluated for hardness ,friability, drug content uniformity, in vitro dissolution time and for in vitro drug release pattern in pH 6.8 phosphate buffer and shorter stability (at 40/75% RH for 3 months) and drug -excipient interaction were studied.
Vilas Sonagre et al ., The matrix tablets are very effective in sustained release dose formulation. The formulation of Metformin hydrochloride sustained release matrix tablets by using polymer, which is preferably used as an anti-diabetic and in case of type 2 diabetes mellitus. Matrix tablets were prepared using polymer with HPMC-K100 (Dow), in different concentration by dry granulation technique. The physical compatibility evaluation was performed in visual basic. The study implies that the drug, polymer and other excipients are physically compatible with other as there was no change of physical description. All the formulations were evaluated on the basis of Pharmacopoeial specification. Shapes of the tablets were standard concave in case of 500mg label claim. Hardness, thickness, weight variation, dissolution were, carried out for all cases. Assay was carried out only for those selected batches and the result was found to be 99.73%, (Label claim 500mg). Stability studies of the selected formulated tablets were carried out by keeping the tablets at room temperature and at 40°C ± 2°C / 75 ± 5% RH (stability chamber) for 30days. All the parameters were within the limit after 30days.The mechanism of drug release form matrix tablet is governed by diffusion and as the drug is so highly soluble. However, when considering in-vivo behavior of this system, the erosion rate will be more important. Selected formulations were compared with the marketed product (Riomet OD) in same strengths.
Prameela Rani et al., The present study an attempt has been made to prepare fast disintegrating tablets of metformin HCL in the oral cavity with enhanced dissolution rate. the tables were prepared with isphagula husk natural super disintegrant and crosspovidoe ,synthetic super disintegrant .The pure drug and formulation blend and tablets are evaluated .The time in the oral cavity was also tested and was found to be around 10 sec. Based on dissolution rate the disintegrants can be rated as isphagula less then crosspovidone.
Shaikh. Shakeel A et al ., Metformin extended release (metformin ER) is a novel gastric-retentive formulation of the anti hyperglycemic agent that can be administered once daily. The polymer matrix of the metformin ER 500mg tablet swells in gastric fluid, causing it to be retained in the stomach in the fed state. Over a period of 8 hours, the drug dissolves and diffuses through the matrix to be absorbed in the upper gastrointestinal tract. Systemic exposure to the drug (assessed by the area under the plasma concentration-time curve) with oral metformin ER 1000mg once daily did not differ from that of immediate-release metformin (metformin IR) 1000 mg/day administered as a divided dose. However, the time to maximum plasma concentration was 7.5 hours with metformin ER versus 4.2 hours with metformin IR. Glycemic control, measured by change from baseline in mean glycosylated hemoglobin (HbA1c) levels at study endpoint, with metformin ER 1500 mg/day (once daily or as divided doses morning and night) or 2000 mg/day (once daily) did not differ from that with metformin IR 1500 mg/day as a divided dose in a 24-week, double-blind, randomized trial in 706 patients with type 2 diabetes mellitus. In the same study, the American Diabetes Association-recommended HbA1c level of <7% was achieved in significantly more metformin ER 2000 mg/day than metformin IR 1500 mg/day recipients. Greater glycemic control was seen with metformin ER 1500-2000 mg/day plus glyburide (glibenclamide) than with glyburide plus placebo in a 24-week, double-blind, randomized trial in 575 patients with type 2 diabetes. Metformin ER is generally well tolerated, with an adverse event profile similar to that of metformin IR. Of interest, the incidence of nausea was significantly lower with metformin ER than with metformin IR in the first week of treatment, suggesting that more rapid dose titration may be possible with metformin ER. The incidence of adverse events with metformin ER 2000 mg/day did not differ from that with metformin IR 1500 mg/day.
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Antona J Wagstaff et al ., In the new oral, once-daily, extended-release (ER), single-composition osmotic tablet formulation of the biguanide metformin hydrochloride (metformin XT), metformin is released at a controlled rate from a central osmotic tablet core through a semi permeable coating. A decrease in fasting plasma insulin, a marker of insulin resistance, was seen with metformin XT but not with immediate-release (IR) metformin in one well designed trial, but changes were similar in another. The pharmacokinetics of metformin XT reflect its extended-release characteristics. While the bioavailability (in terms of area under the plasma concentration-time curve) of metformin XT taken after the evening meal is similar to that of the IR formulation taken in divided doses, time to peak plasma concentrations is prolonged. Increases in metformin XT dose from 1000mg to 2500mg resulted in predictable and consistent dose-associated increases in metformin exposure. As with other ER metformin formulations, the bioavailability of metformin XT is increased after food, in contrast to the slight decrease seen with the IR formulation. The efficacy of metformin XT 1000, 1500, 2000, or 2500mg once daily with the evening meal was found not inferior to a similar dose range of metformin IR given in divided doses (measured by changes in glycosylated hemoglobin HbA(1c)) in a well designed study of 659 evaluable patients with type 2 (non-insulin-dependent) diabetes mellitus previously stabilized on metformin IR. Metformin XT and IR 2000 or 2500 mg/day had clinically similar efficacy (using changes in HbA(1c) and fasting plasma glucose) in another well designed study of 102 evaluable patients with type 2 diabetes. Like the IR formulation, metformin XT is generally well tolerated; gastro-intestinal adverse events are, however, common.
Lian-Dong Hu et al ., The low bioavailability and short half-life of metformin hydrochloride (MH) make the development of sustained-release forms desirable. However, drug absorption is limited to the upper gastrointestinal (GI) tract, thus requiring suitable delivery systems providing complete release during stomach-to-jejunum transit. This study was undertaken to develop a MH sustained-release formulation in compliance with these requirements. The strategy proposed is based on direct-compressed matrix tablets consisting of a combination of MH with the hydrophobic triacetyl-beta-cyclodextrin (TAbetaCD), dispersed in a polymeric material. Different polymers were tested as excipients, i.e. xanthan gum, chitosan, ethylcellulose, Eudragit L100-55, and Precirol. Compatibility among the formulation components was assessed by DSC analysis. All the tablets were examined for drug release pattern in simulated gastric and jejunal fluids used in sequence to mimic the GI transit. Release studies demonstrated that blends of a hydrophobic swelling polymer or chitosan) with a pH-dependent one (Eudragit L100-55) were more useful than single polymers in controlling drug release. Moreover, the main role played by the MH-TAbetaCD system preparation method (i.e. grinding or spray-drying) in determining the behavior of the final formulation was evidenced. In fact, for a given matrix-tablet composition, different sustained-release effects were obtained by varying the relative amounts of MH-TAbetaCD as ground or spray-dried product. In particular, the 1:1 (w/w) blend of such systems, dispersed in a Eudragit-chitosan polymeric matrix, fully achieved the prefixed goal, giving about 30% released drug after 2h at gastric pH, and overcoming 90% released drug within the subsequent 3h in jejunal fluid.
Yang Liu et al ., In this study, metformin hydrochloride (MH) sustained-release pellets were successfully prepared by centrifugal granulation. Seed cores preparation, drug layering, talc modification and coating of polymeric suspensions were carried out in a centrifugal granulator. Talc modification was performed before coating in order to overcome the high water solubility of metformin. The influence of surface modification by talc, the effects of Eudragit types and ratios, as well as the correlation between in vitro release and in vivo absorption were investigated in detail. Experimental results indicated that talc modification made a decisive contribution to controlling the drug release by avoiding drug dumping. Three dissolution media: 0.1 M HCl, distilled water and pH 6.8 phosphate buffer were employed to determine the in vitro release behaviors of the above metformin hydrochloride pellets. The relative bioavailability of the sustained-release pellets was studied in 12 healthy volunteers after oral administration in a fast state using a commercially available immediate release tablet (Glucophage) as a reference. Following coating with a blend of Eudragit L30D-55 and Eudragit NE30D (1:20), at 7% or 10% coating level, respectively (referred to as F-2, F-3), the pellets acquired perfect sustained-release properties and good relative bioavailability. The Cmax, Tmax and relative bioavailability for F-2 and F-3 coated pellets were 1.21 microg/ml, 6 h, 97.6% and 1.65 microg/ml, 8 h, 165%, respectively. Combined use of two Eudragit polymers with different features as coating materials produced the desired results. Restricted delivery of metformin hydrochloride to the small intestine from differently coated pellets resulted in increased relative bioavailability and a sustained release effect. The adoption of several different pH dissolution media established a better relationship between the in vitro release and in vivo absorption of the sustained-release pellets.
Ashutosh Mohapatra et al ., Dionvenience of administration and patient compliance are gaining significant importance in the design of dosage forms. Metformin hydrochloride is an orally administered antihyperglycemic agent, used in the management of non-insulin-dependant (type-2) diabetes mellitus. Difficulty in swallowing (dysphagia) is common among all age groups, especially in elderly and pediatrics. Unfortunately, a high percentage of patients suffering from type-2 diabetes are elderly people showing dysphagia. Persons suffering from dysphagia may get choked when they consume liquid formulation, thus to alleviate such problem liquid formulation of high viscosity was prepared. Formulation of oral soft gel batches of metformin was carried out using hydrophilic polymer gellan gum at concentrations ranging from 0.2-0.4% w/v and sodium citrate at two different concentrations (0.3% and 0.5%). The prepared batches were evaluated for appearance, viscosity, pH, drug content, syneresis, in vitro drug release, and taste masking. The batch with 0.4% w/v gellan gum and 0.5% sodium citrate not only showed 85% drug release at 15 min, but all the desired organoleptic properties. The taste masking was carried out using nonnutritive sugar and flavors. The optimized batch showed substantial stability when subjected to short term stability study (0-8°C and Room temperature). The problem of dose measurement by patients was outweighed as oral medicated gels are to be packed in unit dose container
P. K. Bhoyar et al ., An attempt was made to sustain the release of metformin HCl as well as to mask the bitter taste by complexation technique using strong cation-exchange resins, indion 244 and indion 264. The drug loading onto ion-exchange resin was optimized for mixing time, activation, effect of pH, mode of mixing, ratio of drug:resin and temperature. The resinate was evaluated for micromeritic properties, taste masking and characterized using XRPD and IR.
Kamlesh J Wadher et al ., The overall objective of the present work was to develop an oral sustained-release (SR) metformin tablet prepared by the direct compression method, using hydrophilic hydroxylpropylmethylcellulose (HPMC) and Guar gum polymer alone and in combination at different concentrations. Metformin hydrochloride (HCl), a biguanide, has a relatively short plasma half-life and low absolute bioavailability. All the batches were evaluated for thickness, weight variation, hardness and drug content uniformity and in vitro drug release. Mean dissolution time is used to characterize the drug release rate from a dosage form, and indicates the drug release-retarding efficiency of the polymer. The hydrophilic matrix of HPMC alone could not control the Metformin release effectively for 12 h whereas when combined with Guar gum, it could slow down the release of drug and, thus, can be successfully employed for formulating SR matrix tablets.
R.NagarajuA et al., The present study was focused on optimization of the formulation for the delayed and extended release tablets of mesalamine. Various formulations was prepared by wet granulation technique using the polymers, such as HPMCK-100M, HPMC K4M, HPMCE15 and HPMC E5. It was found that the best formulation ML10 showed 98.75 % of drug release at the end of 10th hour. This way the best formulation was achieved by using the combination of high and low viscous polymers HPMC K4Mand HPMC E5 in the ratio of 60:40 was able to prolong the drug release for about 10 hrs in pH 7.5phosphate buffer. In-vitro drug release studies of mesalamine delayed and extended release tablets showed that, the rate of the drug release follows first order kinetics as indicated straight line with good correlation coefficient for the plot of log percentage drug remaining vs time.
Madhusudhan pogula et al., Recently, controlled release drug delivery has become the standards in the modern pharmaceutical design and intensive research has been undertaken in achieving much better drug product effectiveness, reliability and safety. Oral Extended release drug delivery medication will continue to account for the largest share of drug delivery systems. Hence, in this work to formulate tablets in order to avoid the first pass metabolism and increase the bioavailability. Hence in this work an attempt was made to formulate extended release system in order to achieve plasma concentration profile up to 24 hrs.The extended release formulations are the type of formulations which will improves the therapeutic index of drug concentration. These formulations makes the drug available over extended time period after oral administration. The extended release product will optimize therapeutic effect and safety of a drug at the same time improving the patient convenience and compliance. Here an attempt was made to formulate the Delayed Drug release in to the systemic circulation. This will give detailed information about the formulation and formulation requirements to develop the ideal Delayed drug release formulation.