Polymethacrylate Coated Valsartan Tablets for Ileo-Colonic Delivery: Formulation Development and In Vitro and In Vivo Evaluations

 

Usha Y. Nayak¹*, Srinivas Mutalik¹, Yogendra Nayak²

¹Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University,

Manipal-576104, Karnataka, India

²Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University,

Manipal-576104, Karnataka, India

 

 

ABSTRACT:

The present study was aimed to develop timed/ delayed release Eudragit coated tablets of valsartan for ileo-colonic release to treat early morning surge in blood pressure.  The core-tablets containing 80 mg of valsartan were coated with different grades of methacrylate polymers viz., Eudragit S 100, Eudragit RS, Eudragit RS: RL combination (50:50 and 80:20) at different coating levels. The tablets were characterized for physical properties, in vitro release studies and in vivo release kinetics. The drug release studies indicated a very low drug release in the initial phase (0–6 h) followed by rapid release for next 12 h with the Eudragit S 100 and Eudragit RS alone coated tablets.  The in vitro drug release studies showed that the coating was able to resist the environmental conditions in the gastric and duodenum and delayed the drug release until the tablet reached terminal ileum. In vivo pharmacokinetic study in rabbits and healthy human subjects showed rapid absorption of drug from conventional tablet, whereas absorption was delayed in the case of Eudragit coated tablets. Thus, a rapid release pattern obtained after a lag time of 6-7 h with Eudragit coated tablets could be an ideal approach for the treatment of morning surge using valsartan.

 

 

 

INTRODUCTION:

Time-specific controlled release systems are the formulations designed to release the drug in a precise chronological pattern. Different technologies are utilized to deliver the active drug molecule to a specific region of the gastrointestinal tract (GIT). There are various approaches that have been studied to incorporate a time-specific module to oral controlled release systems (Fix, 1999; Shaji and Shinde, 2011). Pulsatile release capsules (Gohel and Sumitra, 2002), compression coated tablets (Nunthanid et al., 2008; Sridhar et al., 2011) and water insoluble polymer or pH responsive polymer coated dosage forms (McConnell et al., 2008; Rakesh et al., 2011) are the most common technologies employed in delayed / time-specific release systems.

The most commonly used water-insoluble polymers for delayed release applications are the polymethacrylate copolymers (Eudragit RS and RL), polyvinyl acetate and cellulose derivatives (ethylcellulose and cellulose acetate) (Kendall and Basit, 2006). It is well known that the simplest way of achieving colonic specificity is by the use of pH sensitive polymers.

 

Solid drug carriers such as tablets or multiparticulate pellets are coated with a protective coat using suitable polymers with sufficient thickness, to prevent the release of drug contents in the stomach and small intestine. Enteric polymers are used very frequently for coating, because their release is dependent on the pH of the external environment along the GIT. Majority of these polymers dissolve at pH values in the range of 4.8-7.0 (Chourasia and Jain, 2005; Vasanth Kumar et al., 2012). Controlled release dosage forms, which release the drugs based on pH of the GIT, are designed to release drugs depending on the pH at different segments of GIT that can vary from pH 1.2-3.5 in the stomach to pH 6.0-7.5 in the lower small intestine (Kendall and Basit, 2006).

 

The time-specific or delayed-release formulations release the drug after a predetermined time or in a predetermined location. These can be either to target release the drug in proximal small intestine (enteric coating) or the colon. Enteric coating can be attained by coating the dosage form with an ionizable carboxylic acid group containing weakly acidic polymer that will break down only at the basic pH of small intestine while remaining intact in the stomach. pH-sensitive polymers that can dissolve in the range 6.8 to 7.5 may be used for colonic delivery (Kendall and Basit, 2006). Thus the site-specific delivery of drugs to different regions of the GIT can be achieved by the virtue of pH. Polymethacrylic acid-methylmethacrylate copolymers (Eudragit products) are most commonly used enteric polymers. Eudragit L dissolves at pH above 6 and Eudragit S dissolves at pH above 7 (Chourasia and Jain, 2005; McConnell et al., 2008). The ratio of methacrylic acid to methyl methacrylate is 1:2 in Eudragit S. Eudragit RS less permeable to water as it contains less quaternary ammonium groups and being more hydrophilic Eudragit RL takes up more water (Gupta et al., 2001).

 

Valsartan is a long-acting therapeutically proven angiotensin receptor blocker (ARB) used in the treatment of hypertension. It is a good candidate to be delivered at a specified time and region of GIT to exhibit maximum therapeutic effect in the early morning (Nayak et al., 2009). In addition, it was reported that valsartan shows maximum absorption in the lower segment of the GIT where pH is in the range of 6-7 (Muller et al., 1997). In our previous study, valsartan capsules and multiparticulates were developed for time-specific delivery (Nayak et al., 2009; Nayak et al., 2013). The present work has been attempted to develop enteric polymer coated tablets to release valsartan in the ileo-colonic region; this tablet can be taken before going to bed in night so that maximum drug concentration could be achieved in the early morning hours.

 

MATERIALS AND METHODS:

Materials:

Valsartan, Cross-linked polyvinylpyrrolidone (Cross PVP), Avicel PH 112, Magnesium stearate, Talc, Eudragit S 100, Eudragit RS and Eudragit RL were obtained as gift sample from Lupin Research Park, Pune, India. Triethyl citrate (TEC) was procured from HiMedia Laboratories Pvt. Ltd. Mumbai. HPLC grade Acetonitrle and Methanol, were purchased from Merck Specialties Ltd., Mumbai. Milli-Q water was produced in the lab using the Milli-Q water generator (Millipore (India) Pvt. Ltd., Bangalore). All other chemicals and reagents were used are of analytical grade.

 

Drug–excipient compatibility studies:

Infrared spectra of samples a sample (drug, drug-polymer mixtures and coated tablets) were recorded by using KBr-pellet technique (FTIR 8300 Spectrophotometer, Shimadzu, Tokyo, Japan) in the wavelength region of 4000 to 400 cm^-1. The pellet was placed in the light path and the spectrum was obtained (Usha et al., 2008; Gopal et al., 2009).

 

Differential scanning calorimetry (DSC) scans were performed using a DSC-60 (Shimadzu, Tokyo, Japan) calorimeter. The samples (drug, drug-polymer mixture and coated tablets) were heated in sealed aluminum pans under nitrogen flow (30 mL/min) at a scanning rate of 5˚C/ min from 25 to 250˚C (Usha et al., 2008; Gopal et al., 2009).

 

Micromeritic properties:

Micromeritic properties (bulk density, tapped density, Carr’s compressibility index and Hausner’s ratio) of drug and mixture of drug and polymers were determined (Liebermann et al., 1990; Wells and Aulton, 2007).

Preparation of core tablets:

The core tablets containing valsartan were prepared by direct compression method. All ingredients were passed through sieve #60. Valsartan (80 mg) and cross PVP (6 mg) were weighed and mixed with Avicel PH 112 (12 mg). Magnesium stearate and talc (1 % w/w each) were added to each blend. Both blends were mixed and the mixture (100 mg) was compressed using 6.5 mm convex-faced punches to get biconvex tablets (Rotary multi station tablet compression machine, Rimek Mini Press-1, Gujarat, India) (Nayak et al., 2009).

 

Coating of tablets:

Tablets were coated in a laboratory scale coating pan (Model: Delux, Ideal Cures Pvt. Ltd., Mumbai, India). The composition of coating solution is given in Table 1. Eudragit was dispersed/ dissolved separately in solvent mixture. Purified talc was triturated separately in solvent mixture to get paste-like mass, and added to Eudragit dispersion/solution. TEC was added to this mixture by stirring magnetically for 30 min. The coating solution was passed through sieve of aperture size 0.149 mm to get a clear dispersion and used for coating (Gopal et al., 2009). The coatings of all composition were performed for 3 levels, viz., 5, 10 and 15% w/w of tablets. For coating inlet air temperature of 30-35˚C and bed temperature of 30˚C was maintained. Pan was allowed to rotate at 25 rpm and atomizing air pressure was 1 bar. Spray nozzle with diameter 1.0 mm was used at spray rate of 2-2.5 g/min.

 

Table 1. Composition of coating solution (% w/w)

              

Physicochemical characterization of tablets:

The physicochemical characterization of core and coated tablets was carried out such as height, diameter, hardness (Monsanto hardness tester, Electrolab, Mumbai, India) and % friability (Friabilator, USP EF-2, Electrolab, Mumbai, India). Weight variation test of the tablets (n=20) was carried out as per the official method (Indian Pharmacopoeia, 2007). The disintegration time of core tablets was determined by USP Disintegration Tester (ED-2AL, Electrolab, Mumbai, India). The drug content of coated tablets was determined using methanol as solvent by UV-Visible spectrophotometer (UV 1601 PC, Shimadzu, Japan) at 250 nm after appropriate dilution with phosphate buffer (pH 6.8).

 

In vitro dissolution studies:

The dissolution study of core tablets was carried out using a USP Type II dissolution apparatus (TDT-06P, Electrolab, Mumbai, India) at 37 ± 0.5˚C in 900 mL phosphate buffer pH 6.8. Whereas for coated tablets, dissolution study was carried out in 900 mL of 0.1 N HCl for first 2 h, followed by 900 mL of phosphate buffer (pH 6.8) for 4 h and then 900 mL of phosphate buffer (pH 7.4) up to 12 h at 75 rpm (McConnell et al., 2008). During dissolution study, after performing dissolution in 0.1 N HCl, the media was filtered through Whatmann filter paper and content on the filter paper was transferred to the next dissolution media i.e. phosphate buffer (pH 6.8). Similarly, after 4 hours dissolution in phosphate buffer (pH 6.8), the content was transferred to phosphate buffer (pH 7.4). At different time intervals, sample was withdrawn and analyzed by UV-Visible spectrophotometer at 250 nm.

 

The dissolution study of optimized formulations was carried out in simulated gastric fluid (SGF) followed by simulated intestinal fluid (SIF) in the similar way. The samples were analysed by HPLC (LC –2010CHT, Shimadzu, Koyoto, Japan). The analysis was performed by validated HPLC method, chromatographic column was reverse phase C₁₈ column (BDS Hypersil Phenyl, 250 mm × 4.6 mm, 5 µm). The mobile phase consists of 10 mM phosphate buffer (pH adjusted 3.0 with orthophosphoric acid) and acetonitrile with a ratio of 50:50 at a flow rate of 0.8 mL/min. Column oven temperature and sample cooling temperature was set at 25ºC and 4ºC, respectively. The detector was set at 250 nm and injection volume was 20 µL.

 

Stability studies:

After determining drug content, the optimized coated tablets were charged for the accelerated stability studies at 40 ± 2°C/ 75 ± 5% RH as per ICH guidelines in stability chambers (Thermolab, Mumbai, India) for a period of 6 months. The samples (n=3) were taken out at 15, 30, 60, 90 and 180 days and evaluated for the drug content and in vitro drug release study.

 

Pharmacokinetic studies in rabbits:

The study was carried out to compare the pharmacokinetics of valsartan from a selected Eudragit coated tablet formulations to a conventional immediate release tablet (core). Study protocol was approved by the Institutional Animal Ethical Committee (IAEC/KMC/07/2007-2008). The male rabbits weighing 2.0 kg were housed with free access to food and water. The overnight fasted rabbits were divided into 3 groups (n = 3) and treated orally (3.73 mg/kg) as follows:

 

Group I: Conventional tablet formulation

Group II: Eudragit coated tablets (S-15%)

Group III: Eudragit coated tablets (RS-5%)

 

After a single oral administration of 7.5 mg of valsartan tablet, 0.5 mL of blood samples were collected from the marginal ear vein at different time-points (0, 0.5, 1, 1.5, 2, 4, 6, 10 and 24 h for conventional tablets and 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 24 h for coated tablets) into tubes containing EDTA. The plasma was separated immediately using cold centrifugation (Sigma, Germany) at 10000 rpm for 10 min and stored at -72ºC until analysis.

Pharmacokinetic studies in human volunteers:

The pharmacokinetics of the developed tablet in comparison with marketed tablet was carried out in healthy human volunteers. The study protocol was approved by University Ethics Committee, Manipal University, Manipal (UEC/15/2009). Healthy human volunteers were given all the information about the study.

 

Treatment modality:

Dose: 80 mg valsartan

Group I: Conventional tablet formulation

Group II: Eudragit S100-15% coated tablet

 

Overnight fasted human volunteers were given with the formulations orally with sufficient water. The blood samples (1 mL) were withdrawn with the help of phlebotomists from the volunteers at different time intervals: 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 h post dose. After 4 h of dosing, the volunteers were continued with controlled diet.

 

Bioanalytical method for estimation of valsartan in plasma:

Plasma concentrations of valsartan were determined using HPLC (LC –2010CHT, Shimadzu, Koyoto, Japan). Separation was performed on a BDS Hypersil Phenyl C18 column (particle size 5 µm; 250 mm × 4.6 mm i. d.; Thermo Scientific, India). Telmisartan was used as an internal standard (IS) for the estimation of valsartan in plasma. Analysis was performed in isocratic mode at 1.0 mL/min flow rate with acetonitrile: 10 mM KH₂PO₄ buffer solution (pH adjusted 3.0 with orthophosphoric acid) (40:60, v/v) as mobile phase. The eluted peaks were detected at 250 nm. Column oven temperature and sample cooling temperature was set at 25ºC and 4ºC, respectively. Injection volume was 50 µL. The column was equilibrated for 30 min with the mobile phase prior to injecting the solutions.

 

Extraction of valsartan from plasma:

Aliquot of (90 µL) blank plasma was mixed with 10 µL of aqueous standard valsartan solution (different concentrations from 0.5 to 70 µg/mL), 200 µL methanol and 10 µL of IS (100 µg/mL). After vortex mixing, extraction was accomplished by adding 1 mL MTBE following gentle agitation with a tube rotator (Rotospin, Tarsons, Kolkata). The mixture was then centrifuged for 10 min at 10000 rpm and 4°C. The organic supernatant was transferred to a clean glass vial and evaporated using nitrogen gas at 50°C for 12 min (TurboVap^® LV; 15 psi). The residue was then reconstituted with 500 µL mobile phase mixture to get different valsartan concentrations in the analytical range of 10 to 1400 ng/mL and analyzed by HPLC. In the case of test samples, 100 µL of plasma sample was taken without adding aqueous standard valsartan and processed as mentioned above. The pharmacokinetic parameters were calculated by using PK Solutions 2.0^TM Non-compartmental pharmacokinetic data analysis software.

 

Statistical Analysis:

Data was statistically evaluated using independent sample ‘t’ test using SPSS v11.5 software. ‘p’ value of 0.05 or less was considered to be statistically significant.

 

RESULTS AND DISCUSSION:

Valsartan tablets were prepared by direct compression method and different coat weights of various methacrylate polymers were applied to the tablets to produce controlled release in the ileo-colonic region.

 

Drug–Excipient Compatibility Studies:

Drug-excipient compatibility studies were carried out by FTIR spectroscopy and DSC. All Eudragits (S, RL and RS) showed characteristic peak at 1702  cm^-1. Valsartan alone showed two carbonyl absorption bands at 1734 and 1603, assigned to the carboxyl carbonyl and amide carbonyl stretching, respectively (Nayak et al., 2009). These bands are of indicative value to elucidate drug–polymer interactions. There were no interfering peaks of eudragit at carbonyl absorption bands of valsartan. The two absorption bands of the pure drug appeared unchanged in the physical mixture and coated tablets (Fig. 1). The DSC thermograms of pure valsartan and coated tablets are shown in Fig. 2. The thermal curve of valsartan showed a melting endothermic peak at 97.61ºC. Also excipients when subjected to DSC studies did not show any characteristic endothermic peak when heated up to 200 ºC. Thus there was no considerable change in the endotherm values of valsartan when mixed with excipients. Thus FTIR and DSC studies confirmed compatibility of drug with used excipients.

 

Fig. 1. FTIR spectra of valsartan and coated tablets

 

Fig. 2. DSC thermograms of a) valsartan and Eudragit coated tablets (15% w/w) e) S 100 f) RS and g) RS: RL (50:50)

 

Micromeritic properties of tablet mixture:

As the materials should possess good flow and compaction properties for direct compression, various micromeritic properties of tablet mixture were studied (Nayak et al., 2009).  The drug alone showed angle of repose of 34.18 ± 0.12˚ representing poor flow property. The Carr’s index (19.14 ± 1.12 %) and Hausner ratio (1.04 ± 0.03) values were also high.  The formulation mixtures showed good flow properties as indicated by low values of angle of repose (22.31 ± 0.87), Carr’s index (14.86 ± 0.92) and Hausner’s ratio (0.96 ± 0.05).

 

Characterization of tablets:

The core tablets showed uniform height (3.14 ± 0.12 mm) and diameter (6.92 ± 0.24 mm). The hardness was found to be 2.5 ± 0.4 kg/cm². The friability (%) for all the batches was below 1% and weight variation was within the official limits. The core tablet disintegrated within 5 min. The area of core tablet was found to be 122.57 ± 32 mm². The hardness of coated tablets was found to be 3.9 ± 0.5 kg/cm². The friability (%) was below 1.0% and weight variation was within the official limits (Indian Pharmacopoeia, 2007).

 

In vitro drug release study:

The core tablet formulation containing 6% Cross PVP disintegrated rapidly and the drug release was rapid (86.9 ± 3.5% in 60 min), and hence this tablet was found to be appropriate to use in delayed release coating (Indian Pharmacopoeia, 2007).

 

The developed formulations were intended to target lower small intestine or colon after a predetermined lag time. Hence the tablets were coated with different grades of Eudragit polymers viz., Eudragit S 100, Eudragit RS and combinations of Eudraigt RS and Eudragit RL (50:50 and 80:20). The influence of thickness of the coating on release patterns was also investigated, ranging from 5 to 15% w/w of tablets. The in vitro drug release profile of these coated tablets is given in Fig. 3.

 

Fig. 3. Comparative dissolution profile of different Eudragit coated tablets

 

Initially tablets were coated with Eudragit S polymer which dissolves at pH above 7 (McConnell et al., 2008; Chourasia and Jain, 2005). Three coating levels (5, 10 and 15% w/w of tablets) were studied. Coating with Eudragit S hindered drug release at gastric pH and at pH 6.8; but allowed rapid and complete drug release when the pH was increased to pH 7.4. The polymer layer was dissolved rapidly in pH 7.4. The drug release at 6^th h was found to be 19.3 ± 0.5, 14.6 ± 0.32 and 1.4 ± 0.27% for 5, 10 and 15% coating, respectively. The drug release at 10^th h was found to be 94.3 ± 2.5, 80.4 ± 3.0 and 98.4 ± 3.12% for 5, 10 and 15% respectively. As the coating level was increased, it delayed the release of the drug in acidic environment (mimicking stomach) and at pH 6.8 (upper intestinal fluid). This may be due to the increased diffusion path-length and tortuosity at higher coating levels.

 

When tablets were coated with Eudragit RS alone, the drug release at 6^th h was found to be 10.3 ± 0.31, 1.64 ± 0.5 and 2.20 ± 0.4% respectively for 5, 10 and 15% coatings. The drug release at 10^th h was found to be 85.24 ± 4.0, 23.50 ± 3.2 and 8.87 ± 3.2% respectively for 5, 10 and 15% coatings. For Eudragit RS: RL at 50:50, the drug release at 6^th h was found to be 53.52 ± 2.8, 22.06 ± 2.13 and 15.72 ± 2.4% and at 10^th h, 101.27 ± 3.0, 63.67 ± 3.5 and 42.57 ± 2.9% for 5, 10 and 15% coatings respectively; whereas for Eudragit RS: RL at 80:20, the drug release at 6^th h was 20.19 ± 2.02, 17.73 ± 1.94 and 13.75 ± 2.3% and at 10^th h it was 72.58 ± 3.9, 49.26 ± 3.5 and 39.57 ± 2.6% respectively for 5, 10 and 15% coatings.

 

The coating of pH-responsive polymers delayed the release kinetics of coated tablets whereas pH-independent polymers swell and become permeable after coming in contact with digestive fluid (Gupta et al., 2001). In vitro data shows that Eudragit S100 and Eudragit RS coating allows delayed release in the simulated medium. At all coating levels of Eudragit S100 tablets started releasing valsartan in phosphate buffer pH 7.4, which is the expected pH at terminal ileum. Eudragit S100 should theoretically dissolve pH 7 in the distal small intestine. This type of pH-responsive delivery referred to as “ileo-colonic” drug delivery (McConnell  et al., 2008). In order to reduce the amount of drug release before the mid to distal small

intestine, 15% Eudragit S100 and 5% Eudragit RS coated valsartan tablets were found to be optimized formulations, which showed good release with sufficient lag time. The dissolution studies of optimized formulation was also carried out in SGF and SIF and there were no significant changes observed.

 

Stability studies:

In the accelerated stability studies, Eudragit S 100 and Eudragit RS coated tablets did not show any physical changes (appearance) during the study period and the drug content (n=3; mean ± SD) was found above 95% at the end of 180 days (Table 2). Shelf lives calculated by linear extrapolation by first-order kinetics were found to be 1.99 and 2.11 years for Eudragit S100-15% and Eudragit RS-5% coated tablets respectively (Fig. 4).

 

Table 2. Drug content of Eudragit coated tablets stored at 40°C/75%RH

 

Pharmacokinetic study in rabbits:

The mean plasma concentrations versus time profiles following a single oral administration of valsartan tablets to three rabbits are shown in Fig 5. Various pharmacokinetic parameters are summarized in Table 3.

 

Absorption of valsartan after oral administration was rapid with the conventional tablet (T_max: 1 h); but with Eudragit coated tablets, absorption was slow and showed T_max values were 7 h and 10 h for Eudragit S and Eudragit RS coated tablets, respectively. In the case of Eudragit RS coated tablet, the lag time was significantly higher compared to Eudragit S coated tablet. Eudragit S coated tablet showed optimum lag time, which was the objective of the developed formulation. There was no significant difference in the C_max values between the groups. Higher AUC value was observed with Eudragit RS tablets. The volume of distribution and renal clearance were higher in conventional tablets, which was decreased in Eudragit coated tablets, as supported by increased mean residential time. The rate of elimination was also higher with conventional tablet, but the values were not significantly different from each other. Valsartan absorption is rapid in the lower segment of the GIT where pH is in the range of 6-7. The timed release formulations with lag time in drug release might have released drug in lower intestine, which is the site of absorption for valsartan (Muller et al., 1997). Hence, improvement in pharmacokinetic profile of timed release formulations was observed. These results indicate that Eudragit S coated tablets with optimum lag time before drug release may be potentially useful formulation for chronotherapy of hypertension.

 

Fig. 4. Accelerated stability studies of optimized coated tablets at 40°C/75%RH

 

Table 3. Pharmacokinetic parameters of valsartan in rabbits

All values are expressed as mean ± SD, n=3; *significantly different at 95% confidence interval compared to conventional tablet; **significantly different at 95% confidence interval compared to Eudragit S tablets

 

 

Fig. 5. Plasma concentration versus time profile of valsartan tablets and capsules in rabbits (n=3), Conv Tab-Conventional tablet; Eud Tab-Eudragit coated tablet

 

Pharmacokinetic studies in human volunteers:

Healthy human volunteers over the age of 25-30 years and with normal body weight were recruited for the study after signing an informed consent agreement approved by the Ethics Committee of Manipal University. Based on the results obtained from pharmacokinetic study in rabbits Eudragit S100-15% coated tablet was considered as optimized formulation and further studied in healthy human volunteers. Fig. 6 shows the plasma concentration profiles of conventional tablet and coated tablets of valsartan.  Various pharmacokinetic parameters are listed in Table 4.

 

Table 4. Pharmacokinetic parameters of valsartan after a single oral dose in healthy human volunteers

All values are expressed as mean ± SD, n=3; *significantly different at 95% confidence interval compared to conventional tablet; T_max time for maximum plasma concentration; C_max maximum plasma concentration; AUC area under the curve; MRT mean residential time; V_d volume of distribution; CL clearance, T_1/2 elimination half-life; K_e elimination rate constant

 

 

Compared to conventional tablet, the onset of valsartan release from coated tablet was delayed for about 4 h. The mean plasma concentration was negligible initially and then increased rapidly for Eudragit S100 coated tablets of valsartan. Thus, lag time was clearly observed in case of Eudragit S coated tablet and T_max was found to be 7.00 ± 0.25 h, illustrating good performance of the enteric barrier layer in controlling the lag time in the in vivo environment. Valsartan absorption from the conventional formulation was faster. The higher drug plasma levels (C_max) and AUC were found for enteric coated tablet. Thus the extent of absorption of drug from these coated tablets was more due to release of drug in the intestinal region. Drug from Eudragit coated tablet tend to remain for more time in body as evident from MRT of 12 h, less clearance value and rate of elimination.

 

Fig. 6. Plasma concentration versus time profile of valsartan tablets in healthy human volunteers, Conv Tab-Conventional tablet; Eud S100 Tab-Eudragit S100 coated tablet

 

In vitro-In vivo correlation (IVIVC):

The pharmacokinetic profiles of Eudragit S100 coated tablets exhibited a good correlation with in vitro release study which was confirmed by high the R² value of 0.951 and 0.917 in rabbits and human subjects respectively. The in vivo lag time did not differ significantly from the in vitro lag time. The results in Fig. 7, demonstrate a good correlation between in vitro valsartan release and in vivo valsartan absorption of Eudragit S100 coated tablets.

 

CONCLUSION:

The coating of pH-responsive polymers delayed the release kinetics of coated tablets. In vitro drug release data show that Eudragit S and Eudragit RS coating allows delayed release in the simulated terminal ileum. More than 40% drug released initially at pH 7.4, the expected pH of terminal ileum in all coating levels of Eudragit S. In order to reduce the amount of undesired drug release before the mid to distal small intestine arrival of the delivery system, 15% Eudragit S coated valsartan tablets can be used in the night to control the rise in blood pressure in morning hours. This was supported by pharmacokinetic study in animals as well as human subjects. The results of this study clearly indicate that Eudragit coated valsartan tablets can be successfully used to control the morning surge in hypertension.

 

 

Fig. 7. Linear correlations between fraction drug released in vitro and fraction drug absorbed in vivo for Eudragit S100 coated tablets in a) rabbits and b) healthy human volunteers

 

 

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Received on 25.10.2013       Modified on 01.11.2013

Accepted on 04.11.2013      © RJPT All right reserved