Treatment Of Ulcerative Colitis Biology Essay


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In patients with UC in remission, the rate of adherence to maintenance treatment is reported to be as low as 40% (Kane et al., 2001; Van Hees and Van Tongeren, 1982). The causes of non-adherence are multi-factorial, but include the number of pills (up to 12/day) and frequency of dosing (three- or four-times daily). Once-daily oral formulations of mesalazine are likely to be a better therapeutic option in clinical practice, partly due to improved adherence. More recent studies have demonstrated the efficacy and safety of once daily administration of once daily mesalazine preparation in maintenance of remission in patients with UC, compared with the well established conventional multiple daily dosing regimen (Katz et al., 2010).

In 2007, Lialda® (Mezavant® in UK) 1,200 mg mesalazine tablets were approved for the treatment of active UC at a dosage of 2.4-4.8 g given only once daily with a view of improving patients compliance by reducing the frequency of drug administration per day (2007). Preparation of Lialda® includes the dispersion of the active drug into a lipophilic matrix containing carnuba wax with the aid of heating. The resulting mixture is then granulated with cooling and dispersed into an outer hydrophilic matrix to be tabletted. Tablets are finally film-coated to prevent premature drug release in the upper GIT (Villa, 2004).

The aim of the current study is to formulate mesalazine into a modified release dosage form suitable for once daily administration utilizing the simple wet granulation technique followed by film-coating of the resulting tables with the acrylic-based resin, Eudragit S, that dissolves at pH 7 or greater, releasing mesalazine in the terminal ileum and colon with the aid of design of experiment (DOE).

DOE has been widely used in pharmaceutical field to study the effect of formulation variables and their interactions on response variables (Lunney et al., 2008). BBD is rotatable or nearly rotatable second-order experimental design based on three-level incomplete factorial design and was selected for this study, because it can evaluate quadratic interactions between pairs of factors while minimizing the number of required experiments. BBD have been applied to the optimization of variables affecting the formulation processes and to get certain response by changing those variables (Ferreira et al., 2007; Guo et al., 2008).

Materials and methods


Mesalazine was kindly donated by Minipharm Pharmaceuticals, (Cairo, Egypt), Eudragit® S PO and Eudragit® RS 100 were generously donated by Röhm Pharma, GmbH, (Germany), triethyl citrate was purchased from Alfa Aesar (Karlsruhe, Germany), Carbopol® 940 from Noveon Inc., (USA), polyvinylpyrrolidone (PVP) K-30 from Fluka AG, (Buchs, Switzerland), talc and magnesium stearate from Adwic, El-Nasr Pharmaceutical Chemicals Co., (Egypt), croscarmellose Na was kindly donated by FMC BioPolymer, (Brussels, Belgium). All other chemicals and solvents were of analytical grade.


Experimental design

A three-factor, three-level BBD was used for the optimization procedure with Carbopol® content (X1), Eudragit® RS (X2) and croscarmellose Na content (X3) as the independent variables (table 1). The levels for these three parameters were determined from the preliminary trials. The percentages of the drug released at 6, 10 and 14 h were used as dependent variables for desirable drug release. A zero order release profile of mesalazine over 16 h was suggested as a targeted release profile which was based on a theoretical release of about 8.3% of the drug per hour after a lag time of 4 h and was deduced from mesalazine release profile of the once daily marketed product (ODMP). Design-Expert® 7.1.5 (Stat-Ease, Inc., USA) was used to generate the (DOE) matrix and analyze the response surface models.

The significance of independent variables and their interactions were tested by means of the analysis of variance (ANOVA) (Bogdanova et al.). An alpha (α) level of 0.05 was used to determine the statistical significance in all analyses. The standardized effects of the independent variables and their interactions on the dependent variable were also investigated by preparing a Pareto chart and calculating the standardized main effects (SME).

Results were assessed with various descriptive statistics such as p value, determination coefficient (R2), adjusted determination coefficient (Ra2), correlation coefficient (R), Durbin-Watson (DW) statistic and sum of squares (SS) to reflect the statistical significance of the quadratic model.

Compatibility of mesalazine with Different Pharmaceutical Excipients

Coground physical mixtures of mesalazine with various excipients used namely; Eudragit® S, Eudragit® RS, Carbopol®, and PVP K 30, were prepared by mixing in 1:1 w/w ratio using glass mortar. The prepared mixtures were examined visually and evaluated for the possible interactions using differential scanning calorimetry.

Preparation of core tablets

Accurately weighed quantity of mesalazine and the polymer(s) for the evaluated formulas were mixed for 20 minutes using a glass mortar and pestle. The mixture then granulated using a binder PVP K-30 (5% w/w) in isopropyl alcohol. The wet mass was passed through 16# sieve and the resulted granules were dried in a tray drier for 30 min at 50°C. The dried granules were sieved and mixed uniformly with ascertained amounts of croscarmellose Na, 2% w/w of talc and 1% w/w magnesium stearate. Certain amounts of the resulting granules equivalent to 1200 mg of mesalazine were compressed on a tablet single punch press machine, (Royal Artist, Bombay, India.) using a 20mm x 9mm local made oblong punch and die set.

Physicochemical characterization of core tablets

The designed formulations were studied for their physicochemical properties like hardness, friability and drug content. The hardness of 10 tablets was measured using Monsanto (standard type) tablet hardness tester. Friability was determined by taking 10 tablets in digital tablet friability tester (Model DFI-1, Veego, Bombay, India) for 4 min at 25 rpm. For estimating drug content, ten tablets were crushed and powdered. The aliquot of powder equivalent to 1200 mg of drug was weighed and dissolved in freshly prepared phosphate buffer (pH 7.4). The resultant solution was filtered and suitably diluted and analyzed spectrophotometrically at predetermined λmax of mesalazine (330 nm) using Jenway UV/Vis. Spectrophotometer (Barloworld Scientific Limited, Essex, UK). From the absorbance value drug content was calculated on average weight basis.

Preparation of coated tablets

25 g of Eudragit® S PO was dissolved in 350 g of 95% ethanol under high speed stirring until a clear solution was obtained. Triethyl citrate (10% (w/w) on dry polymer) was added as a plasticizer and talc (5% (w/w) on dry polymer) as a glidant (Akhgari et al., 2006; Ibekwe et al., 2006).Then the mixture was stirred for 24 h to ensure sufficient plasticization of the polymer and to get homogeneous solution (Piao et al., 2008a). Coating of tablets was performed by immersion (Alvarez-Fuentes et al., 2004) in the coating solution followed by solvent evaporation using hot air electric hand dryer (Piao et al., 2008b). The process was repeated until the target weight gain of 5% (w/w) was achieved. This ratio was selected based on sufficient preliminary trials.

In-vitro release Studies and kinetic analysis

In-vitro drug release studies in bio-relevant dissolution media with a sequential pH gradient was employed for evaluation to the USP dissolution II paddle method using a Vision® Classic 6TM Dissolution Tester (Hanson Research Corporation, California, USA). The initial condition was 350 ml of 0.1N HCl (pH 1.2) for 0-2 h. At the end of second hour, the pH of the media was raised to 4.5 and the total dissolution media volume to 600ml by the addition of 250 ml solution composed of 3.75 g of KH2PO4 and 1.2 g of NaOH. At the end of fourth hour, pH was raised to 7.4 by adding 300 ml phosphate buffer concentrate (2.18 g of KH2PO4 and 1.46 g of NaOH in distilled water). The study was further continued till the end in 900 ml volume. At predetermined time intervals, a 5ml sample was withdrawn and replaced with fresh dissolution media. After appropriate dilutions, the samples were analyzed spectrophotometrically for their concentrations. The paddle was operated at 50 rpm and the system was kept at a temperature between 30 and 37°C.We omitted bacterial effect since they have no relation to the release profile of mesalazine in the tested formulations (Asghar and Chandran, 2008).

Zero order kinetics (Harland et al., 1988), Higuchi (Higuchi, 1963), and Korsmeyer-Peppas (Ritger and Peppas, 1987) models were used for the analysis of the in-vitro drug release mechanism. The large value of the coefficient of determination (r2) indicated a superiority of the in-vitro release profile fitting to mathematical equations.

Stability study

According to the ICH guidelines the optimized formula were exposed to six months stability study at 40°C/75% RH (2003). The tested tablets were enclosed in a glass bottle and loaded in a desiccator containing a saturated solution of sodium chloride (75% RH). The desiccator was kept in an oven at 40 °C for 6 months (Tadros, 2010). At the end of one, three and six months, the tablets were subjected to visual observation of any physical changes in both the core and coat of the tablets, determination of drug content and in-vitro release studies.

Results and discussion

Preformulation studies revealed the presence of desirable or no interactions between mesalazine and various pharmaceutical excipients used in this study. A little or no changes were observed in cases of drug mixtures with Eudragit® RS, croscarmellose Na or Eudragit® S (figure 1).

On the contrary, with PVP, the DSC profiles of mesalazine appeared to be significantly changed. This implies that there is a chance of strong solid-solid interactions. However, this does not necessarily indicate an incompatibility, rather this could be attributed to the molecular adduct formation properties of povidone which may be considered advantageously in slow-release solid-dosage forms. Such molecular adducts have been reported to be formed with many products including salicylic acid (2009; Şanli et al., 2006; Sultana et al., 1979; Tarantino et al., 1990). A second endothermic peak 230°C, was observed from the DSC thermogram of the Carbopol® alone which might be caused by the loss of water by condensation (Lin and Yu, 1999). In the case of drug Carbopol® mixture the peak of mesalazine appeared to fused with that of the polymer indicating physical interaction which appeared to be desirable to affect drug release (French and Mauger, 1993a).

The prepared tablets from all the batches were found to be of good quality with acceptable physical characteristics. The hardness for the different batches was found to vary between 10 and 11 kg. The percentage of friability in all the formulations was not more than 0.9%. Drug content varied between ± 5% of the theoretical value (1200 mg) for all formulations.

After application of Eudragit® S coating, all the evaluated formulations met the USP requirements for oral colon targeted drug delivery systems and no formulation released more than 1% of contained drug in the first two stages of the in-vitro release studies. Coating using Eudragit® S has been widely studied for the purposes of colon targeting and no need to further investigate factors affecting its properties (Ceschiat et al., 1997; Faber and Korelitz, 1993; Goto et al., 1986; Goto et al., 1988; Nichols Jr, 1994; Peeters and Kinget, 1993).

Because of the high loading of the drug, we aimed to develop a formulation containing polymers and other excipients at amounts as little as possible, as well as releasing its content in a sustained release profile over a specified length of time, and preferably with a zero-order kinetic. Waxes (Cheboyina and Wyandt, 2008; De Brabander et al., 2000) and water-insoluble polymers (Genç et al., 1999) are a good choice to address all of these requirements. Eudragit® RS is a hydrophobic polymer which has been widely applied in modified release formulations (Apu et al., 2009b; Kim and Park, 2010; Maghsoodi and Esfahani, 2009; Socha et al., 2009). In the production of matrix tables Eudragit® RS has the advantages of excellent compression properties, being suitable for producing tablets using all common process technologies, good binding properties, thermostability, thermoplastic properties, and plastic properties. The plastic properties of Eudragit® RS produce stable characteristics across a range of relevant production parameters such as compression force (Cameron and McGinit, 1987). Such property give rise to similar in-vitro release profiles for tablets produced at different compression forces.

Carbopol® is a highly hydrophilic polyacrylic acid polymer which has gel-forming and bioadhesive properties. Due to the chemical nature of Carbopol® polymers, swelling of the polymer occurs in the pH range 5-9, as a result of ionization of the carboxylic acid groups that lead to electronic repulsion of the polymer (Majid Khan and Zhu, 1999). Such pH dependent swelling behavior of Carbopol® suggests it as a good choice ingredient to be included in colon targeting delivery systems.

Wet granulation technique, although more costly and time consuming than direct compression (Augsburger and Zellhofer, 2006), was employed in this study because of the high load of the drug which has poor flowability and compressibility along with high liability to compaction (Bacher et al., 2008; Tugcu-Demiröz et al., 2007).

Determination of the regression model and statistical evaluation

The BBD is one of the most efficient (DOE) methods and requires fewer runs than three level factorial designs. Hence, can be used as an alternative to three level factorial designs (Ferreira et al., 2007). A total of 15 experiments were performed for three factors at three levels each. This number is equal to the mid-point of each edge and the three replicated center points of the cube. The experiment runs with independent variables and the observed responses for the 15 formulations are shown in (figure 2) and (table 2).

In our experimental design an interactive second order polynomial model was utilized to evaluate the response variables with the following equation:


Where Y is the measured response associated with each factor level combination; bo is an intercept; b1 to b33 are the estimated regression coefficients computed from the observed experimental values of Y; and X1, X2 and X3 are the coded levels of independent variables. The terms XiXi and Xi2 (i = 1, 2 or 3) represent the interaction and quadratic terms, respectively (Gannu et al., 2010).

Sen and Swaminathanhave reported that ANOVA is essential to test the significance of the model. Therefore, ANOVA was conducted to test the significance of the fit of the second-order polynomial equation for the experimental data as given in (table 3). The ANOVA of the regression models showed that the quadratic model was highly significant for all responses, as was evident from the Fisher's F-test (table 3) with a very low probability value as suggested by Liu et al (2004). These significant values for second order terms indicate that, the generated surfaces will show some curvature.

Furthermore the ANOVA table partitions the variability in each response into separate pieces for each of the effects. It then tests the statistical significance of each effect by comparing the mean square against an estimate of the experimental error. The effects have P-values less than 0.05 are significantly different from zero at the 95.0% confidence level (table 4).

The P-values were used also as a tool to check the significance of each of the coefficients which, in turn, are necessary to understand the pattern of the mutual interactions between the test variables. The smaller the P-value, the more significant is the corresponding coefficient.

Predicted residual sum of squares (PRESS) is a measure of the fit of the model to the points in the design. The smaller the PRESS statistic is, the better the model fits to the data points (Segurola et al., 1999).  The quadratic model was therefore selected as a suitable statistical model for optimized coating formulations because it had the smallest value of PRESS (Kim et al., 2007).

Checking the adequacy of the model needs all of the information on lack of fit, which is contained in the residuals (Liu et al., 2004). Considering the quadratic model, the ''Lack of Fit" is not significant for all responses relative to the pure error (table 3).

The goodness of fit of the model was checked by the determination coefficient (R2). The R2 values provide a measure of how much variability in the observed response values can be explained by the experimental factors and their interactions. The R2 value is always between 0 and 1. The closer the R2 value is to 1, the stronger the model is and the better it predicts the response. When expressed as a percentage, R2 is interpreted as the percent variability in the response explained by the statistical model. The high value of determination coefficient indicated that only small percent of the total variations were not explained by the regression model (Liu et al., 2004).

The adjusted determination coefficient (Ra2) corrects the R2 value for the sample size and the number of terms in the model. If there are many terms in the model and the sample size is not very large, the (Ra2) may be noticeably smaller than the R2. High values of R2 and Ra2 ensured a satisfactory adjustment of the polynomial model to the experimental data. R2 and Ra2 values for the ascertained responses are listed in the (table 3).

The Durbin-Watson statistic is another value that shows whether autocorrelation, or correlation between errors, is present in a model (Dufour and Dagenais, 1985). The range of DW statistic is between 0 and 4, and is used for testing the linear association between adjacent residuals. The DW values below 2 can indicate positive autocorrelation and values above 2 can indicate negative autocorrelation. Hewings et al. (Hewings et al., 2002) have reported that for all estimations, analysis was performed to be sure that the DW value would be as close as possible to 2. If the DW value is typically around 2, this implies a good fit of the model. In our case, the DW statistic was determined to be within the range of 2.38-2.98, indicating the goodness of fit of the used model. Since the associated P-values are greater than 5.0% (table 3), there is no indication of serial autocorrelation in the residuals at the 5.0% significance level for all of the evaluated responses.

The standardized effects of the independent variables and their interactions on the dependent variable were investigated by preparing Pareto charts (figure 3). Pareto Chart is a series of bars used to determine the magnitude and the importance of effects (Wilkinson, 2006).The length of each bar in the charts indicates the standardized effect of that factor on the specified response. The chart includes a vertical line at the critical P-value of 0.05. An effect that exceeds the vertical line is considered to be statistically significant while the bars for factors remained inside the reference line, and the smaller coefficients for these terms compared to other terms in the polynomial equation, indicated that these terms contributed the least in prediction of the corresponding responses.

The coefficient estimate and standardized main effects (SME) values in the form of a polynomial equation for the responses are listed in (table 4). SME values were calculated by dividing the main effects by the standard error of the main effects. The largest SME of Eudragit® RS content (X2) indicated that the effect of Eudragit® RS level was found to be the main influential factor on the drug release from tested tablets in the whole stage in-vitro release. In addition, the contour plots and three-dimensional response surface plots were presented to estimate the effects of the independent variables on each response (figure 4). Three-dimensional response surface plots show the decrease in drug release with increasing Eudragit® RS level. Such finding was as expected and is in agreement with the findings of many previous reports (Apu et al., 2009a; Sadeghi et al., 2004; Tsai et al., 1998). These results stem from the fact that Eudragit® RS is insoluble in aqueous media but it is permeable and has pH-independent release profiles. Such permeability is due to the presence of quaternary ammonium groups in its structure (Fujimori et al., 2005; Haznedar and Dortunç, 2004).

Although, incorporation of Carbopol® to the formulations caused more linearity to drug release (Singla et al., 2000), a curvature was observed in its effect on the release rate (table 4). Eudragit® RS matrix tablets can be thought as coherent system, similar to a sponge in which the drug is dispersed. The presence of cross-links between polymeric chains hinders polymer dissolution in the liquid phase that can only swell the network (Grassi and Grassi, 2005). The structure is anticipated to be weakened by incorporating the water swellable polymer, Carbopol®, which swell in water up to 1000 times its original volume (and 10 times its original diameter) to form a gel when exposed to a pH environment above 4.0 to 6.0 (Shah et al., 2004). Swelling is supposed to increase matrix porosity, decrease the strength of polymeric chain cross linking and assist the drug leaking out. Practically in Carbopol® containing tablets, a gradual detachment of smaller granules from the core were noted to take place with time. A consequent increase in drug release is suspected due to the greater surface area available for the dissolution media (Patel et al., 2007). However such effects were opposed by the formation of a visible viscous gel layer on the surface of the granules which is postulated to hinder drug release (French et al., 1995). The net action of Carbopol® depends on which effect is predominant. At the low concentration used in this study, Carbopol® enhanced mesalazine release from the detached granules. Such finding met that reported by Haney and Dash (1997). On the other hand, at a level of 8% Carbopol® caused a reduction in the rate of drug release and this result confirms other previous reports (Andrews et al., 2008; French et al., 1995; French and Mauger, 1993b).

(Figure 3) shows that, the effect of Carbopol® became significant only at 14 hours. This might also be attributed to the need of water by Carbopol® to swell (Shah et al., 2004), which is time dependent and a function of both solvent concentration and temperature. Availability of solvent for Carbopol® to swell is opposed by the coherent structure and hydrophobic nature of mesalazine-Eudragit® RS matrices (Grassi and Grassi, 2005) and by the competition of croscarmellose Na.

The detachment of granules is aided by the inclusion of the superdisintegrant croscarmellose Na into the tablets. Although the correlation between tablet disintegration and drug dissolution is not always observable (Johnson et al., 1991), the results shown in (figure 4) demonstrate that even included extragranularly at the 2% level or less croscarmellose Na increased the in-vitro release rate of mesalazine formulations. This confirms the results of Rudnic, Rhodes et al (1981),and Gorman, Rhodes et al.(1982). Superdisintegrants facilitate tablet disintegration by increasing the surface area exposed to dissolution media (Setty et al., 2008). In this study all of the superdisintegrant was included extragranularly to insure that the tablet will break up into granules, but the granules may not disintegrate further, rather only dissolve (Gordon et al., 1990).

There is no single mechanism can explain the complex behavior of superdisintegrants. However, the mechanisms proposed in the past include water wicking, swelling, deformation recovery, repulsion, and heat of wetting. Although swelling is probably the most widely accepted mechanism of action for tablet disintegrants, water penetration is a necessary first step for disintegration. The hydrophobic nature of Eudragit® RS matrices hindered water wicking and hence swelling of croscarmellose Na (Augsburger et al., 2006). Such statements may give explanation for interaction between croscarmellose Na and Eudragit® RS (table 4).

Optimization of drug release and validation of optimized formulation

After generating the polynomial equations relating the dependent and independent variables, the coating formulation was optimized for the responses Y1, Y2 and Y3. The desirable range of these responses was restricted to the values listed in (table 1). The optimum values of the variables were obtained by graphical and numerical analyses using the Design-Expert software and based on the criterion of desirability (Myers and Montgomery, 1995). The optimized formulation was achieved with 6.77% Carbopol®, 1.02% Eudragit® RS and 2% croscarmellose Na. Therefore, a new batch of the coated tablets with the predicted levels of formulation factors was prepared to confirm the validity of the optimization procedure. (Table 5) and (figure 5) demonstrate that the observed values of a new batch were mostly similar with predicted values within 5% of predicted error. The similarity factors (f2) were also calculated to compare the in-vitro mesalazine release profile of the optimized formulation with that of the ideal targeted profile and the commercial product and were found to be 68.04 and 90.51 respectively. Such values indicate that the release profiles of the optimized formulation and the commercial product were similar and not significantly different from that of the ideal targeted profile.

Three models were applied to study the kinetics of mesalazine release from all the prepared formulations as well as the commercial product and some drug release kinetic parameters are presented in (table 6). It was revealed that inclusion of Carbopol® and croscarmellose Na imparted more linearity to the release rate of the drug from the tested formulation.

As shown in (table 6), zero-order kinetic model gave the highest value of the squared correlation coefficient (r2) for both the optimized formulation and the commercial product, indicating that zero-order kinetic model would be the most suitable model for describing the release of mesalazine from these formulations. This result suggests that the release of mesalazine from the hydrophilic-hydrophobic matrix is not controlled by the drug diffusion in the tablet, but controlled by the disintegration of the tablet. From these results, the mechanism of mesalazine release from the hydrophilic-hydrophobic matrix tablet could be considered as follows: 1) the penetration of solvent into the tablet which is effectively limited by the hydrophobic polymer, 2) the superdisintegrant between the granules and the hydrophilic polymer are swollen by the penetrated solvent, 3) the swollen granules separate from the surface of the tablet,4) drug dissolves inside the separated granules and 5) dissolved drug diffuses through the swollen hydrophilic Carbopol layer while the hydrophobic polymer erodes.

The effects of formulation variables on drug release could be further analyzed using t20%, t50% and t80% values (time required for 20, 50 and 90% of drug release, respectively) and the obtained results could be similar to that using Y1, Y2 and Y3. However, these release parameters (table 6) are more important variables for assessing how much drug is available at the site of action. Depending on the proposed targeted release profile 6.4, 10 and 13.6 are ideal values for t20%, t50% and t80% respectively. Both the optimized formulation and the commercial products produce similar results (table 6) regarding these parameters.

Stability study

Neither physical changes nor significant changes in drug content of tablets from the optimized formulation had been detected on storage and drug content of the tested tablets was found to be 98.77058 ± 0.460%. Such results suggest the high stability of mesalazine in enteric coated tablets and come in agreements with previous reports in which the decrease in the content of mesalazine did not exceed 1% in solid dosage forms even placed in stressed conditions for a period up to 2 years (Jensen et al., 1992). The pair-wise procedures indicated statistical insignificant difference in the in-vitro drug release profile from the fresh and stored tablets of the optimized formulation.


The optimized hydrophilic-hydrophobic, high loading mesalazine matrix tablets demonstrated a modified drug release manner suitable for once daily administration. The optimized formulation, containing 6.77% Carbopol®, 1.02% Eudragit® RS and 2% croscarmellose Na in addition to other excipients, was fabricated utilizing the simple wet granulation technique and produced a zero-order drug release profile comparable to that of the once daily marketed product.

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