Design, formulation, and in vitro evaluation of sustained release tablets for losartan potassium

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Objective: The purpose of the present research investigation was to formulate sustained release (SR) formulations for losartan potassium using 32 factorial designs. Methods: Losartan potassium is an antihypertensive agent, non-peptide angiotensin-II receptor (type AT1) blocker, and BCS class-III agent. SR tablet formulations of losartan potassium were formulated using variable quantities of hydroxymethyl propyl cellulose (HPMC) K100M and xanthan gum in combinations by direct compression technique. The amount of polymers, HPMC K100M, and xanthan gum required to achieve the drug release was selected as independent variables, X1 and X2 , respectively, whereas time required to release 10% (t10%), 50% (t50%), 75% (t75%), and 90% (t90%) of drug from formulation was selected as dependent variables. Nine formulations were prepared and evaluated for various pharmacopoeial tests. Results: The results reveal that all formulations were found to be with in the pharmacopoeial limits and in vitro drug release profiles of all formulations were subjected to kinetic modeling. The statistical parameters such as intercept, slope, and correlation coefficient were determined. Polynomial equations were developed for dependent variables. Validity of developed polynomial equations was checked by designing two checkpoint formulations (C1 and C2 ). According to SUPAC guidelines, formulation (F4 ) containing mixture of 15% HPMC K100M and 20% xanthan gum is the most identical formulation (similarity factor f2 = 86.747, dissimilarity factor f1 = 1.760, and no significant difference, t = 0.0477) to marketed product (LOSACAR). Conclusion: Best Formulation F4 follows the first-order, Higuchi kinetics, and the mechanism of drug release was found to be non-Fickian diffusion anomalous transport (n = 0.825). KEY WORDS: 32 factorial design, First-order kinetics, Hydroxymethyl propyl cellulose K100M, Losartan potassium, Non-fickian diffusion mechanism, Sustained release tablet, Xanthan gum
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  • 1. 315Drug Invention Today | Vol 10 • Issue 3 • 2018 Design, formulation, and in vitro evaluation of sustained release tablets for losartan potassium Raghavendra Kumar Gunda, A. Vijayalakshmi* INTRODUCTION Oral administration is the most convenient, widely used route of administration for both prompt drug delivery systems and new drug delivery systems. Tablets are the most famous oral solid formulations available in the market and are preferred by patients and physicians alike. In case of treatment of chronic disease conditions, immediate release formulations are required to be administered in frequent manner and therefore have patient non-compliance.[1] However, ingestion of majority of drugs shows first pass effect and/or first- pass hepatic metabolism pre-systemic elimination by gastrointestinal degradation as a result of which low systemic bioavailability and shorter duration of action and development of non-active or toxic metabolites.[2] Research Article Department of Pharmacognosy, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Pallavaram, Chennai, Tamil Nadu, India *Corresponding author: A. Vijayalakshmi, Department of Pharmacognosy, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Pallavaram, Chennai - 600 117, Tamil Nadu, India. Phone: +91-9176093990. E-mail: avijibaskaran@gmail.com Received on: 22-10-2017; Revised on: 25-11-2017; Accepted on: 17-02-2018 Access this article online Website: jprsolutions.info ISSN: 0975-7619 Sustained release (SR) tablet formulations are preferred for such chronic therapy because they produce patient compliance, maintain steady-state drug levels, and dose reduction and increase the safety margin/threshold for high-potency drugs.[3] The objective of a SR formulation is to maintain plasma or tissue drug levels for prolonged period. SR systems generally do not attain constant rate of release mechanism and usually try to mimic zero-order release by providing drug in a slow first-order manner (i.e., concentration dependent). Systems that are designated as prolonged release/timed release will be taken into consideration as attempts at achieving prolonged and targeted release delivery.[4,5] SR products provide an advantage over immediate release formulations by optimizing biopharmaceutical, pharmacokinetic, and pharmacodynamic properties of active ingredient. SR formulations have been proved to improve therapeutic efficacy bythe maintenance of a steady-state serum drug concentration.[6] ABSTRACT Objective: The purpose of the present research investigation was to formulate sustained release (SR) formulations for losartan potassium using 32 factorial designs. Methods: Losartan potassium is an antihypertensive agent, non-peptide angiotensin-II receptor (type AT1) blocker, and BCS class-III agent. SR tablet formulations of losartan potassium were formulated using variable quantities of hydroxymethyl propyl cellulose (HPMC) K100M and xanthan gum in combinations by direct compression technique. The amount of polymers, HPMC K100M, and xanthan gum required to achieve the drug release was selected as independent variables, X1 and X2 , respectively, whereas time required to release 10% (t10% ), 50% (t50% ), 75% (t75% ), and 90% (t90% ) of drug from formulation was selected as dependent variables. Nine formulations were prepared and evaluated for various pharmacopoeial tests. Results: The results reveal that all formulations were found to be with in the pharmacopoeial limits and in vitro drug release profiles of all formulations were subjected to kinetic modeling. The statistical parameters such as intercept, slope, and correlation coefficient were determined. Polynomial equations were developed for dependent variables. Validity of developed polynomial equations was checked by designing two checkpoint formulations (C1 and C2 ). According to SUPAC guidelines, formulation (F4 ) containing mixture of 15% HPMC K100M and 20% xanthan gum is the most identical formulation (similarity factor f2 = 86.747, dissimilarity factor f1 = 1.760, and no significant difference, t = 0.0477) to marketed product (LOSACAR). Conclusion: Best Formulation F4 follows the first-order, Higuchi kinetics, and the mechanism of drug release was found to be non-Fickian diffusion anomalous transport (n = 0.825). KEY WORDS: 32 factorial design, First-order kinetics, Hydroxymethyl propyl cellulose K100M, Losartan potassium, Non-fickian diffusion mechanism, Sustained release tablet, Xanthan gum
  • 2. Raghavendra Kumar Gunda and A. Vijayalakshmi Drug Invention Today | Vol 10 • Issue 3 • 2018316 The utilization of polymers in controlling the drug release rate has become an important tool in the product development of pharmaceutical dosage forms. Over many years, various studies have been reported in the literature on the applicability of polymers in the formulation development of sustained drug release systems for various drugs. Natural polymers preferred primarily because they were economic, high drug holding capacity, high thermal stability, non-carcinogenicity, mucoadhesivity, biodegradable, biocompatible, broad regulatory acceptance, and ease of compression. Various gums and mucilages were used for the development of SR formulations in the past few decades such as xanthan gum, alginates, guar gum, tragacanth gum, pectin, and cellulose derivatives such as hydroxypropyl cellulose, hydroxymethyl propyl cellulose (HPMC), carboxymethyl cellulose (CMC), and sodium CMC have been extensively studied as release retardants in the prolonged release formulations. The future of SR products is promising in novel drug delivery area such as chronopharmacotherapeutic delivery system, mucoadhesive system, chronopharmacokinetic system, targeted drug delivery system, and particulate system that provide high promise and acceptability. Oral SR formulations by direct compression technique were a simple approach due to its ease, faster production. No hydrolytic or oxidative reactions were occurred during manufacturing and compliance.[7] The suitability of drug candidates for SR system was based on biopharmaceutical, pharmacokinetic, and pharmacodynamic properties of it. MATERIALS AND METHODS Materials Materials used in this study were obtained from the different sources. Losartan potassium was a gift sample from Aurobindo Pharma Ltd., Hyderabad, India. HPMC K100M, xanthan gum, MCC, and lactose were procured from Loba Chemie Pvt. Ltd., Mumbai. Other excipients such as magnesium stearate and Talc were procured from S.D. Fine Chem. Ltd., Mumbai. Drug profile and rationality for experimental design In the present research investigation, a SR formulation of losartan potassium has been developed that reduces dosing frequency. Losartan potassium was a non- peptide angiotensin-II receptor (type  AT1 ) blocker, used for the management of hypertension. The main problem associated with this drug is its low therapeutic effectiveness due to poor bioavailability (25–35%) and shorter biological half-life (2 ± 0.5 h). Prompt release tablets should be administered 2–3  times a day to maintain steady-state level. Administration of losartan potassium in a SR formulation would be more beneficial for the management of hypertension. Hence, to improve therapeutic efficacy, reduce dosing frequency, and for better patient compliance, once daily SR losartan potassium is desirable.[8-15] The study was carried out to design, formulate, and evaluate SR tablet formulation of losartan potassium as a model drug and had an aim that final batch formulation parameters should meetthe objective ofthe present study. Itisanimportantissue,fordesigningabestformulation with an desired and predicted release rate in a shorter time period and less heuristics. Response surface methodology (RSM) utilizing a polynomial equation has been prominently used. Various types of RSM designs include Box–Behnken design, 32 factorial design, central composite design, and D-optimal design. RSM is applicable when only a few significant factors are involved in experimental optimization. The technique needs less experimentation and time, thus proving to be far more effective and cost-effective than the traditional methods of formulation designs.[3-6] Hence, an trail is made in this research investigation to formulate SR tablet formulations of losartan potassium using HPMC K100M and xanthan gum. Instead of heuristic method, a standard statistical optimization methodisemployedtoevaluatetheeffectofformulation variables on the release properties. Large-scale production requires more simplicity in the formulation with the economic point of view in all aspects. A 32 full factorial design was utilized to study the drug release profile in a systematic approach. A 32 full factorial design was employed to examine the effect of two independent variables (factors), i.e. the quantities of HPMC K100M and xanthan gum on the dependent variables, i.e., t10% , t50% , t75% , and t90% (time required to release 10%, 50%, 75%, and 90% of drug from formulation, respectively). Formulation development of losartan potassium SR tablets The factorial design is a statistical optimization technique that allows identification of factors involved in a method and assesses their relative importance. In addition, any interaction between factors chosen can be identified. The development of a factorial design involves the selection of variables (factors) and the choice of responses.[3-6] 32 factorialdesign describes the proportion in which the independent variables, i.e., quantities of HPMC K100M and xanthan gum were used inthe formulation of losartan potassium SR tablets. The time required to release 10% (t10% ), 50% (t50% ), 75% (t75% ), and 90% (t90% ) drug from formulation was selected as dependent variables. Significance terms were chosen at 95%
  • 3. Raghavendra Kumar Gunda and A. Vijayalakshmi 317Drug Invention Today | Vol 10 • Issue 3 • 2018 confidence interval (P < 0.05) for final resultant equations. Polynomial equations were developed for t10% , t50% , t75% , and t90% ,using step-wise backward linear regression analysis. The three levels of factor X1 (HPMC K100M) at a concentration of 10%, 15%, and 20% and three levels of factor X2 (xanthan gum) at a concentration of 10%, 15%, and 20% (% with respect to total tablet weight) were taken as the rationale for the design of the losartan potassium SR tablet formulation. A total of nine losartan potassium SR tablet formulations were prepared employing selected combinations of the two factors, i.e., X1 and X2 as per 32 factorial design and evaluated to find out the significance of combined effects of X1 and X2 to select the best combination and the concentration required to achieve the desired prolonged/SR of drug from the dosage form. Preparation of losartan potassium SR tablets Losartan potassium SR tablets were processed by direct compression technique. Formulae of each tablet are shown in Table 1. All ingredients required for formulation were collected and weighed accurately and passed through sieve no  40. They were mixed uniformly in a polybag or triturate for 15 min. Add magnesium stearate and then again blend for 5–6 min. Blend was subjected to compression using 8 station rotary tablet punching machine (Minipress, RIMEK, Ahmedabad) using 8  mm circular punches and the same hardness used for required number of tablets. Tablets were evaluated as per pharmacopoeial and unofficial tests. Tablets were packaged in airtight, light resistance containers. Experimental design Experimental design employed in the present research work for the optimization of retardants concentration such as quantity of HPMC K100M was taken as X1 and quantity of xanthan gum was taken as X2 . Experimental design is presented in Table 2. Three levels for X1 were selected and coded as −1 = 10%, 0 = 15%, and +1 = 20%. Three levels for the X2 were selected and coded as −1 = 10%, 0 = 15%, and +1 = 20%. Formulae for all the experimental trails are presented in Table 1. Evaluation of losartan potassium SR tablets Hardness The hardness of the tablets was determined by diametric breakdown of tablet using a Monsanto hardness tester. A tablet hardness of about 2–4 kg/cm2 is considered adequate for breaking strength.[16] Friability The friability of the tablets was executed using Roche friabilator. A sample of 20 tablets are taken, weighed (W), and dedusted in a drum for 4 min at a speed of 25  rpm or 100 free falls and weighed (W1 ) again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 0.8%. Friability (%) = [(W−W1 )/W)] × 100 Content uniformity In this test, 20 tablets were randomly selected and assay was performed, and the tablets having not <85% or more than 115% of the labeled claim can be considered as passes the test. Assay The drug content in each formulation was determined by triturating 20 tablets and powder equivalent to 40 mg was dissolved in 100 ml of phosphate buffer pH  6.8, followed by agitation. The solution was filtered through a 0.45 μ membrane filter and diluted suitably, and the absorbance of resultant solution was measured spectrophotometrically at 254  nm using phosphate buffer pH 6.8 as blank. Thickness Thickness of the all tablet formulations was measured using Vernier calipers by placing tablet between two arms of the Vernier calipers. In vitro dissolution study The in vitro dissolution study for the losartan potassium SR tablets was carried out in USP XXIII type-II dissolution test apparatus (Paddle type) using 900 ml of 0.1 N HCl as dissolution medium for first 2 h followed by phosphate buffer pH 6.8 at 50 rpm Table 1: Formulae for the preparation of losartan potassium sustained release tablets Name of ingredients Quantity of ingredients per each tablet (mg) F1 F2 F3 F4 F5 F6 F7 F8 F9 Losartan potassium 50 50 50 50 50 50 50 50 50 Emcompress 46 56 66 56 66 76 66 76 86 Microcrystalline cellulose pH‑103 20 20 20 20 20 20 20 20 20 HPMC K100M 40 40 40 30 30 30 20 20 20 Xanthan gum 40 30 20 40 30 20 40 30 20 Magnesium stearate 2 2 2 2 2 2 2 2 2 Talc 2 2 2 2 2 2 2 2 2 Total weight 200 200 200 200 200 200 200 200 200 HPMC: Hydroxymethyl propyl cellulose
  • 4. Raghavendra Kumar Gunda and A. Vijayalakshmi Drug Invention Today | Vol 10 • Issue 3 • 2018318 and temperature 37 ± 0.5°C. 5  ml of the samples were withdrawn by means of a syringe fitted with a pre-filter at predetermined time intervals, and the volume withdrawn at each interval was replaced with the same quantity of fresh dissolution medium. The resultant samples were analyzed for the presence of the drug release by measuring the absorbance at 254  nm using UV visible spectrophotometer after suitable dilutions. The determinations were performed in triplicate (n =  3). Kinetic modeling of drug release The dissolution profile of all the formulations was fitted in to zero-order, first-order, Higuchi and Korsmeyer–Peppas models to ascertain the kinetic modeling of drug release.[17,18] RESULTS AND DISCUSSION SR tablets of losartan potassium were prepared and optimized by 32 factorial designs to select the best combination quantities of drug release retardants, HPMC K100M, and xanthan gum and also to achieve the desired prolonged release of drug from the formulation. The 2 factorial parameters involved in the development of formulations are amounts of HPMC K100M and xanthan gum as independent variables (X1 and X2 ) and in vitro drug release parameters such Figure 1: Comparative zero-order plots for F1 –F9 Figure 2: Comparative first-order plots for F1 –F9 Figure 3: Comparative Higuchi plots for F1 –F9 Figure 4: Comparative Korsmeyer–Peppas plots for F1 –F9 as t10% , t50% , t75% , and t90% as dependent variables. Nine formulations were prepared using 3 levels of 2 factors, and all the formulations containing 50 mg of losartan potassium were prepared as a SR tablet formulation by direct compression method as per the formulae presented in Table 1. All the tablets were subjected to different pharmacopoeial tests such as drug content, mean hardness, friability, and mean thickness as per official methods. The crushing strength of tablets was found to be in the range of 4.525 ± 0.43–5.07 ± 0.42 kg/cm2 . Weight loss in the friability test was <0.445%. Drug content of prepared tablets was within acceptance range only. Results for all quality control tests were summarized in Table 3. In vitro drug release rate studies were performed for prepared tablets using 0.1 N HCl for first 2 h followed by phosphate buffer pH 6.8 as a dissolution medium and operated at 50  rpm speed and temperature 37 ± 0.5°C using USP XXIII type-II dissolution test apparatus. Comparative kinetic plots for all prepared formulations are shown in Figures 1-4, and the dissolution parameters are summarized in Table 4. The percentage of drug release for formulations F1 –F9 at 12 h was found to be in the range of 89.20–96.325%.
  • 5. Raghavendra Kumar Gunda and A. Vijayalakshmi 319Drug Invention Today | Vol 10 • Issue 3 • 2018 From the result, it reveals that the release rate was higher for formulations containing a low level of HPMCK100M compared with other formulations containing higher level, and due to high concentration of retardant the drug may have entrapped within a polymer matrix causing a decrease in the rate of drug release. Therefore, desired rate of drug release can be obtained by manipulating the quantities of retardants. Much difference was observed in the dependent variables due to formulation variables. Formulation F4 containing 30 mg of HPMC K100M and 40 mg of xanthan gum showed promising results (t10%  =  0.383 h, t50% = 2.519  h, t75% = 5.038  h, and t90% = 8.371  h). The variation in initial burst result is a result of the difference in the thickness of polymeric matrix. The increase in viscosity results in a corresponding decrease in the drug release, which might be due to the result of thicker gel layer formulation. The in vitro dissolution data of losartan potassium SR tablet formulations were subjected to various kinetic modeling by goodness of fit by linear regression analysis. The results of kinetic modeling are shown in Table  4. The results also reveal that majority of formulations follows first-order kinetics and r values were found to be above 0.974  (0.974–0.982). The Figure 5: Response surface plots for t10% Figure 6: Response surface plots for t50% r values for Higuchi equation were found to be in the range of 0.956–0.965, which shows that the drug release follows diffusion mechanism. Kinetic data were fitted to Peppas equation, the slope (n) values range from 0.67 to 0.902 that shows non-Fickian diffusion mechanism (anomalous drug transport). Polynomial equations were derived for all dependent variables using backward stepwise linear regression analysis using PCP Disso software, and response surface plots were constructed using SIGMAPLOT V13 software. The response surface plots are shown in Figures 5-8 for t10% , t50% , t75% , and t90% using X1 and X2 on both the Table 2: Experimental design layout Formulation code X1 X2 F1 1 1 F2 1 0 F3 1 −1 F4 0 1 F5 0 0 F6 0 −1 F7 −1 1 F8 −1 0 F9 −1 −1 C1 −0.5 −0.5 C2 +0.5 +0.5 Figure 7: Response surface plots for t75% Figure 8: Response surface plots for t90%
  • 6. Raghavendra Kumar Gunda and A. Vijayalakshmi Drug Invention Today | Vol 10 • Issue 3 • 2018320 axes, respectively. The kinetic parameters for factorial formulations F1 to F9 are presented in Table 5. Polynomial equation for 3² full factorial designs was explained as follows: Y=b0 +b1 X1 +b2 X2 +b12 X1 X2 +b11 X1 ²+b22 X2 ² Where Y is dependent variable, b0 is average response of 9 trails, and b1 is estimated coefficient for X1 . The main effects (X1 and X2 ) represent the average result of changing one factor at a time from its low to high
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