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RESEARCH ARTICLE
Development of colon targeted multiparticulate pulsatile drug delivery system for treating nocturnal asthma
Vinayak D. Kadam, and Surendra G. Gattani
Department of Pharmaceutics and Quality assurance, R. C. Patel Institute of Pharmaceutical Education and Research, Near Karwand Naka, Shirpur, Dist. Dhule, Maharashtra, India
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Abstract The aim of the present study was to develop theophylline fast release enteric-coated pellets as a pulsatile drug delivery to the colon. The novelty of this work is the combination of pH and time-dependant enteric polymers as a single coating for the development of multiparticulate formulation. Theophylline pellets were optimized by applying a 2-factors 3-levels full factorial design. Continuous dissolution studies were carried out in simulated gastric, intestinal, and colonic fluid with pH 1.2 (0.1 N HCl), pH 7.4 and pH 6.8 (phosphate buffer), respectively. The lag time prior to the drug release was highly affected by combination of two factors, i.e. the percentage of Eudragit RL100 in polymer mixture and coating level. The formulation containing Eudragit RL100 and Eudragit S100 with a ratio of 4:1 and coating level of 12%w/w was found to be optimum. The results of serum study in New Zealand rabbits showed that the developed formulation provided a significant lag phase of 5 h. The present study demonstrates that the theophylline enteric-coated pellets could be successfully colon targeted by the design of pH- and time-dependant modified chronopharmaceutical formulation. In conclusion, pulsatile drug release over a period of 312 h is consistent with the requirements for chronopharmaceutical drug delivery. Keywords: Nocturnal asthma; colon targeted; pulsatile drug delivery; multiparticulate; factorial design
Introduction
There is a growing awareness of the importance of disease state and drug action in chronopharmaceutics and chronopharmacology. The time-controlled and pulsatile release is increasingly being considered as desirable modes of drug delivery (Bussermar et al., 2001; Youan, 2004; Chaudhari et al., 2007). At present the drug must be administered in the right amount at a proper rate and at the right time for many drugs including anti-asthmatic, anti-histaminic, psychotropic, anesthetic, cardiovascular, and NSAIDS (Lemmer, 1992). Significant daily variations in pharmacokinetics or drug effects have been demonstrated in man. Depending upon the physiological and pathophysiological changes of circadian rhythmicity, nocturnal symptoms and overnight decrements in lung functions are a common part of the asthma clinical syndrome (Lemmer, 1992). Circadian changes are seen in
normal lung function, which reaches a low point in the early morning hours. The dip is particularly pronounced in people with asthma, because bronchoconstriction and exacerbation of symptoms vary in a circadian fashion. Asthma is well controlled with oral corticosteroids, theophylline (TP), and 2 agonists (Sutherland & Nalson, 1996). For such conditions a drug delivery system administered at bed time, but releasing drug during morning hours would be ideal one (Tekade & Gattani, 2009). Pulsatile unit formulations with suitable lag time were developed in recent days for betterment of the patient (Kadam & Gattani, 2009; Rane et al., 2009). The recent interest in multiple-unit dosage forms is the result of the advantages they offer over the single-unit systems. Multiple-unit dosage forms offer more predictable gastric emptying, less dependent on the state of nutrition, less variance in transit time through the gastrointestinal tract (GIT), a higher degree of dispersion
Address for Correspondence: Dr Surendra G. Gattani, Department of Pharmaceutics and Quality Assurance, R. C. Patel Institute of Pharmaceutical Education and Research, Near Karwand Naka, Shirpur 425 405, Dist. Dhule, Maharashtra, India. Tel: (+91) 09970816927. Fax: (+91) 02563-255189. Email: sggattani@ rediffmail.com (Received 26 November 2009; revised 05 March 2010; accepted 09 March 2010) ISSN 1071-7544 print/ISSN 1521-0464 online 2010 Informa UK Ltd DOI: 10.3109/10717541003762821 http://www.informahealthcare.com/drd
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Vinayak D. Kadam and Surendra G.Gattani as lubricants and glidants used to prepare the pellets were of standard Pharmacopoeial grade. Methods Experimental design To optimize the formulation, the 32 design was implemented. The independent variables were ratio of ES to ERL (X1) and percentage coating level (X2). The dependent variables (responses) were lag time (Y1) and drug release in 7 h in 6.8 pH buffer (Y2). The independent and dependent variables and the used levels are summarized in Table 1. The resulting formulations are listed in Table 2. Preparation of drug-layered pellets Drug-loaded pellets were prepared by a spray-drying technique. TP was homogeneously dispersed in an aqueous solution of HPC-L while stirring with a magnetic stirrer. The drug dispersion was passed through a 100 mesh sieve. The drug dispersion was then sprayed on celphere seeds using the fluidized bed coater, bottom spray (Miniglatt, Glatt GmbH, Binzen, Germany) with a 0.5 mm nozzle at a feed rate of 0.53 g/min using a peristaltic pump. The spraying process with the drug dispersion was continued to achieve the target drug loading level. The drug-loaded pellets were finally dried at 45C for 15 min and were used for further coating with acrylic polymers. The composition of the drug-loaded pellets and the other processing parameters utilized for the spray-drying method are listed in Tables 3 and 4, respectively. Enteric coating of pellets Six per cent (w/w) solutions of polymethacrylates (ERL and ES) were prepared in IPA:DCM (7:3) mixture. Based on the experimental design, the detailed composition of different batches was given in Table 5. The solution was plasticized with TEC (15%, w/w, with respect to dry polymer), and then talc was added as a glidant (5%, w/w, related to dry polymer). Forty-five grams of TP pellets were coated in a fluidized bed coating apparatus (Wurster insert, Werner Glatt). Coating conditions are listed in Table 4. Samples of coated pellets were removed from the apparatus when the coating load had reached 6, 12, and 18% (w/w). At each stage the pellets were gently fluidized for 10 min.
Table 1. Independent and dependent variables and the levels used for factorial design. Levels used Factors (independent Responses (dependent variables) 1 0 1 variables) 20% 40% Y1 = lag time (h) X1 = ratio of Eudragit S 0% 100 to Eudragit RL 100 (1:0) (1:2) (1:4) 12 18 Y2 = drug release in X2 = percentage coating 6 level 7 h (%)
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in the digestive tract, less absorption variability, and a lesser risk of dose dumping than single-unit dosage forms (Kramer & Blume, 1994; Nykanen et al., 2001). Various pharmaceutical approaches that have been used for targeting drug to the colon are mainly based on pH-dependant, time-dependant, and/or bacterially degradable systems (Watts & Illum, 1997; Chourasia & Jain, 2003). Among these approaches, pH-dependant systems are simple, but the suitability of them for using alone as a colonic delivery in different physiological and pathological conditions in GIT has been doubtful (Ashford et al., 1993, Ibekwe et al., 2008, Schellekens et al., 2008). Therefore, the pH-dependant system was evaluated in combination with time-dependant system in order to alleviate the pH dependency of former system and to ensure drug release under different physiological conditions. The use of pH-dependant and time-dependant polymers as coating materials for colonic drug delivery has been reported previously. In those studies sustained release and pH-dependant polymers have been applied as separate coating layers on top of each other (Gupta et al., 1993; Fukui et al., 2000; Qi et al., 2003). The combination of time- and pH-dependant polymer as a single coating has been used to provide the pulsatile drug release in the unit formulation (Kadam & Gattani, 2009). There is no report on the use of mixtures of these two kinds of polymers as a single or in combination coating system for the development of a multiparticulate drug delivery system. The objective of the present study was to optimize the formulation consisting of Eudragit RL100 (ERL), a time-dependant polymer, and Eudragit S100 (ES), a pHdependant polymer for the coating of TP pellets to achieve the colon-targeted drug delivery system (CTDDS). It has been nicely shown that in nocturnal asthma, evening dosing of TP or -agonists can be of advantage in treating the asthma attacks (Bose et al., 1987). TP was used as a model drug due to its suitable pharmacokinetic properties for colonic delivery and good absorption in the large intestine (Staib et al., 1986; Paola et al., 2003).
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in 900 ml medium at 37C in media with pH 1.2 (HCl 0.1 N), pH 7.4 and pH 6.8 (phosphate buffer) for 2 h, 3 h, and the remaining 7 h, respectively. The 5 ml aliquots of the dissolution fluid were removed at specified time intervals and assayed for the amount of TP by spectrophotometer (Shimadzu, UV 1700, Japan) at wavelength 271 nm for all three media (Zahirul, 1999; Gang et al., 2004; Akhgari et al., 2005; 2006; Mastiholimath et al., 2007; Siepmann et al., 2008; Kadam & Gattani, 2009; Tekade & Gattani, 2009). Scanning electron microscopy (SEM) SEM (JEOL JSM-6360A scanning electron microscope, Japan) has been used to examine the surface morphology and texture of drug layered and polymer-coated pellets. Pellets were sputter-coated with platinum to a thickness of 30 nm for 67 min in a coating machine (Gupta et al., 2001; Rao & Patil, 2007). Differential scanning calorimetry (DSC) The possibility of any interaction between TP, polymers, and other excipients was assessed by DSC (Mettler Toledo Stare DSC 822c, Germany). The thermogram of the samples were obtained at a scanning rate of 10C/min conducted over a range of 0350C under an inert atmosphere flushed with nitrogen at a rate of 20 ml/min. Statistical analysis of data The effects of independent variables upon the responses were modelled using a second order polynomial equation. The mathematical model of the effects of independent variables upon the dependent variables was performed using Stat-Ease Design Expert (Version 7.1.6) with a manual linear regression technique. A significant term (p < 0.05) was chosen for final equations. Finally, response surface plots resulting from equations were drawn. Y = b0 + b1 X 1 + b2 X 2 + b12 X 1 X 2 + b11 X 12 + b22 X 2 2 (1)
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Table 3. Composition of drug-loaded celphere pellets. mg/capsule Composition Cores Celphere CP 203 45 Solids in layering dispersion Theophylline 200 HPC L 60 Water qs. Total 305 q.s.- 6 % W/W aqueous solution was prepared Table 4. The process parameter of the drug layering processes and polymer coating on Glatt. Process parameter Drug layering Polymer coating Inlet temperature (C) 5055 4550 Product temperature (C) 4547 3536 Fluidization air (bar) 0.400.60 0.400.60 Suspension spray rate (g/min) 0.53 0.53 Atomization pressure (bar) 0.400.60 0.400.60 Nozzle diameter (mm) 0.5 0.5 Drying in the equipment after layer15 10 ing (min) Yield calculated after processing (%) 90 8085
Dissolution studies Dissolution study of drug loaded pellets. To verify how the dissolution media interferes with drug release profile from the cores or drug loaded pellets, in vitro release behavior of cores was studied. Accurately weighed drug layered pellets equivalent to 200 mg of TP were transferred to the dissolution medium. The test was carried out in a USP dissolution type I assembly (Electrolab, TDT-08L, India) at a rotation speed of 100 rpm in 900 ml medium at 37C for 1 h in media with pH 1.2 (0.1 N HCl), pH 7.4 and pH 6.8 (phosphate buffer). The 5 ml aliquots of the dissolution fluid were removed at specified time intervals and assayed for the amount of TP by spectrophotometer (Shimadzu, UV 1700, Japan) at wavelength 271 nm (Akhgari et al., 2005). Dissolution studies of enteric coated pellets. Accurately weighed enteric-coated pellets equivalent to 200 mg of TP were transferred to the dissolution medium. The test was carried out in a USP dissolution type I assembly (Electrolab, TDT-08L, India) at a rotation speed of 100 rpm
where Y is the dependent variable, b0 is the arithmetic mean response of the nine runs, and bi (b1, b2, b12, b11, and b22) is the estimated coefficient for the corresponding factor Xi (X1, X2, X1X2, X12, and X22), which represents the average result of changing one factor at a time from its low to high value. The interaction term (X1X2) shows how the response changes when two factors are simultaneously changed. The polynomial terms (X12 and X22) are included to investigate non-linearity. All nine batches of design have shown wide variation in lag time and percentage drug release in 7 h (312 h and 899%, respectively). The fitted equations relating the response Y1 and Y2 to the transformed factor are shown in equations (2) and (4), respectively. A backward elimination procedure was adopted to fit the data into different predictor equations.
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Table 5. Composition of experimental formulations. ES:ERL(1:4) 6% 12% A B Drug layered pellets (mg) 305 305 ERL (mg) 14.64 29.28 ES (mg) 3.66 7.32 TEC (mg) 2.74 5.49 IPA (mg) 200.69 401.38 DCM (mg) 86.01 172.01 Total wt. of enteric-coated 323.3 341.6 pellets (mg) Lubrication talc (2.5%) 8.08 8.54 (mg) Total wt. of lubricated 331.38 350.14 pellets (mg)
18% C 305 43.92 10.98 8.23 602.07 258.03 359.9 8.99 368.89
ES:ERL(1:2) 12% E 305 24.4 12.2 5.49 401.38 172.01 341.6 8.54 350.14
18% F 305 36.6 18.3 8.23 602.07 258.03 359.9 8.99 368.89
ES:ERL(1:0) 12% H 305 36.6 5.49 401.38 172.01 341.6 8.54 350.14
The quadratic model generated by regression analysis were used to construct the three dimensional graphs in which the response parameter Y was represented by a curvature surface as a function of X. Numerical optimization using desirability approach was employed to locate the optimal setting of the formulation variables to obtain the desired response. In-vivo study Six male New Zealand white strain rabbits, weighing 2.12.6 kg, were used for study. Animals were housed in a 12-h light-dark, constant temperature environment prior to study. All rabbits were fasted for 24-h before the experiment. For treatment with TP, rabbits were given a vehicle (glycofurol, 2 ml/kg) right before TP administration. TP was given as an aqueous suspension (8 mg/ml) at a dose of 25 mg/kg. Blood samples (1 ml) were withdrawn via right ear vein at 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 h after administration of TP. The blood was centrifuged for 15 min at 9860 x g and the serum samples obtained were stored at 20C until analysis. Assay method The TP concentration in serum was determined according to the previously reported HPLC method (Hui et al., 2001). Sample was prepared by adding 400 l of acetonitrile solution containing 5.0 g/ml of internal standard to 100 l of serum. Caffeine was used as the internal standard. After being vortexed for 30 s and then centrifuged at 9860 x g for 15 min, the clear supernatant was transferred to another micro-tube and evaporated to dryness by blowing nitrogen. The residue was reconstituted with 100 l of mobile phase, and 20 l of this solution was subjected to HPLC analysis. The mobile phase used was methanol and water (20:80, v/v) with a flow rate of 1.0 ml/min. An UV detector was set at 270 nm. The HPLC apparatus included one pump and a detector. The assay employed an ODS-2 column (4.6 250 mm, 5 m).
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Figure 1. The basic structure of the film-coated pellets. 100 80 Drug Delivery Downloaded from informahealthcare.com by St Johns University on 07/05/11 For personal use only. % Drug Release 60 40 20 0 20 0.1N HCI 0 10 20 30 Time (min) pH7.4 PB 04 50 60
pH6.8 PB
Figure 2. Dissolution profile of drug layered pellets at pH 1.2, 7.4, and 6.8.
The equations of the responses are given below: Final equation in terms of coded factors:
Y1 ( lag time in pH 6.8 ) = + 7.67 2.5 x1 + 1.8 * X 2 + 2 1.00 * * X 2 + 0.83 * X 1 (2)
(3)
(5)
Analysis of variance (ANOVA) (Table 6) indicated the assumed regression models were significant and valid for each considered responses. The three-dimensional response surfaces were plotted to estimate the effect of independent variables on each response (Figures 3 and 4). Figure 3 shows the effect of two formulation factors on lag time and indicates that increase in ratio of ES rises lag time significantly. ERL is a copolymer of ethyl acrylate, methyl methacrylate, and a low content of a methacrylic acid ester with quaternary ammonium groups (trimethylammonioethyl methacrylate chloride). The ammonium groups are present as salts and make the polymers permeable. ES is a copolymer of methacrylic acid and methyl methacrylate, and the ratio of carboxyl to ester group is 1:2. Lower ratio of carboxyl group in ES causes less ionization in neutral to alkaline media than ERL, and hence shows slower solubilization (Chourasia & Jain, 2003). Also ERL has good swelling properties than ES and Eudragit ERS (Kadam, 2009). The effect of coating thickness on lag time is lesser at low levels of ES and rises at a higher ratio (Figure 3). However, by using proper combinations of ES, ERL, and coating level, the release of drug from formulation after an optimum lag time will be ensured. This is an advantage for using the combination of polymers against using a single polymer (ES) which sometimes does not release drug at all (Watts & Illum, 1997). A numerical optimization technique using the desirability approach was employed to develop a new formulation with the desired responses. Constraints were applied to the factors (X1 and X2) and (Y1 and Y2) for optimizing the desired formulation. The optimized formulation was evaluated for lag time and percentage drug release after 7 h. The values of predicted and observed responses are shown in Table 7. The drug release profiles of different enteric coated formulations were given in Figure 5. According to the design the best area for formulation to obtain desired responses was found. The best conditions to optimize drug release corresponded to a ratio of ES:ERL (1:4) and a coating level of 12%. By substituting X1 and X2 by the amounts of optimized formulation in equations (3) and (5), predicted responses were obtained. In order to check the validity of the optimization procedure, a new batch of pellets with the predicted levels was prepared. The result shows that the observed responses were inside the constraints and close to predicted responses, and, therefore, factorial design is valid for predicting the optimum formulation (Table 7). The pellets were prepared according to optimum formulation and released no drug at pH 1.2 (0.1 N HCl), pH 7.4, and showed burst release at pH 6.8. Scanning electron microscopy (SEM) Figure 6 shows SEM of optimum formulation (a) drug layered (85), (b) drug layered (3000), (c) polymer coated
The equation represents the quantitative effect of independent variables (X1 and X2) upon the responses (Y1 and Y2).
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Table 6. Analysis of variance (ANOVA) of dependent variables. Source of variation Sum of squares Degree of freedom Analysis of variance for Y1 (lag time in h) Model 63.055 4 A-A 37.5 1 B-B 20.166 1 AB 4 1 A^2 1.3888 1 Residual 0.5 4 Total 63.555 8 Analysis of variance for Y2 (% drug release in 6.8) Model 9,754.667 3 A-A 4,760.167 1 B-B 3,313.5 1 AB 1,681 1 Residual 1,254.222 5 Total 11,008.89 8
Mean square 15.763 37.5 20.166 4 1.3888 0.125 3251.556 4760.167 3313.500 1681 250.844
p-value 0.0002 0.0001 0.0002 0.0048 0.0290 0.0086 0.0073 0.0150 0.0489
Prob > F significant significant significant significant significant significant significant significant significant
11.9 lag time (h) 9.7 7.5 5.3 3.1 0.00 1:0 Polymer ratio 1:2 1:3 9:00 1:4 6:00 12:00 18:00 15:00
Table 7. Observed and predicted values for the optimum formulation. Response Constrains Predicted Observed Residual parameters set values values Ratio of polymers In range 40 (4:1) 40 (4:1) 0 % coating level In range 12 12.07 0.13 0.07 Lag time in pH 6.8 6 h 5.99 6 0.01 Drug release in Maximize 63.05 87 1.52 23.95 at 7 h
100.00 80.00 % Drug release 60.00 40.00 20.00 0.00 0 2 4 6 Time (h) 8 10 12
A B C D E F G H I
Differential scanning calorimetry (DSC) The DSC thermogram shows a sharp endothermic peak at 269.95C for TP (Figure 7a). While in final optimum formulation, the endothermic peak was observed at 266.95C (Figure 7b). Evaluation of the thermogram revealed no interaction between the polymer and drug in the formulation. In-vivo evaluation of optimum formulation The in vivo serum study was performed to see if the colon-targeted release functions of the CTDDS could
1:3
1:2
1:1
1:0 18:00
15:00
12:00
(85), and (d) polymer coated (3000s). The drug layered pellet surface (Figure 6a and b) became smoother after polymeric coating (Figures 6c and d).
Pulsatile drug delivery for nocturnal asthma work in the GIT as expected and shows a lag phase of 6 h. To minimize the variation of gastric pH, male New Zealand white rabbits were used for this study. The average pH in rabbits stomach has been reported to be 1.9 (Smith, 1965; Illet et al., 1990), 68 in small intestine, and 7.2 in colon (Karali, 1995). Serum concentration vs time profiles of TP after the administration was shown in Figure 8. Pharmacokinetic parameters necessary for discussion, calculated from the serum drug concentration vs time profiles using kinetica 5 software, are listed in Table 8.
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When the TP enteric-coated pellets were administered, a lag time of 5 h was obtained before serum concentration could be detected. The peak serum concentration was achieved within 6 h of administration, showing thereby that TP was immediately absorbed from the rabbit GIT. The time of onset of drug release can therefore be considered close to the time of appearance of drug in the serum. From the in-vivo study it is concluded that the colon-targeted polymer-coated pellets did not release any significant amount of drug in 5 h and shows burst release in 6 h.
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Conclusion
The present study concludes that the TP enteric-coated pellets could be successfully colon targeted by the design of pH and time-dependant modified chronopharmaceutical formulation. The formulation can be easily optimized by using the factorial design. Pulsatile drug release over a period of 312 h, consistent with the requirements for chronopharmaceutical drug delivery, was achieved from enteric-coated pellets. Thus, the designed device can be considered as one of the promising formulation technique for preparing a colon-specific pulsatile drug delivery system and hence in chronopharmaceutical management of asthma by opening a new chapter of life to an existing drug molecule.
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METTLER TOLEDO STAR SYSTEM Figure 7. DSC thermogram of TP (a) and optimum formulation (b).
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12 11 10 9 8 7 6 5 4 3 2 1 0
Concentration (mcg/ml)
4 5 Time (h)
Figure 8. The serum concentration vs time profiles of TP after the administration. Drug Delivery Downloaded from informahealthcare.com by St Johns University on 07/05/11 For personal use only.
Table 8. Pharmacokinetic parameters obtained after oral administration of TP ER-coated optimum formulation in rabbits at a dose of 25 mg/kg. PK parameter Theophylline enteric-coated formulations 10.203 1.1 Cmax (ng/ml) 6.00 Tmax (h) Tlag (h) 5.00d
d Graphically determined by extrapolating the initial linear portion of plasma drug concentration vs time data to the x-axis.
Declaration of interest
Mr Vinayak D. Kadam immensely thanks the Council of Scientific and Industrial Research, New Delhi for providing Senior Research Fellowship [08540(0001)/2009EMR-I] during his PhD work. The authors are thankful to Mr Sachin S. Kushare for his support in the experimental design. The authors are thankful to Aarti Chemicals and Rohm Pharma for providing the free samples of theophylline and Eudragits, respectively.
References
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Watts, P.J., Illum, L. (1997). Colonic drug delivery. Drug Dev Ind Pharm. 23:893913. Youan, B.C. (2004). Chronopharmaceutics, gimmick or clinically relevant approach to drug delivery. J Contr Rel. 98:33753. Zahirul, K., Zeljko, M.I.P., Nevenka, K. (1999). A pH-dependent colon targeted oral drug delivery system using methacrylic acid copolymers. I. Manipulation of drug release using Eudragit L100-55 and Eudragit; S100 combinations. J Contr Rel. 58:21522.
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