J Pharm Innov (2014) 9:95–105 DOI 10.1007/s12247-014-9176-3
RESEARCH ARTICLE
Optimization of Chronomodulated Delivery System Coated with a Blend of Ethyl Cellulose and Eudragit L100 by Central Composite Design: In Vitro and In Vivo Evaluation Om Prakash Ranjan & Usha Y. Nayak & M. Sreenivasa Reddy & Swapnil J. Dengale & Prashant B. Musmade & Nayanabhirama Udupa
Published online: 27 March 2014 # Springer Science+Business Media New York 2014
Abstract Introduction In this study, we present the development of a chronomodulated delivery system consisting of a fast-swelling tablet core containing montelukast sodium coated with a blend of different ratios of ethyl cellulose (gastrointestinal tract (GIT)-insoluble polymer) and Eudragit L100 (enteric polymer). Montelukast sodium is a leukotriene receptor antagonist commonly prescribed for patients of asthma and allergic rhinitis. Asthma and allergic rhinitis share a common core pathophysiology and have almost similar temporal pattern in their occurrence or exacerbation of their respective symptoms, suggesting a role for chronotherapy. Methods The developed formulation was optimized statistically using central composite design to achieve desired release profile. The coated tablets were studied for water uptake, bursting time, and in vitro release study. Results The bursting time (lag time) of coated tablet was affected by the pH of buffer, molarity of ions, and concentration of different types of surfactant in dissolution media. With increasing percentage of Eudragit L100 in coating composition, the lag time decreased and release rates significantly increased—could be attributed due to O. P. Ranjan : U. Y. Nayak : M. S. Reddy (*) Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576104, Karnataka, India e-mail:
[email protected] S. J. Dengale : P. B. Musmade Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576104, Karnataka, India N. Udupa Department of Pharmaceutical Management, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576104, Karnataka, India
increase in water uptake and polymer leaching. As expected, with increasing coating level, lag time increased and release rate decreased due to the increased diffusion pathways. In vivo study revealed comparative pharmacokinetic profiles of core tablets and pulsatile release tablets (PRTs); however, Tmax of 2 h for core tablets and 6 h for PRTs were observed. Conclusion Thus, designed PRTs were found to be suitable in treating episodic attack of asthma in early morning and associated allergic rhinitis. Keywords Chronotherapy . Pulsatile release . Lag time . Enteric polymer . Central composite design
Introduction The temporal control of drug delivery has been of attention to achieve improved drug therapies [1] for many diseased conditions, such as asthma, hypertension, rheumatoid arthritis, etc. [13]. Chronotherapeutics is the discipline concerned with administration of medicines according to inherent activities of a disease over a certain period of time [3]. Bronchial asthma and allergic rhinitis share a common core pathophysiology and exhibit similar temporal pattern in the occurrence or exacerbation of their respective symptoms suggesting a role for chronotherapy [8]. In patients with asthma, symptoms generally worsen during the early hours of the morning, and pulmonary function often deteriorates at the same time [7, 8]; also, the symptoms of allergic rhinitis such as sneezing, nasal rhinorrhea, red itchy eyes, nasal pruritus, and nasal congestion were found to occur most recurrently before breakfast in the morning and least frequently in the middle of the day [8].
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Montelukast sodium (MKS) is leukotriene receptor antagonists most commonly used in the treatment of asthma and allergic rhinitis [4]. Presently, montelukast sodium is available in market as conventional immediate release film-coated tablets. It is indicated for the treatment of asthma, exerciseinduced bronchoconstriction, and for the relief of allergic rhinitis. As the marketed formulation releases the drug immediately within an hour of intake, so there is a need for chronomodulated drug delivery system of montelukast sodium, which will lag the drug release till midnight and then releases the drug, which will take care of asthma as well as allergic rhinitis. Polymeric film coatings are frequently used to control and modify drug release profile from solid pharmaceutical dosage forms. Fan et al. [1] used polymeric blend of gastrointestinal tract (GIT)-insoluble polymer (ethyl cellulose, EC) and enteric polymer (Eudragit L) to coat diltiazem HCl tablets to achieve pulsatile drug delivery and rapid drug release after a pre-determined lag time in the intestine [5]. Soni et al. [9] attempted to achieve the chronotherapy for bronchial asthma by utilizing dual approach for the effective colonic delivery of theophylline using pH-dependent solubility behavior of Eudragit and susceptibility of guar gum to colonic environment. Yassin et al. [12] designed a chronotherapeutic delivery system of theophylline with high potential benefits in treating nocturnal asthma. In this paper, we present the development of a chronomodulated delivery system consisting of a fastswelling tablet core containing montelukast sodium coated with a blend of different ratios of EC (GIT-insoluble polymer) and Eudragit L100 (enteric polymer). Eudragit L as a polymer, only dissolved at pH above 6, was selected to be the coating material along with ethyl cellulose to fit the mentioned purpose [1]. The lag time before drug release is mainly controlled by the properties of the outer polymeric coating, and the water uptake and the swelling behavior of the swelling core [13]. The major objectives of the present study were: (i) to study the effect of polymer blend ratio and coating level of a GIT-insoluble and an enteric/polymer on lag time of drug release and (ii) to optimize the polymer blend ratio in coating to get a desired lag time with wide range of drug release profile. A comprehensible approach for fruitful appraisal and optimization of the formulation parameters is necessary. Central composite design (CCD), one of the techniques in response surface methodology (RSM), is used for optimization of formulation development. RSM, supported by statistical software, is a well-established approach for pharmaceutical formulation development and optimization allowing extraction of maximal information out of few well-designed experiments. CCD is suitable for pharmaceutical blending problems allowing investigation
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with the least number of experiments and selection of the optimal composition for achieving the presetting target [2].
Material and Methods Materials MKS was obtained from the Lupin Limited, (Pune, India). Cross-carmellose sodium (Ac-di-sol) was supplied by FMC BioPolymer. Low-substituted hydroxypropyl cellulose (LHPC; LH 11) and microcrystalline cellulose (Avicel 112) were obtained from the Signet. EC (Ethocel standard 10 premium) supplied by Dow Chemical Company, USA and Eudragit L100 (Eud L100) by Evonic Degussa were used for film coating. Dibutyl pthalate (DBP) was obtained from Sigma Aldrich, magnesium stearate from Himedia Laboratories Pvt. Ltd., Mumbai, and talc from Lobachemie Pvt. Ltd., Mumbai, India. All other chemicals were of analytical grade. Preformulation studies Fourier Transform Infrared Spectroscopy Fourier transform infrared spectroscopy (FTIR) was carried out using a Shimadzu FT-IR 8300 Spectrophotometer (Shimadzu, Tokyo, Japan) in the wavelength region of 4,000 to 400 cm−1. The process consisted of dispersing a sample (drug alone or mixture of drug and excipients) in KBr and compressing into discs by applying pressure in a hydraulic press. The pellet was placed in the light path, and the spectrum was obtained [6]. Differential Scanning Calorimetry Differential scanning calorimetry (DSC) was performed using a DSC-60 (Shimadzu, Tokyo, Japan) calorimeter. The instrument comprised of a calorimeter (DSC 60), flow controller (FCL 60), thermal analyzer (TA 60), and operating software (TA 60). The samples (drug alone or drug–polymer mixture) were heated in sealed aluminum pans under nitrogen flow (30 mL/min) at a scanning rate of 5 °C min up to 250 °C. Indium was used as a reference [6]. Solubility Studies Solubility studies of MKS were performed in different media (with or without Tween 80) such as water, 0.1 N HCl, acetate buffer pH 4.5, and phosphate buffer pH 6.8 and pH 7.4. An excess amount of drug was added in different vials with different media and shaken in water bath shaker for 24 h at 37 °C (Remi Equipments Ltd., Bangalore, India). The media
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were filtered using a 0.45-μm filter paper and were estimated by validated high-performance liquid chromatography (HPLC) method.
Carr0 s indexð%Þ ¼
h
i ρtapped −ρbulk =ρtapped 100
Hausnerratio ¼ ρtapped =ρbulk
Analytical Method for Estimation of Montelukast Sodium Analysis of montelukast sodium was done by HPLC (LC2010CHT, Shimadzu, Kyoto, Japan), equipped with lowpressure quaternary gradient pump along with dual wavelength UV detector, column oven, and autosampler. Chromatographic data were recorded and processed using LC solution 1.24SP1 software. Phenomenex®Luna C18 (250.0× 4.6 mm, 5 μm) column was used for the estimation of montelukast sodium. The mobile phase consisted of acetonitrile and 20 mM ammonium acetate buffer (pH 5±0.02) with a volumetric ratio of 80:20 at a flow rate of 1.0 mL/min. The detector was set at 345 nm, and injection volume was 25 μL. The calibration curve was generated for concentrations ranging from 0.5 to 25.0 μg/mL.
Preparation of Pulsatile Release Tablets Micromeritic Properties The composition of the core tablets is given in Table 1. The blends for core tablets were prepared by mixing drug, crosscarmellose sodium, L-HPC with Avicel pH 112, and lactose anhydrous (with or without) for 10 min. Purified talc, magnesium stearate, and silicon dioxide were added to each blend and further mixed for 5 min. The final blend ready for compression was characterized for angle of repose, Carr’s index, and Hausner ratio. The angle of repose of formulation blend was determined by the fixed funnel method [6]. The bulk density (BD) and tapped densities (TD) were determined by using a density apparatus (Serwell Instruments, Bangalore, India). The Carr's index (%) and the Hausner ratio were calculated as follows [6]:
Table 1 Composition of core tablets Ingredients
Quantity/tablet (mg)
Batch No. Montelukast sodium Microcrystalline cellulose Lactose anhydrous Cross-carmellose sodium L-Hydroxypropyl cellulose Purified talc Magnesium stearate
C-1 10.40 50.00 34.00 3.00 – 1.60 1.00
C-2 10.40 84.00 – 3.00 – 1.60 1.00
C-3 10.40 82.00 – 5.00 – 1.60 1.00
C-4 10.40 72.00 – 5.00 10.00 1.60 1.00
Preparation of Core Tablets Direct compression method was employed for preparation of fast disintegrating core tablet. The blends for compression were prepared by mixing drug, cross-carmellose sodium, and L-HPC with Avicel pH 112 for 10 min. Purified talc, and magnesium stearate, were added to above blend and further mixed for 5 min. The final blend was compressed to 100 mg weight tablet using 6.4 mm concave punch on rotary tablet press (10 station tablet compression machine, Cadmach, Ahmedabad, India). The hardness of the tablets (n=6) was determined by using the Monsanto hardness tester Electrolab, Mumbai, India. The thickness and diameter of the tablets (n= 3) were measured using Vernier caliper. The friability (%) of the tablets was determined using Friabilator (USP EF-2), Electrolab, Mumbai, India. The disintegration test of core tablets was carried out by the disintegration tester USP (ED2AL), Electrolab, Mumbai, India. The drug content was determined after crushing core tablet (n=3); 100 mg of powder was dissolved in 100 mL of methanol. The solution was filtered through a 0.45-μm filter and analyzed by validated HPLC method after sufficient dilution. Coating of Core Tablets The Pharma R&D coater (model: Delux, Ideal Cures Pvt. Ltd., Mumbai, India) was used to coat core tablets. The 4 % (w/v) solution of EC/Eudragit L100 in different ratios (60:40, 70:30, 80:20, and 90:10) was prepared in solvent mixture of isopropyl alcohol, acetone, and water. To avoid sticking, talc (20 % (w/w) based on total polymer mass) was added to the coating solutions and DBP (20 % (w/w) based on total polymer mass) as plasticizer. The process parameters for the coatings were as follows: product temperature 35+2 °C, pan speed 40 rpm, pump speed 1–2 rpm, and atomization pressure 1.0 bar. Subsequent to the coating, the tablets were further cured for 30 min in coating pan at 40 °C to remove residual solvent. Optimization Using Experimental Design For systematic optimization of developed formulations, the experimental design methodology was employed by CCD with the help of Design Expert software 8.0.5 (Stat-Ease Inc., Minneapolis, MN, USA). A CCD with α = 1 was employed in the development of montelukast pulsatile release
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Table 2 Formulation trials as per experimental design and coded values Batch No.
X1: % of Eud L100 X2: % coat weight
F1 F2 F3 F4
0 0 −1 1
1 −1 1 0
F5 F6 F7 F8 F9 F 10 F 11 F 12 F 13 Factors
−1 0 0 −1 0 1 1 0 0 Coded values −1
−1 0 0 0 0 −1 1 0 0 0
1
X1: Eudragit L100 (%, w/w) X2: coat weight (%, w/w) Responses Y1 =lag time (h) Y2 =release at 6 h (%)
20 8 Constraints 4.5 Maximize
30 10
40 12
of pH, types, and concentration of surfactant and ionic concentration of media on bursting time was studied. The media of different pH 1.2, 4.5, 6.8, and 7.4 were prepared as per USP. The bursting time of coated tablet in different pH media was determined by visual observation. Different media were prepared in molar concentrations (20, 50, and 100 mM) containing the electrolyte stated, and pH of the media was adjusted to 6.8 either with 1 M HCl or 1 M NaOH. The bursting time of coated tablet in different media was determined by visual observation. The media of pH 6.8 were prepared as per USP. The effect of different surfactants (SLS and Tween 80) in different concentrations (0.1, 0.2, 0.5, and 1.0 % (w/v)) on bursting time was observed by visual observation. The bursting time of optimized formulation in dissolution media was determined [medium 0.1 N HCl (with 0.5 % (w/v) Tween 80) for 2 h and phosphate buffer pH 6.8 (with 0.5 % (w/v) Tween 80)] in USP type II (paddle) apparatus at 37 °C, rotation speed 75 rpm. In Vitro Dissolution Studies
Characterization of Pulsatile Release Tablets
The in vitro dissolution study was carried out using paddle type (USP type II) dissolution apparatus (TDT-06P, Electrolab, Mumbai, India. The in vitro dissolution study of core tablets was performed in 900 mL of phosphate buffer pH 6.8 with 0.5 % (w/v) Tween 80, whereas for coated tablet in 500 mL 0.1 N HCl (with 0.5 % (w/v) Tween 80) for the first 2 h, followed by 900 mL of phosphate buffer pH 6.8 (with 0.5 % (w/v) Tween 80). The temperature of dissolution medium was maintained at 37±0.5 °C and paddle speed of 75 rpm. At different time intervals, 5 mL of sample was withdrawn and analyzed by UV–visible spectrophotometer. At each time of withdrawal, 5 mL of fresh corresponding medium was replaced into the dissolution vessel. The MKS has shown maximum absorbance at wavelength of 385 and 345 nm in 0.1 N HCl and phosphate buffer pH 6.8, respectively, so corresponding wavelength was used for sample analysis.
Water Uptake Study
Scanning Electron Microscopy
Water uptake by the pulsatile release tablets was examined at the condition of drug release test. The media were 0.1 N HCl (with 0.5 % (w/v) Tween 80) for 2 h and phosphate buffer pH 6.8 (with 0.5 % (w/v) Tween 80) for further till just before the rupture time. The weight of pulsatile release tablets was measured with elapse of time at predetermined time interval (n=3).
Photographs of the outer surface of the coating film of pulsatile release tablets were taken using a scanning electron microscope (Zeiss, EVO 18, Carl Zeiss SMT Ltd, UK) at initial and after predetermined time points (2, 3, and 4 h) in dissolution media [1].
tablet formulations. Eudragit L100 (X1) and total coat weight (X2) were selected as factors (independent variables), while release lag time (Y1) and percentage drug release at 6 h (Y2) were selected as obtained responses (dependent variables). Each factor was studied at three different levels (−1, 0, and +1). Table 2 summarizes an account of the 13 formulation batches studied, their factor combinations, and the translation of the coded levels to the experimental units employed during the study.
Pharmacokinetic Studies In Vitro Bursting Time Study The bursting time is time point, when the outer coating ruptured and was noted (n=3) by visual observation of the pulsatile release tablets in a USP type II (paddle) apparatus at 37 °C, rotation speed 75 rpm in different media. The effect
The pharmacokinetic study was carried out in male rabbits to compare the pharmacokinetic parameters of optimized PRTs of montelukast sodium with immediate release core tablet. Study protocol was approved by the Institutional Animal Ethical Committee (IAEC/KMC/75/2011-2012). The
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overnight fasted rabbits of weight 2.5 kg were divided into two groups (n=3) and treated orally (10 mg MKS per tablets) as follows: Group I Core tablets Group II PRTs (F 14) After a single oral administration of core tablet and PRTs, 0.6 mL of blood samples was collected from the marginal ear vein at different time-points into tubes containing EDTA. The plasma was separated immediately using spinwin centrifugation at 10,000 rpm for 10 min and stored at −70 °C until analysis. Bioanalysis of MKS in Rabbit Plasma The RP-HPLC method was used for bioanalysis of MKS in rabbit plasma. The HPLC system used was HPLC LC2010CHT (Shimadzu, Kyoto, Japan) equipped with lowpressure quaternary gradient pump along with dual wavelength UV detector. The mobile phase consisting of a mixture of acetonitrile and ammonium acetate buffer (20 mM, pH adjusted to 5.5±0.02) in the ratio 80:20 (v/v) was delivered isocratically at a flow rate of 1.0 mL min−1. The detection wavelength was 345 nm. Extraction was accomplished by liquid–liquid extraction method adding 1.5 mL MTBE following gentle vortex for 15 min on spinwin. The mixture was then centrifuged for 10 min at 10,000 rpm at 4 °C. The organic supernatant was transferred to a clean glass vial and evaporated using nitrogen gas, TurboVap® LV (15 psi) at 50 °C for 5 min. The residue was then reconstituted with 150 μL mobile phase mixture, and 50 μL was injected to HPLC. Lercanidipine HCL was used as internal standard. Calibration curve was plotted in the concentration range of 20–5,000 ng/mL. The developed method was validated as per USFDA guidelines.
Result and Discussion Preformulation Studies Fourier Transform Infrared Spectroscopy The FTIR spectra of pure MKS, MKS–polymer mixture, and PRTs are shown in Fig. 1. Pure MKS has shown a broad peak of tertiary hydroxyl group at around 3,443 cm−1 and a strong peak of carboxylic acid group near 1,568 and 1,600 cm−1. Numbers of aromatic C–H peaks are also observed between 2,900 to 3,000 cm−1. These are the characteristic absorption peak of MKS. These bands are of indicative value to elucidate drug–polymer interactions which are appeared unchanged in MKS–polymer mixture and PRTs confirming no interaction.
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Differential Scanning Calorimetry The thermal curve of MKS showed absence of sharp endothermic peak up to 250 °C (Fig. 2) which confirms that MKS is amorphous in nature. MKS has shown glass transition (Tg) at 62.1 °C. There was no significant change in glass transition Tg (MKS 62.1 °C and drug–polymer mixture 60.2 °C) or absence of sharp endothermic peak of MKS in drug polymer mixture, confirming no interaction. Solubility Study The solubility study result is shown in Table 3. The solubility of MKS is observed to be pH dependent. It has shown higher solubility at higher pH, and significant improvement in solubility was observed along with surfactant, Tween 80 in different pH media. Preparation of Pulsatile Release Tablets Micromeritic Properties Angle of repose, Carr’s index, and Hausner ratio have been used most popularly in predicting flow characteristics of powder. For direct compression of materials, it is required to possess good flow and compacting properties. Values for angle of repose 31–35° (USP) generally indicate good flow property. Hausner ratio of less than 1.25 and Carr's index of less than 20 indicate fair to good flow (USP). The prepared formulation mixtures showed good flow properties. Evaluation of Core Tablets Different tablet formulations of MKS were prepared by direct compression. Tablets were studied for hardness, disintegration, friability, and weight variation. To improve disintegration, super disintegrant was added in the formulation. Ac-di-sol is a water insoluble fibrous nature cross-carmellose sodium type super-disintegrant exhibiting good water uptake, high capillary activity, and rapid hydration properties. The fibrous nature of Ac-di-sol provides many sites for fluid uptake and gives it excellent wicking capabilities. Core tablet (C-4) was considered as optimized formulation based on rapid disintegration and was selected for further studies and coating process. The hardness of optimized formulation (C-4) was found to be 30– 35 N, and disintegration time was less than 1 min. The friability was less than 0.5 % which is within the acceptance limit. Statistical Analysis of Experimental Data The results of the experimental design indicated that this system was highly influenced by the % Eudragit L100 in
100 Fig 1 FTIR of pure MKS and PRTs
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101 Table 4 Presentation of values and responses in CCD (13 possible combinations) Batch No.
X1: % of Eud L100
X2: coat weight in %
Y1: lag time (h)
Y2: release at 6 h (%)
F1 F2 F3 F4 F5 F6 F7 F8 F9
30 30 20 40 20 30 30 20 30
12 8 12 10 8 10 10 10 10
5.2 3.4 6.3 2.8 4.2 4.3 4.2 5.3 4.4
78.45 96.54 0.92 98.35 89.39 91.41 88.73 79.92 84.29
F 10 F 11 F 12 F 13
40 40 30 30
8 12 10 10
2.3 3.4 4.3 4.3
97.65 97.65 89.15 92.35
The regression coefficients for each term in the regression model are summarized as follows:
Fig 2 DSC thermogram of pure MKS and PRTs
coating composition and total weight gain in % which resulted in desired lag time and release profile. Responses obtained from all 13 formulations (Table 4) were fed into DesignExpert® trial version 8 software for design of experiments using CCD. A polynomial equation with six coefficients was produced for the account of the measured responses as a function of the process variables and expressed in as follows: Y i ¼ A0 þ A1 X 1 þ A2 X 2 þ A3 X 1 X 2 þ A4 X 21 þ A5 X 22 where Y is the measured response, A0 is an intercept, and A1– A5 are the regression coefficients; X1, X2 represents the main effect; X12, X22 the quadratic effect and X1X2 interaction effect.
Y 1 ¼ 4:30−1:22X 1 þ 0:83X 2 −0:25X 1 X 2 −0:25X 21 Y 2 ¼ þ91:40 þ 20:57X 1 −17:76X 2 þ 22:12X 1 X 2 −7:80X 21 −9:44X 22
A positive value in the regression equation indicates direct relationship, while a negative value an inverse relationship between the factor and the response [11, 2]. For estimation of the significance of the model, the analysis of variance was determined as per the provision of Design Expert software. A model is considered significant if the p value (significance probability value) is less than 0.05 [10, 2]. Based on the largest r2 value for all responses, quadratic model was suggested for both lag time and release at 6 h. The three-dimensional response surface plots for the effect of factors (X1: % Eudragit L100; X2: % Coat weight) on responses related to lag time (Y1) and drug release at 6 h (Y2) are shown Fig. 3.
Table 3 Solubility study of MKS in different media Media
Solubility (mg/ mL)
0.1 N HCl pH 1.2 Acetate buffer pH 4.5 Phosphate buffer pH 6.8 Phosphate buffer pH 7.4 0.1 N HCl pH 1.2 with 0.5 % (w/v) Tween 80 Acetate buffer pH 4.6 with 0.5 % (w/v) Tween 80 Phosphate buffer pH 6.8 with 0.5 % (w/v) Tween 80 Phosphate buffer pH 7.4 with 0.5 % (w/v) Tween 80
0.0040 0.0132 0.0145 0.0212 0.0069 0.0235 3.70 6.79
Optimization and Validation After generating the polynomial equations relating the factors and responses, a further optimization process was undertaken with desirable characteristics to probe the optimal formula solution of PRTs which depended on the prescriptive criteria of 4.5 h of drug release lag time and maximize the release at 6 h. The list of solutions was sorted with the highest desirability first; solutions that meet the criteria are reported in Table 5. Desirability for optimization of PRTs of MKS coated with EC/Eudragit L100 is shown in Fig. 4.
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Fig 4 Desirability for optimization of PRTs of MKS coated with EC/ Eudragit L100
Characterization of Pulsatile Release Tablets Water Uptake Study The water imbibition rate and extent were strongly affected by polymer blend ratio. With increasing Eudragit L content, the water uptake increased in both media (Fig. 5), which can be attributed to the higher hydrophilicity of Eud L100 compared to ethyl cellulose [5]. In Vitro Bursting Time Study Fig 3 Response surface plots for the effect of percentage Eudragit L100 and coat weight on responses related to a lag time and b drug release at 6h
The optimum formulation was selected based on the drug release lag time of 4.5 h, maximize % drug release at 6 h; satisfying these parameters, the first solution from Table 5 was chosen as optimized formulation with the highest desirability of 0.947 (F 14). The optimum formulation was evaluated for all the evaluation parameters. The observed values for the optimized formulation were compared with the predicted values. The results were found to be close to the predicted values, which confirm the practicability of the model. The comparative table is shown in Table 6.
Table 5 Solutions suggested by Design Expert that meet the criteria required for PRTs S. No. HPMC Coat wt. Lag time Release at Desirability coded/actual coded/actual (h) 6 h (%) F 14 F 15
−0.48 −0.47
−0.34 −0.33
4.5 4.5
88.33 88.33
0.947 0.947
The burst time of the PRTs in dissolution media was investigated and could be mainly controlled by the coating level (%) and EC/Eudragit ratio of outer polymer coating (Fig. 6a). The bursting time increased with higher coating levels and decreasing Eudragit content in outer coating composition because of the increased mechanical strength of the coating membrane and the reduced medium permeation rate. The bursting time was affected by the pH of buffer (Fig. 6b), molarity of ions (Fig. 6c) and concentration of different types of surfactant (Fig. 6d) in dissolution Table 6 Comparison of predicted and observed responses for the statistically optimized formulation F 14 Formulation
Response
Observed
Predicted
Relative error (%)
F 14
Drug release lag time in h (Y1) % drug release at 6 h (Y2) Drug release lag time in h (Y1) % drug release at 6 h (Y2)
4.60
4.5
2.22
83.52
88.33
5.75
4.75
4.5
5.55
81.26
88.33
8.00
F 15
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Fig 5 Water uptake study by PRTs coated with EC/Eud L100 in different ratios at 10 % coating level
media. In media of different pH, the coated tablets (F 8) have shown significant difference in bursting time maybe due to pH-dependent solubility of Eudragit polymer. At higher pH, decrease in bursting time was observed maybe because of pH-dependent solubility of Eudragit polymer used in coating composition. It was observed that at higher molar concentration, tablets burst fast as shown in Fig. 6c. Surfactant plays a major role in release profile; SLS has shown less bursting time compared to Tween 80 may be due to fast wettability of tablet surface leading to fast erosion of polymer coating because of greater reduction in surface tension of media. As concentration of surfactant (SLS and Tween 80) increased from 0.1 to 1.0 % (w/v), there was significant reduction in bursting time observed (Fig. 6d).
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Fig 7 Release profile of core tablet (C-4) and PRTs (F-14)
In Vitro Dissolution Study The drug release of core tablet (C-4) and optimized batch (F 14) is shown in Fig. 7. The release study of different batches was carried to study the effect of EC/ Eudragit L100 blend ratio at different coating levels. The effects of the EC/Eudragit L100 blend ratio (90:10, 80:20, 70:30, and 60:40) and coating level (8, 10, and 12 % w/w) on the in vitro release study of PRTs are shown in Fig. 8a, b, respectively. A large range of drug release profile with different lag times can be obtained by varying the Eud L100 content in polymer blend and thickness of coating membrane. As expected, the release rate decreased with increasing coating level, due to the increased diffusion pathways.
Fig 6 Effect of a % of Eudragit L100 and coat weight, b pH of media, c molarity of ions, and d surfactant concentration on bursting time of PRTs coated with EC/Eud L100 (80:20) at 10 % (w/w) coating level
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Fig 10 Pharmacokinetic parameters of core tablet (C-4) and PRTs (F-14)
Eudragit L100 [5] leading to formation of a large number of pores on polymeric coating membrane. Scanning Electron Microscopy
Fig 8 Release profile of a EC/Eud L100 coated tablet in different ratios of 10 % (w/w) coating level and b EC/Eud L100 (80:20) coated tablet at different weight gain levels
With increasing Eudragit L100 content, the release rate increased (irrespective of the coating level), which can be attributed to the higher permeability and leaching of
Fig 9 Scanning electron microscopy images of optimized formulation at a 0 h, b 2 h, c 3 h, and d 4 h in dissolution media
The optimized formulations were subjected to scanning electron microscopy (SEM) studies, and resulting images are shown below in Fig. 9. From these studies, it is clearly evident that tablet surface was smooth as initial even after 2 h dissolution in pH 0.1 N HCl because of no solubility of Eudragit L100 in acidic media, whereas after 3 and 4 h tablet has shown a considerable change in surface morphology due to formation of pores and cracks maybe because of leaching of Eudragit L100 in buffer pH 6.8 from outer coating membrane.
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Table 7 Pharmacokinetic parameters of MKS after oral administration of core tablet and PRTs (n=3) Parameters
Core tablet (C-4)
PRTs (F 14)
Cmax (ng/mL) Tmax (h) AUC0–t (ng h/mL) AUC0–∞ (ng h/mL)
607.985+29.11 2 5,438.43+317.63 5,732.39+376.83
632.6+39.16 6 6,677.78+511.25* 7,612.91+551.47*
MRT (h) Vd (L) CL (L/h) T1/2 (h) Ke (1/h)
9.0+0.96 4.5+0.71 0.698+0.065 4.5+0.44 0.154+0.041
13.9+1.43* 4.5+0.76 0.525+0.056* 5.96+0.56* 0.116+0.037
of the coating film. The pharmacokinetic study indicates that the developed system can release the drug in the GI tract in a manner similar to that in vitro as supported by pharmacokinetic study. Thus, the designed device can be considered as promising delivery system in management of asthma and associated allergic rhinitis. Acknowledgments The authors are grateful to acknowledge Manipal College of Pharmaceutical Sciences, Manipal University, Manipal for providing infrastructure facility and ICMR, New Delhi, India for financial support. Conflicts of Interest Authors have no conflict of interest.
Data were represented as the mean±SD *p
