Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007, 2 (6): 227-238

Preparation and evaluation of taste-masked orally disintegrating tablets of prednisolone
V. Ananda, *, R. Kandarapub, S. Gargc
a

Department of Pharmaceutics, Seth G. L. Bihani S. D. College of Technical Education, Sri Ganganagar, Rajasthan, India b Research and Development, Dr. Reddy’s Laboratories Ltd. (Generics), Bachupally, Hyderabad, India c School of Pharmacy, University of Aukland, New Zealand
Received 20 June 2007; Revised 18 September 2007; Accepted 13 October 2007

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Abstract
Purpose: To prepare taste-masked orally disintegrating tablets (ODTs) of prednisolone (PDL) by incorporation of microspheres in the tablets for use in specific populations viz. pediatrics, geriatrics and patients experiencing difficulty in swallowing. Methods: Microspheres containing PDL were prepared by the solvent evaporation method using acetone as solvent for pH-sensitive polymer and light liquid paraffin as the encapsulating medium. Prepared microspheres were characterized with regard to the yield, drug content, particle size and size distribution, surface features, in vitro drug release and taste. Tablets, prepared by direct compression containing microspheres, were evaluated with regard to crushing strength, friability, disintegration time, drug content and in vitro drug release and taste. Results: The results obtained showed that the average size of microspheres is influenced greatly by the speed of stirring. Microspheres prepared by the solvent evaporation method in acetone were of a regular spherical shape with satisfactory results in terms of the size and size distribution. The comparison of the dissolution profiles of microspheres in different media shows that microspheres produce a retarding effect in pH 6.8 buffer. Taste evaluation studies confirmed that microspheres of PDL having a drug to polymer ratio of 1: 10 are tasteless and these were further used for formulation into ODTs. Compression of microspheres resulted in breaking of a fraction of the microspheres but this did not adversely affect the taste. Conclusion: Effective taste-masking was achieved for PDL using the technique of microencapsulation and ODTs of acceptable characteristics were obtained by disintegrant addition and direct compression. Keywords: Taste masking; Orally disintegrating tablets; Prednisolone; Microspheres; Solvent evaporation; pH sensitive polymer _____________________________________________________________________________________________________________

1. Introduction
Asthma, an inflammatory disease of the airways, is the most common chronic disease of childhood. Children reported to have had asthma at some time in their lives in the Indian subcontinent account for 6.1% of the 13–14 year age group and 5.2% of the 6–7 year age group [1]. A worldwide increase in the prevalence of asthma is being reported with an increase at rate of 0.28% per year in the 13–14 year age group and by 0.18% per year in the 6–7 year age group [1]. Prednisolone effectively controls the inflammation by inhibition of T cell function [2] and, thus, provides good control of asthma. Well controlled asthma allows normal growth in children as asthma
__________ *Corresponding author. Address: Department of Pharmaceutics, Committee for Higher Education Guidance, Seth G. L. Bihani S. D. College of Technical Education, Sri Ganganagar, Rajasthan, India. Tel.: +91-154-2466777; Fax: +91-154-2466774. E-mail: vikas.pharmaceutics@gmail.com

itself retards the growth [3]. Despite the side effects, oral prednisolone is a treatment of choice due to its advantages of reliability, simplicity, convenience, and low cost [4]. It can be used for the treatment of acute, chronic and moderately severe asthma in adults as well as children [5, 6]. Moreover, it is an alternative for children unable to use a metered inhaler. The main problem with the prednisolone formulations is their extremely bitter taste, a critical factor as far as compliance is concerned. Studies have shown that prednisolone tastemasked or flavored formulations are better tolerated than crushed tablets in the treatment of acute severe asthma in children [7]. Various taste-masking technologies have been extensively reviewed [8-10]. Solvent evaporation is a relatively simple and convenient method for the preparation of taste-masked microspheres. The drug particles are surrounded by a polymer which prevent leaching of the drug into the saliva but allow the release of the drug in

227

disintegrants and other excipients are mixed and ODTs were prepared by the direct compression method. croscarmellose sodium (Vivasol Type A.1.89 J/g. and color sunset yellow (Arun Chemical Industries.000. The temperature was increased from 25˚C to 300˚C at a heating rate of 10˚C/min under a flow of nitrogen (80 ml/min). and Eudragit E100 were separately placed in vials and blended with PDL (1: 1 ratio) without added water. In the present work. In a similar fashion. Materials and methods 2. sodium chlor- 228 . acetone (Qualigens Fine Chemicals. J. microcrystalline cellulose (Avicel PH 102. 2. Eudragit E films swell and are permeable in water and buffer solutions above pH 5. 2. The dispersion was poured slowly into light liquid paraffin at a low 2. approximately 5 mg of the sample was weighed and subjected to DSC.. L-hydroxypropylcellulose (Type LH11. Rettenmaier & Sohne. magnesium stearate (kindly supplied by Unichem. Avicel PH101. Therefore. Germany). Stressed samples were stored at 40˚C temperature & 75% relative humidity (RH) in stability chambers for 4 weeks. 2. Stressed samples were covered with aluminium foil containing pores. screw capped and stored at 5˚C in the refrigerator. eudragit E100 (Rohm Pharma. menthol (All-Wells Chemicals. Microspheres.3. At salivary pH.2. the polymer is insoluble in water but permeable. Preparation of samples for thermal stress testing All ingredients had been previously passed through a sieve number 60 before the start of the study to ensure the uniform mixing of drug and excipients. It becomes water soluble via salt formation with acids. The most widely used solvent systems in solvent evaporation process are methylene chloride/ water [11] and acetone/light liquid paraffin [12-15]. methyl methacrylate) 1: 2: 1] (Rohm GmbH). FMC. it does not retard the release of PDL from the formulation to an extent that may affect its bioavailability. cross linked polyvinylpyrollidone (Polyplasdone XL. aspartame (Ajinomoto Co.000. This technology has been applied to mask the bitter taste of antibiotics such as bacampicilin [12. light liquid paraffin (Loba Chemie. prednisolone (PDL) was microencapsulated by the solvent evaporation method using Eudragit E100 to mask the taste of the drug. A.63˚C and a calibration energy ∆fus of 28. Thermal analysis of the samples Thermal analysis was carried out with the help of DSC equipment (DSC821e Mettler Toledo) calibrated using indium as a standard with a melting point (Tfus) of 156. orange dry mix flavor (Lux flavors. Delhi. Compatibility studies 2. is a cationic copolymer with an average molecular weight of about 150. L-HPC. Eudragit E100 [poly(butyl methacrylate. Preparation of microspheres Microspheres were prepared by the solvent evaporation method previously reported and modified for our purpose [14. pseudoephedrine [11] and cefuroxime axetil [14]. Japan). New Delhi). Germany). A specific quantity of each ingredient was weighed separately and monitored to note any change in the physical and chemical characteristics.2. 16]. Germany).1. Rosenberg. thus providing gastro-soluble film coatings. its gastro-soluble nature allows the release of PDL in the gastric environment. Chennai). Chandigarh).2. Moreover. New Delhi).. sodium starch glycollate (Vivastar P5. microcrystalline cellulose. Eudragit E100 prevents the release of drug in the mouth and thus it prevents the bitter taste sensation. sodium starch glycollate. J. ISP Pharma). 2 (6): 227-238 the stomach. Rettenmaier & Sohne. Mumbai). Eudragit E100 and PDL were codissolved in acetone followed by dispersion of magnesium stearate in polymer drug solution. Shin Etsu. Bombay). (2-dimethyl aminoethyl) methacrylate. another set of samples (control) were prepared. Materials The materials used were: prednisolone (obtained as a gift from Arbro Pharmaceuticals. Rosenberg. New Delhi). 16]. Inc. Japan). ide (Ranbaxy. From each stressed sample and control sample vials. India). Belgium).Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007.2.

1 ― 290.3 79.3 78.5 8.4.6 80.8 80.1 8. The formulation parameters and process parameters for different batches of microspheres are given in Table 1.6 270.5 338. 2.1 360 ― 299. Drug content determination in microspheres Microspheres (50 mg) were dissolved in 10 ml 0.5 1.5 1.2 80.8 Stirring speed (r/min) 2000 2000 2000 2000 2000 4000 4000 4000 4000 4000 4000 3000 3000 4000 2000 4000 4000 Beaker Light liquid Acetone volume paraffin (ml) (mg) (ml) 250 250 250 250 250 1000 1000 1000 1000 1000 1000 500 500 1000 1000 1000 1000 80 40 80 80 150 500 500 500 500 500 500 250 250 500 500 500 500 20 10 20 20 40 150 150 150 150 150 200 150 100 200 200 100 200 82.7 235.6.8 79.5.5 81. the percentage yield was determined by the formula given below.9 80.1 85.2 0.7 Microsphere evaluation parameters Loading PDL Yield Diameter efficiency loading (%) (µm) (%) (%) 79.5 0.6 288.9 307.3 361 81. Microspheres were separated by decantation following filtration. n-Hexane was added to the system for hardening of the microspheres and to accelerate settling. Dried microspheres were stored at room temperature.9 ― 85. 2 (6): 227-238 stirring speed.9 77.8 78.6 82.3 8.4 8.5 1 0.2 0. After complete addition.3 8. the speed was increased and the stirring rate was maintained for 8 h until all the acetone evaporated.1 81.6 ― 79.2 8.5 8.4 8.75 15 15 15 15 0.3 329.4 VMP/OPT/01 1500 VMP/OPT/02 1500 VMP/OPT/03 1500 VMP/OPT/04 1500 Batch failed 229 .5 1.1 0.5 1.2 0.5 75. Microspheres were then washed with n-hexane and the washed microspheres were dried in an oven maintained at 37˚C for 24 h.7 79.07 mol/l HCl by vigorous shaking and the volume was made up to 25 ml.5 1.3 ― 6.1 258. Yield% = 2.5 1. The PDL content of the microspheres was calculated using a standard calibration curve.8 8.4 1.4 85.9 353.4 8.25 3.9 74.4 333.0 80.8 85 85.2 14. Percentage yield determination After complete drying of microspheres.75 1.3 8.0 84.2 8. Micromeritics of microspheres The size distribution and average size of the microspheres were determined by sieve analysis using British standard sieves (BSS) mounted on a sieve shaker unit. Microsphere ingredients and process parameters Formulation code VMP/01A VMP/02A VMP/03A VMP/04A VMP/05A VMP/06A VMP/7A VMP/8A VMP/9A VMP/10A VMP/01X RVMP/01 RVMP/02 PDL (mg) 200 100 200 200 400 1500 1500 1500 1500 1500 0 750 750 Eudragit Magnesium E100 (g) stearate (g) 2 2 2 2 4 15 15 15 15 15 15 11.07 mol/l HCl (1 ml diluted to 10 ml) and the absorbance was determined spectrophotometrically (Perkin Elmer Lambda 20 UV Visible Spectrophotometer). process parameters and evaluation. 2. Weight of the dried microspheres _______________________________________________ ×100 Weight of (PDL + Eudragit E 100 + magnesium stearate) Table 1 Taste-masked PDL microsphere ingredients.4 8. The solution was further diluted with 0.7 78.1 77.Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007.7 78.3 84.3 270.5 1.

2.3.8. India). 3 = moderately bitter and 4 = extremely bitter).9.000 ml) equilibrated at 37˚C ± 0. Measurement of disintegration time A single tablet was placed in the mouth to determine in vivo disintegration time of the tablet. Microspheres of batches VMP/06A to VMP/10A (five batches) were pooled and used for preparing ODTs. Different batches of tablets were prepared using different combinations of disintegrants to achieve ODTs. The collected samples were analyzed spectrophotometrically at 247 nm. 2 = slightly bitter. Electrolab. As soon as it disin- 230 . India). Microscopic evaluation Microspheres of different batches were observed at magnifications of × 100 times and × 250 under a Leika photomicroscope (Leitz Labor Lux S. Pure drug (2 mg). PDL microspheres (equivalent to 2 mg prednisolone). A prototype of the tablet formulation was developed. and blank microspheres (without drug) were provided randomly to 12 healthy volunteers divided into three different groups. Taste assessment studies were conducted according to the approved protocol on twelve healthy human volunteers recruited among the students and staff at NIPER. Erwka GmbH.11. Determination of tablet crushing strength The compression force applied diametrically to crush the tablet was determined in KiloPascal (KP) using an Erweka hardness tester (Model TBH 220. 5 ml aliquots of the dissolution medium were withdrawn and replaced with 5 ml of fresh dissolution medium. The composition of the tablets prepared with pooled PDL microspheres are given in Table 2. mannitol. Subjects scored the intensity of bitterness by placing the given amount of sample on the tongue. like avicel. and thoroughly rinsing their mouths with water after each sample evaluation. Cadmach. tasting it for one minute.5˚C. At specific times.2.1. 2.10. 2 (6): 227-238 2. flavors. sweeteners. PDL microspheres were mixed with different diluents. advantose and lactose. India). 2. The results obtained from the initial studies were used in the selection of a suitable diluent for compression of the microspheres. The tests were carried out in pH 1.5 buffer (1. Each volunteer judged the taste of the sample using a score involving a five point scale which ranged from 0 to 4 (0 = pleasant.11. Microspheres were incorporated into the tablets on the basis the drug loading so as to give the required dose of 10 mg/tablet.8 buffer (1. and lubricants) and processed to allow direct compression tabletting in a single punch tablet machine (Model: CMS H/437/96. each of four volunteers. 2. In vitro release studies In vitro drug release studies were carried out using USP XXIV dissolution apparatus II (Model. 2. 2. The paddles were rotated at 100 r/min.000 ml) and pH 6. Taste evaluation of microspheres A protocol for conducting taste assessment by taste panel studies was submitted to the Institutional Ethical Committee of NIPER. Germany) fitted with an MPS 52 camera. TDT-06T. All the volunteers signed an informed consent form. respectively. 1 = tasteless. Mumbai. Electrolab. and the resulting mixture was compressed into tablets of 8 mm diameter and weighing 100 mg. Evaluation of tablets 2.Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007. Compression of microspheres In initial experiments. The PDL microspheres were blended along with the other excipients (super-disintegrants.11. Accurately weighed PDL microspheres were added to the medium under test. The sequence of the taste testing was different for each group to avoid any bias pure drug (taste score 4) and placebo (taste score 1) were used as positive and negative controls. Heusenstamm).11. Ahmedabad. Mumbai. Determination of tablet friability Tablet friability was reported as the percentage weight loss from ten tablets after 100 rotations in a friabilator (Model EF-2.7.

22) and the sieve screen was checked for any material retained.11.5 4.5 4. Drug content analysis Five tablets were crushed to a powder and powder equivalent to 10 mg PDL was taken and extracted with 0. After suitable dilution.Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007. There was no change in the peak of PDL when it was subjected to stress conditions for 4 weeks (peak at 236. The in vitro disintegration time was determined in 10 ml DM water in a 50 ml glass beaker.6.1 0.5 ― 3 0.5 4. 3.4 2 ― VMP/ TAB/17 30 41 10 ― ― 5 5 0. The speed of rotation (100 r/min).5. Two tablets were placed in 100 ml water (at 25˚C in a beaker). the drug content was analyzed by UV spectrophotometry. The DSC trace of PDL shows one endothermic peak at 242. 18]. 2.1 0.4 2 ― VMP/ TAB/12 30 45 10 5 ― ― 3 0. India) apparatus was used. Results and discussion 3.25 231 . Dispersion test Uniformity of dispersion was checked according to the procedure in the Indian Pharmacopoeia [19].07 mol/l HCl.50 VMP/ TAB/15 30 45 ― 7.0˚C ± 0. indicating the absence of any incompatibility between the mixture components.2 2 0. The samples were then diluted and the concentrations determined by spectrophotometry using the calibrated standard curve.000 ml) were kept constant throughout the study. The tablets were allowed to disintegrate and the dispersion was stirred with a glass rod until a smooth dispersion was obtained.11.1. HCl and pH 6. Dissolution studies The drug release from the tablets was evaluated by carrying out in vitro dissolution studies in 0. the changes in the endothermic peak Amount (%. temperature of the bath (37. 2. The dispersion was passed through a 710 µm sieve (No.33 VMP/ TAB/16 30 45 ― 10 ― 5 3 0.2 2 0.5 4.80).4 2 ― VMP/ TAB/13 30 45 10 ― ― 5 3 0.1 0. 5 ml of the samples was withdrawn and the samples were immediately analyzed or refrigerated until analyzed.1 2 0. Mumbai.1 0.5 7. and the volume of the dissolution medium (1. indicating the stability of drug under these conditions.5 6. A USP XXIV Type II (Model. Electrolab.5˚C).11. w/w) Ingredients PDL Microspheres Avicel PH 102 L-HPC Sodium starch glycollate Croscarmellose sodium Polyplasdone XL Aspartame Menthol Sodium chloride Flavor Aerosil Color (Sunset yellow) VMP/ TAB/11 30 45 10 ― 5 ― 3 0. TDT-06T. which is associated with the melting of PDL.9 2 0.1 0.94.5 3.4 2 ― VMP/ TAB/14 30 45 ― ― 5 10 3 0. 2 (6): 227-238 tegrated it was spat out and the disintegration time was recorded [17. At predetermined time intervals.07 mol/l Table 2 Compositions of prepared ODTs. Compatibility studies No color change or difference in color in the stress samples and control samples was observed during or after a 4-week storage period.1 0.8 buffer.5 4.4.5 6.1 0. 2.1 0. In the DSC of Eudragit E100 and PDL control and stress mixtures.25 VMP/ TAB/18 30 41 10 ― ― 5 5 0.

Completely spherical microspheres were obtained for batch VMP/OPT/01 [Fig. These slight changes in the melting endotherm of the drug may be attributed to the mixing process. Percentage yield and drug content High yields of free flowing. Microspheres were spherical in the size range of 355–710 µm (fraction # 22/44) and 250–355 µm (# 44/60.09. all batches were prepared 232 . respectively) are poorly miscible. Evaporation was allowed to take place in an open system. Microscopic evaluation Photomicrographs of PDL microspheres of several batches are presented in Fig. 3.g. A reduction in the volume of acetone for preparing the drug polymer solution produced aggregated microspheres.74 for microspheres with PDL-Eudragit E100 in a ratio of 1:10 while the loading efficiency for PDL-Eudragit E100 in ratios of 1: 5 and 1: 10 were 85.. 6(a) and Fig. Formulation of microspheres also reduces the microsphere sphericity. 3. Magnesium stearate is widely used to prevent electrification and flocculation in the preparation of microcapsules [13. 1: 5 and 1: 15. if it is too small. broadening or shifting towards a lower temperature (Fig. Preparation of microspheres Acetone and liquid paraffin (i. The sphericity of microspheres was also reduced when quantity of magnesium stearate was reduced by half. The yield. Satisfactory results were obtained and spherical solid PDL microcapsules could be prepared by adding a small amount of magnesium stearate (1: 1 ratio with the drug). The size distribution of microspheres prepared under identical conditions is represented by the histogram in Fig. the polymer solvent and encapsulating medium. Once the desired oil phase droplet size and emulsion stability was obtained. We were able to obtain free flowing microspheres even at a light liquid paraffin: acetone ratio of 2. 1).47% (mean ± SD). percentage loading and loading efficiency for different batches of microspheres are given in Table 1. the capsules easily adhere to each other and form lumps while. Other ratios. dispersing a core substance (PDL) in the resulting solution. Thereafter. A PDL: Eudragit E100 ratio of 1: 10 resulted in the best spherical microspheres.31 and 85.5. 3.5. 4. 2. Magnesium stearate acts as a deflocculating agent in the preparation of microspheres by solvent evaporation.12% ± 2. respectively. the mean diameter of the microspheres was found to decrease. A drastic reduction in stirring speed resulted in a batch failure (e. Therefore.4. the system was stirred at a constant rate for a sufficient time to allow solvent evaporation.3. the production and recovery of the capsules become complicated [21]. 3.2. The impressions produced by microspheres sticking can be seen in Fig. acetone has a poor compatibility with liquid paraffin. 16]. The amount of the liquid paraffin to be used as the encapsulating medium was found to be 4 to 15 times that of the dispersion liquid of the core substance in the polymer solution.Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007. Addition of a low amount of magnesium stearate to the dispersion media results in agglomeration of microspheres. 6 (c).. 2 (6): 227-238 of the PDL were well preserved with little change in sharpening.e. The loading efficiency was 77. but not truly representing any incompatibility [20]. Most of the acetone disappeared by evaporation.88 to 85. Micromeritics of microspheres The average diameter (Dav) of microspheres determined by sieve analysis is given in Table 1. thus resulting in slightly broader and lower melting points. resulted in asymmetric microsphere (Fig. VMP/OPT/02).7 and liquid paraffin one of about 2) [21]. since acetone has a dielectric constant of 20. if it is too large. major fraction) and microspheres of other sieve fractions 180–250 µm (# 60/85) and 150–180 µm (# 85/100) were not perfect spheres. On increasing the stirring rate. The effect of microsphere size on the sphericity is shown in Fig. non-aggregated microspheres were obtained. All microspheres appeared porous in nature and the sphericity of the microspheres varied with the size and from batch to batch. 5). For final five batches prepared under the same conditions the percentage yield obtained was 80. 6(b)]. which lowers the purity of each component in the mixture. 3.

(c) Batch VMP05A. (b) Batch VMP03A. (a) (b) (c) Fig. (a) Batch VMP02A. 233 . 80 70 Percentage (%) 60 50 40 30 20 10 0 18/22 22/44 44/60 60/85 85/100 100/120 120/150 Sieve fraction Fig. 2. Histogram representing the size distribution of PDL microspheres. Each value represents a mean of five determinations with different batches. Photomicrographs of different batches of PDL microspheres (magnification 100 ×). The c and s in parenthesis after the name of each drug or mixture refer to control samples and stressed samples respectively. 2 (6): 227-238 PDL (C) PDL (S) 20 mW Polymer Z Polymer Z + PDL (C) Polymer Z + PDL (S) 50 0 5 100 10 150 15 200 20 250 25 300 30 350 35 ˚C min Fig.Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007. 3. 1. DSC thermograms of PDL with Eudragit E100 (polymer Z). Error bars represent the standard error of mean.

(a) PDL to Eudragit E100 ratio 1:15. (a) Sieve Fraction #22/44. (d) Batch VMP/OPT/04 (magnification 100 ×). 5. (b) Sieve Fraction #85/100. (b) Batch VMP/OPT/02 (magnification 250 ×). (a) (b) Fig. 6. (b) PDL to Eudragit E100 ratio 1:5. (a) (b) (c) (d) Fig. Photomicrographs showing the shape of microspheres of different sizes of PDL microspheres (magnification 100 ×).Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007. Photomicrographs of PDL microspheres prepared using the optimizing process parameters. 4. 234 . (a) Batch VMP/OPT/01 (magnification 100 ×). (c) Batch VMP/OPT/03 (magnification 100 ×). Photomicrographs of PDL microspheres with different drug loading showing the effect of drug loading on the shape of microspheres (magnification 100 ×). 2 (6): 227-238 (a) (b) Fig.

9). 3. advantose and lactose. the diluent avicel was found to be the most suitable and this was used for the compression of microspheres without significant damage (breaking or cracking) to the microspheres. Therefore. it is expected that as soon as the polymer dissolves in the acidic contents of stomach. The final composition of formulations was decided on the basis of the disintegration time of tablets.34% PDL was released in 10 min in pH 6. Dissolution studies with microspheres Dissolution studies of PDL microspheres (Batch VMP/ 07A) were performed in two different pH media (pH 1.5 hydrochloric acid buffer and pH 6.9. The gastric emptying time ranges from 32–87 min in fasted states for particles with a size in the micron range and the corresponding value is 34–75 min in fed state [22]. The slightly bitter taste could be due to some crushed and broken microspheres. The dissolution profile in hydrochloric buffer pH 1. Therefore. The comparative dissolution profile is shown in Fig. It is proposed that once the drug is released in the gastric medium it will remain in the free form and become bioavailable.7. Approximately 90% of the drug was released within 10 min. Dissolution studies Dissolution studies of prepared tablets were conducted in pH 6. but the release of PDL from the marketed product (Wysolone tablets) was immediate. A further increase in polymer did not significantly affect the taste of the microspheres as three volunteers reported a moderately bitter taste when the drug polymer ratio was kept at 1: 15. Taste evaluation of ODTs Eight out of twelve volunteers rated the tablets pleasant while the others reported a slightly bitter taste (Table 5). the release profile obtained proved that the tablet could provide effective taste-masking characteristics without compromising the bioavailability. 8. The drug release from in-house tablets was retarded at a salivary pH of 6.5 medium.8 medium. A prototype composition for compression of microspheres was developed based on these preliminary results. the drug will be release in the stomach and then absorbed from the gastrointestinal tract. Tablets prepared from the microspheres were evaluated with regard to various parameters and the results are given in Table 4.8. Drug release in pH 6. were these produced tablets with damaged microspheres. Eudragit E100 is insoluble in media with a pH greater than 5 but it becomes permeable and allows the release of PDL. The dissolution profiles of these studies are given in Fig.5 indicated that > 94% of the drug was released from the microspheres after 30 min. Preparation and evaluation of ODTs In several initial experimental runs. the drug is released from the microspheres very rapidly in pH 1. The release of PDL from in-house tablets in pH 1. Therefore. 3. Four volunteers rated microspheres with a drug polymer ratio 1: 10 moderately bitter.5 medium. All of the prepared batches passed the dispersion test. Eudragit E100 is soluble in an acidic environment by formation of salts. Accordingly. A slight grittiness was also reported which could be due to the insoluble nature of the Eudragit E100 235 .10. L-HPC and cross linked PVP in combination produced the fastest disintegrating tablets with an in vitro disintegration time of 15 s and a time 25 s for disintegration in saliva (mouth). Microspheres having a 1: 10 drug polymer ratio were chosen for development of ODTs. 3.5 buffer was immediate (Fig. About 31. 2 (6): 227-238 under the same formulation and processing variables as those used in VMP/OPT/01. 3. 7. Other.8 phosphate buffer). which released drug rapidly in the oral cavity.6. diluents such as mannitol.8 buffer. 3.8.Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007. Formulations containing avicel as the diluent were less susceptible to pressure effects while capable of accepting larger quantities of microcapsules. the final batch was prepared and evaluated for taste.8 buffer was comparatively slower than that in pH 1. Microspheres having a drug: polymer ratio of 1: 10 and 1: 15 were tasteless to most of the volunteers. Taste evaluation of microspheres Taste evaluation results for microspheres with different drug to polymer ratios are given in Table 3.

92 4.8 phosphate buffer Fig.Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007. Dissolution profiles of PDL taste-masked microspheres in pH 1.5 hydrochloric acid buffer 20 0 0 10 20 30 40 Time (min) 50 60 70 in pH 6. 7.4 32 18 80 60 40 in pH 1.18 100.80 5.66 102.82 107.2 60 25 VMP/ TAB/17 1.9 25 15 VMP/ TAB/14 1.99 5. 2 (6): 227-238 Table 3 Taste panel scores for taste assessment of microspheres. Volunteer code 100964 189767 130063 969067 989563 39865 920168 919468 989564 209265 980163 149762 Volunteer group I I I I II II II II III III III III PDL 4 4 3 4 4 4 4 4 4 4 4 4 PDL microspheres D: P = 1:5 2 3 1 2 2 2 3 2 1 3 3 2 D: P = 1:5 2 2 2 1 1 1 1 1 1 2 1 1 D: P = 1:15 1 1 2 1 1 2 2 1 1 1 1 1 Blank microspheres 1 1 1 1 1 1 1 1 1 1 1 1 Table 4 Evaluation of prepared ODTs. 236 .0 28 18 VMP/ TAB/18 1.80 5. Parameters Friability (%) Average hardness (kP) Assay (%) In vivo (Oral) DT (s) In vitro DT (s) VMP/ TAB/11 1.60 5.4 40 25 VMP/ TAB/16 1.70 103. Each value represents an average of three determinations.34 98.22 100.96 98.1 80 22 VMP/ TAB/13 2.56 5.8 phosphate buffer.10 6.1 30 20 VMP/ TAB/15 2. Error bars represent the standard error of the mean.5 hydrochloric acid buffer and pH 6.06 101.7 60 20 120 100 Cumulative release of PDL (%) VMP/ TAB/12 1.54 8.

It is suggested that this technique may be used for masking the bitter taste of other drugs. 8. Effective taste-masking was achieved for PDL using the microencapsulation technique. Three out of twelve volunteers rated ODTs moderately bitter while the remaining volunteers found them pleasant tasting. Volunteer code 989564 919468 980163 209265 920168 39865 130063 189767 100964 149762 989563 969067 Volunteer group I I I I II II II II III III III III Marketed tablets 3 4 4 4 4 4 4 4 4 4 4 4 PDL in-house formulation 0 0 0 2 0 0 2 2 0 2 0 0 Placebo tablets 0 0 0 2 0 0 0 0 0 0 0 0 120 Cumulative release of PDL (%) Cumulative release of PDL (%) 100 80 60 40 20 0 0 15 30 Time (min) Fig. On comparison of the results for the taste evaluation of microspheres. Each value represents an average of three determinations. 45 60 In-house PDL ODTs Wysolone tablets 105 90 75 60 45 30 15 0 0 20 40 60 Time (min) Fig. Dissolution profile of PDL ODTs in pH 1. Other dosage forms like granules. Error bars represent the standard error of the mean.5 hydrochloric acid buffer.8 phosphate buffers. Error bars represent the standard error of the mean. 9. it was concluded that the addition of sweetener to ODTs further suppressed the bitter taste and provided a pleasant sweet taste. 237 .Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007. dry syrup or suspensions or non aqueous suspensions may also be formulated in this way. One volunteer (Volunteer code 209265) rated ODT and the placebo tablet moderately bitter and it was rather difficult to explain why the placebo tablet was rated moderately bitter. 80 100 120 in pH 1. From this result it was concluded that there was no difference in the rating of taste between the placebo tablet and ODT. Each value represents an average of three determinations.5 hydrochloric acid buffer and other water insoluble excipients. 2 (6): 227-238 Table 5 Taste panel scores for taste-masked PDL ODTs. Comparison of the dissolution profiles of in-house PDL ODTs and Wysolone tablets in pH 6.

chemicals and laboratory facilities provided by NIPER. A. An update on oral taste masking technologies for oral pharmaceuticals. Lucas-Bouwman. et al. J. and Toyo Jozo Co. The gastric emptying of pellets contained in hard gelatin capsules. Walsh. 64: 10-17.. Sunada. Ind. 8: 751-757. et al. 56: 279-284. Microencapsul. Control. J. Delhi. Formulation and production of rapidly disintegrating tablets by lyophilisation using hydrochlorothiazide as a model drug. Trembath. [16] M. 18: 85-91. 1997. 17: 373-383. Kristl. M. H. Pearce. Chest.. Today. Process for preparing a microcapsule. J. 2007. S. Pharm. J. therefore. et al. Roy. [2] R.. A.000) were provided by Ms. [20] A. Pharm. Bi. Pharm. disintegrants. L. Ait-Khaled. Eudragit RS and RL (acrylic resins) microcapsules as pH insensitive and sustained release preparations of ketoprofen. B. Y. [21] M. Fell. H.. L. Alternative pharmacotherapies for steroiddependent asthma. Vila-Jato. Assined to Fuji Photo Film Co. Design of drug excipient interaction study. A. 20: 81-86. and size distribution of the microspheres. Lorenzo-Lamosa. 15: 2295-2313. Bogataj. Kristl. J.. 84: 947-948. [5] P. Consoli. Characterization of the ODTs confirmed that adequate taste masking and faster disintegration could be achieved for PDL.. 2000. [18] S. Chen. Taste evaluation of the microspheres confirmed this. Garg. et al. Ind. Nanda. Sharma. [6] L. et al. [10] V. P. et al. Jansman. 152: 215-225. Ind. Puglisi. [15] R. 1973. Goto. Garg. et al. Raghupathi. 2001. Preparation and evaluation of Eudragit E microspheres containing bacampicillin. Rosenberg. Thorax. Central Instrumentation Laboratory. V. Higher dose inhaled corticosteroids in childhood asthma. Japan. sweetener and other excipients were prepared by the direct compression method.G. [8] G. R. Rettenmaier & Sohne. Hunter. W. H. [14] M. Mrhar. Ltd. Drugs used in the treatment of asthma. [12] M. Yonezawa. 1996. Mrhar. 322: 504-505. Taste masking in oral pharmaceuticals. A. Thorax. for his help in carrying out the DSC analysis. R. J. Pignatello. M. The procedure gave satisfactory results in terms of the size. Tyle. [9] A. 1980.. Moss.. et al. 8: 65-77. Kondo. R. J. Worldwide trends in the prevalence of asthma symptoms: phase III of the International study of asthma and allergies in childhood (ISAAC). E. Wong. J. 238 . [22] E. Germany. 62: 757-765. A. Dooran. Drugs. K. 107: 817-825. Bodmeier.. the drug is not expected to be released in saliva after oral administration. 44: 2121-2127. J. Ion-Exchange resins: carrying drug delivery forward. Pharm. 1986. Roorda. et al. Crushed prednisolone tablets or oral solution for acute asthma? Arch. Eudragit E microspheres containing bacampicillin: preparation by solvent removal methods. 1991. N. 2001. M. Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity. 9: 43-45. Tech. References [1] N. Pseudoephedrine HCl microspheres formulated into an oral suspension dosage form. New Delhi. Bogataj. E. Morishita.8 media and. Chem. M. M. Anand. 1991. T. J. [7] M. G. Sci. Beasley. 1991. Remon. Kawata. 8: 401-406. 1983.. Bull. Drug Dev. Ltd. A. 659-682. P. Microencapsul.. Ms Rohm Pharma GmbH. Inc. Child.. [3] W. Pharm. [17] Y. Development of a microencapsulated form of cefuroxime axetil using pH-sensitive acrylic polymers. NIPER. The authors are also grateful for the gift of prednisolone by Arbro Pharmaceuticals. Oborne. 6: 905-914. US Patent 3714065. Keelay. ODTs containing taste-masked PDL microspheres. Pharm. A. Release. 1995. Kitajima. A. J. Novel taste-masked formulations and ODTs would be helpful in increasing drug compliance in children and other special populations. J.. J. 14: 607-616. Indian J. Cuna. 1996. 2002. We are also grateful to all these excipient manufacturers for their generous support by providing gift samples for our research. Adverse effects of oral corticosteroids in relation to dose in patients with lung disease. Corveleyn. Microencapsul. Thanks are also due to Vikas Grover. 2 (6): 227-238 4. Drug Discov. Ajinomoto Co. 1997. 2001. S. C.. Int. Microencapsul. Ministry of Health and Family Welfare. Kandarapu. The dissolution experiment showed that the release of drug is retarded in pH 6. In 1996McGraw Hill. 1982. 1994. Published by Controller of Publications. P. [13] S. Drug Dev. 3: 293-304. 2001. Japan kindly donated aspartame and croscarmellose sodium (Vivasol Type A) and sodium starch glycollate (Vivastar P5. shape. Acknowledgements We gratefully acknowledge the financial assistance. Dramstadt was very kind in providing us with Eudragit E100. [11] R.Taste-masked orally disintegrating tablets of prednisolone/Asian Journal of Pharmaceutical Sciences 2007. F. Pharm. BMJ. A. Conclusions Eudragit E microspheres loaded with PDL can be easily prepared by the use of the solvent evaporation method.. [4] D. Serafin. [19] Indian Pharmacopoeia 1996. Drug Dev. et al. Corticosteroids in asthma: Inhaled or oral. Dis. Nakamura.. In vitro release kinetics of Tolmetin from tabletted Eudragit microparticles.

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