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Introduction
Most pharmaceutical forms for oral administration are formulated for direct ingestion, for chewing, for prior dispersion and/or dissolution in water; some of them are absorbed in mouth (sublingual or buccal tablets). Many patients express difficulty in swallowing tablets and hard gelatin capsules, tending to non-compliance and ineffective therapy. Recent advances in novel drug delivery systems aim to enhance safety and efficacy of drug molecules by formulating a convenient dosage form for administration and to achieve better patient compliance. To obviate the problems associated with conventional dosage forms, orodispersible tablets (ODTs) that combine hardness, dosage uniformity, stability and other parameters, with extremely easy administration were developed. Advantages of ODTs include ease of administration without water, accuracy of dosage, easy portability, alternative to liquid dosage forms, ideal for pediatric and geriatric patients and rapid onset of action. *Corresponding author: Prof. Y. Madhusudan Rao Centre for Biopharmaceutics and Pharmacokinetics University College of Pharmaceutical Sciences, Kakatiya University Warangal- 506 009 (A.P) India Tel.: +91 870 2438844, Fax.: +91 870 2453508 E-mail: ymrao123@yahoo.com
Buspirone, is an anxiolytic agent and a serotonin receptor agonist belonging to the azaspirodecanedione class of compounds used in the treatment of anxiety disorder (Cohn and Rickels, 1989). It was selected as drug candidate in this study as it is not available as ODTs, which is the clinical need. ODTs are also called as mouth dissolving tablets, orodispersible tablets, quick disintegrating tablets, rapid dissolving tablets, porous tablets and rapimelts (Battu et al., 2007; Fu et al., 2004). During the last decade, ODT technology has drawn a great deal of attention (Fu et al., 2004). The European Pharmacopoeia defines the term orodisperse as a tablet that can be placed in the mouth where it disperses or disintegrates rapidly before swallowing (Pharmeuropa, 1998). The objective of present study was to develop orally disintegrating tablets of buspirone by wet granulation, direct compression and freeze drying techniques in order to achieve rapid disintegration time. It was also aimed to evaluate these buspirone formulations by in vitro methods and to select the best formulation. 327
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aspartame, peppermint flavor were mixed and granulated with drug solution. The wet mass was passed through a sieve No.16 to form the granules. The granules were dried in tray drier at 60 C for 20 min. The dried granules were passed through sieve No 20 and lubricated with aerosil and magnesium stearate. The lubricated blend was compressed into tablets using 16 station rotary tableting machine and 8 mm punches. Direct compression technique The drug, Pearlitol SD 200, Avicel PH 101, Aspartame and flavor were passed through 40 mesh. The sifted ingredients were blended for 10-15 minutes in mortar and pestle. The blend was lubricated with sifted (#80) magnesium stearate. The blend was compressed into tablets with 6 mm biconcave punches using 16 station rotary tabletting machine (Riddhi, Ahmedabad, India). The composition was given in Table 1 and 2.
Table 1. Tablet Formulations for Buspirone ODTs by wet granulation and direct compression
Ingredients Super disintegrants concentration (%) of PXLa / ADSb/EXTc 4% 10.00 53.35 23.15 4.00 5.00 3.00 1.00 0.50 6% 10.00 52.15 22.35 6.00 5.00 3.00 1.00 0.50
c
Buspirone Pearlitol SD 200 Avicel pH 101/102d Super disintegrantse Aspartame (5%) Pipppermint flavour (3%) Aerosil (1%) Mg. stearate (0.5%)
a b
All the amounts given in above table are in milligrams. PXL -Cross povidone; ADS- Crosscaremellose sodium; EXT- Sodium starch glycolate Avicel PH101/102d- Avicel PH101 and Avicel PH102 were used in wet granulation and direct compression techniques, respectively. Superdisintegrantse- Cross povidone, crosscaremellose sodium and sodium starch glycollate
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Freeze drying method Freeze drying was carried using a lyophilizer (LYODEL, India) using blisters. Slurry was prepared by dissolving or dispersing drug, Pearlitol, poly vinyl pyrrolidone and Indion 204 in water. Required quantity of prepared slurry was accurately filled in the cavities (8 mm) of blister. The slurry was frozen within the cavities by using deep freezer (- 20 C). The frozen units are placed on to the shelves of the freeze dryer and dried at 50 C. The tablets are produced within the cavities which are very porous.
Physicochemical Evaluation
Weight and thickness variation The weights of buspirone ODTs were measured using digital balance (Denver, Germany). The average values, standard deviation and relative standard deviation were calculated. The thickness was measured using a digital screw gauge (Mitutoyo, Japan). Assay of the tablets Twenty tablets were taken and powdered; powder equivalent to one tablet was taken and was allowed to dissolve in 100 mL of phosphate buffer (pH 6.6) on a rotary shaker overnight. The solution was centrifuged and the supernatant was filtered through 0.22 membrane filter. The absorbance of filtrate was measured using a UVVis spectrophotometer (Elico, India) at 235 nm against pH 6.4 phosphate buffer as blank.
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granulation technique ranged from 99.3 to 101.6 mg with RSD values 2.71 - 2.99 % and thicknesses ranged between 3.61 and 3.87 mm with RSD of 0.51 to 2.21 %. The weights of tablets prepared by direct compression technique ranged from 99.5 to 101.8 mg with RSD values 1.23-4.43 % and thicknesses ranged between 3.62 and 3.81 mm with RSD of 0.26 to 0.28 %. The drug content of tablets ranged from 90.1 (EXT4) to 96.9 (PXL8) and 96.0 (EXT4) to 104.4 (PXL8) prepared by wet granulation and direct compression techniques respectively. A good content uniformity was observed among all the formulations of buspirone by using direct compression and freeze drying.
Wetting time
The wetting time of ODTs prepared by wet granulation method were found to be higher than the tablets prepared by direct compression method (Fig 1). The wetting times were found to be ranging from 120-390 (PXL); 240-420 (ADS); 300-420 (EXT) and 47-68 (PXL); 81-92 (ADS); 171-202 (EXT) for the ODTs prepared by wet granulation and direct compression method respectively. The results reveal that ODTs prepared by direct compression showed quicker disintegration than the tablets prepared by wet granulation method.
Table 3. Mean weights, thicknesses and assay of BUSP ODT prepared by wet granulation method
Formulation code PXL4 PXL6 PXL8 ADS4 ADS6 ADS8 EXT4 EXT6 EXT8 Weighta (mg) 99.3 2.88 99.8 4.07 100.4 2.51 101.6 2.76 100.0 1.74 100.0 4.11 99.5 3.84 101.1 2.79 100.8 3.02 Thicknessb (m) 3.87 0.02 3.80 0.03 3.77 0.02 3.74 0.04 3.84 0.01 3.70 0.06 3.73 0.03 3.70 0.03 3.61 0.08
a
DTc (Sec) 189.0 8.26 147.5 7.23 250.0 8.87 578.3 10.21 413.3 9.63 250.0 6.41 886.2 7.63 755.8 5.34 660.8 4.68
b
Drug content (%)a 94.7 1.74 94.9 2.80 96.9 1.95 95.8 2.32 96.1 2.27 96.4 2.82 90.1 1.05 95.5 2.28 96.1 2.54
c
Q5 (%)c 23.1 1.21 25.6 0.82 30.3 0.16 13.5 0.15 16.7 0.26 23.6 1.41 10.4 0.13 13.9 0.21 15.2 1.16
Table 4. Mean weights, thicknesses, assay and drug release (Q5) of BUSP ODT prepared by direct compression and freeze drying
Formulation Code PXL4 PXL6 PXL8 ADS4 ADS6 ADS8 EXT4 EXT6 EXT8 Freeze drying
Weight a (mg) 99.4 1.23 99.6 1.14 100.1 4.14 99.6 4.13 101.8 4.51 99.7 1.52 100.3 2.86 100.1 1.37 100.5 1.39 100.5 1.70
Thickness b (m) 3.72 0.02 3.81 0.01 3.76 0.05 3.69 0.03 3.68 0.03 3.62 0.01 3.71 0.06 3.64 0.03 3.65 0.05 3.69 0.02
a
DTc (Sec) 44.5 1.04 41.8 2.13 35.2 2.56 58.7 1.21 55.5 3.39 46.7 4.13 460.0 6.58 340.8 5.26 226.6 2.86 30.3 0.82
b
Drug content (%) a 100.7 0.21 98.8 1.17 104.4 0.77 98.8 2.83 100.3 1.25 97.1 2.81 96.0 3.07 96.1 5.41 96.9 1.17 98.3 1.56
c
Q5 (%)c 98.7 1.25 99.0 1.46 99.7 1.16 97.3 2.01 97.3 1.38 98.4 1.65 45.4 0.86 46.8 1.29 55.8 1.37 99.1 1.64
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500 450 400 350 Wetting time (Sec) 300 250 200 150 100 50 0 PXL4 PXL6 PXL8 ADS4 ADS6 ADS8 EXT4 EXT6 EXT8 Wet granulation Direct compression Freeze drying
Formulation code
Fig 1. Wetting time of different buspirone ODT, values represented are mean SD (n=3) PXL-Polyplasdone XL; ADS- Ac-di-sol; EXT- Explotab; 4, 6 and 8 are the concentration of disintegrant.
140 120 100 80 60 40 20 0 PXL4 PXL6 PXL8 ADS4 ADS6 ADS8 EXT4 EXT6 EXT8 Formulation code
Fig 2. Water absorption ratio of different buspirone ODT, values represented are mean SD (n=6) PXL-Polyplasdone XL; ADS-Ac-di-sol; EXT-Explotab; 4, 6 and 8 are the concentration of disintegrant.
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formulation. This increase was due to the water up taking ability of the superdisintegrants. More the superdisintegrant concentration greater was the water up take and there by increase in the R value was observed. This pattern was observed in all the 3 superdisintegrants used in wet granulation method and direct compression method, an increased value was observed for the freeze dried formulations (Fig 3).
80
60
40
20
0 0 5 10 15 20 Time (Min) 25 30
Fig 3. Dissolution profiles of Buspirone ODT containing Polyplasdone 8 %, values represented are mean SD (n=6).
Disintegration of ODTs
Disintegration time was given the major importance in selection of the best ODT formulation among all the formulations. For all the formulations, with increase in the superdisintegrant concentration from 4-8 %, the disintegration time was found to be decreased accordingly (Table 3 & 4). An increase in superdisintegrant concentration from 4 to 8 % showed a decrease in DT. The DT of formulations containing PXL was lower than those containing ADS and EXT at similar concentration which might be attributed to its rapid water absorbing nature involving both capillary and swelling mechanisms (Kornblum SS, Stoopak, 1973), building up the pressure internally leading to the faster disintegration. The tablets prepared with EXT as a superdisintegrant took more time to disintegrate than the ODTs prepared using other superdisintegrants. The probable reason for delayed disintegration and wetting of the tablets might be slow water uptake or more gelling tendency of the Ac-di-sol (ADS) and Explotab (EXT). From the above results PXL8 was selected as the best ODT formulation among all the
buspirone formulations for direct compression. The time for an ODT to disintegrate in the oral cavity also varies by product and the method of manufacturing. Buspirone ODT formulations prepared by wet granulation method took more time to disintegrate than the tablets prepared by direct compression method and freeze drying method. The tablets prepared from blister packs using freeze drying method took less time compared to wet granulation and direct compression. Compressed tablets will typically take slightly longer time to disintegrate than freeze-dried wafers due to a different bonding mechanism and differences in porosity between the two dosage forms. The buspirone ODTs prepared by direct and wet granulation techniques showed bitter ness. To mask the bitter taste and improve acceptability, the drug was complexed with an ion exchange resin, Indion 204.
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DTs as a function of the concentrations of different superdisintegrants (Fig 4a-b). As the superdisintegrant concentration was increased, R value increased and DT was decreased. The more the amount of superdisintegrant in the formulation, the greater the volume of water being
absorbed (increased R value), which is an inherent property of each superdisintegrant. Also, this volume expansion of each formulation led to faster disintegration of the same due to increased hydrostatic pressure inside the tablet (ISP, 2006).
Fig 4. Correlation between water absorption ratio and disintegration time of buspirone ODT prepared by (a) wet granulation technique and (b) direct compression method. Values represented are mean SD (n=6).
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In vitro dissolution
The results of in vitro study are shown in Table 3, 4 and Fig 3. The cumulative % of drug release increased in 5 min with increase in the concentration of superdisintegrant. Formulation PXL and ADS prepared by direct compression method showed a release of 99 % of drug in 5 min. But formulation EXT released the drug very slowly and 99 % of drug was released in 30 min (Fig 3). The rapid drug dissolution was observed for direct compression and freeze drying techniques; it may be due to easy breakdown of particles and rapid dissolution of drug into the dissolution medium. Buspirone is a highly water soluble drug and hence rapid disintegration by super disintegrants promotes rapid dissolution also. The tablets prepared with wet granulation were found to take more time to release the drug than the tablets prepared by direct compression and freeze drying technique. The taste of the tablets was found to be improved with the inclusion of resin. Freeze drying process is one of the first generation techniques of preparing ODT, in which water sublimes from the product after freezing (Bi et., al 1996). The product obtained by freeze drying process dissolves more rapidly than other available solid products. Primary problems associated with water soluble drugs are formation of eutectic mixture, resulting in freezing point depression and formation of glassy solid on freezing which might collapse during sublimation. The addition of cryoprotectants like poly vinyl pyrrolidone imparts rigidity to amorphous material and can prevent collapse of structure (Kuchekar et al., 2003).
These results demonstrate that the formulations afford high utility as oral drug delivery systems.
Acknowledgement
We acknowledge generous help of Dr Reddys Laboratories, Hyderabad, India and Zydus Cadila, Ahmedabad, India for providing gift samples of Buspirone hydrochloride and superdisintegrents, respectively.
References
Battu S, Repka M.A, Majumdar S and Madhusudan Rao. Y. Formulation and evaluation of rapid disintegrating fenoverine tablets: effect of superdisintigrants. Drug Dev. Ind. Pharm. 33: 1225-1232 (2007). Bi Y, Sunada H, Yonezawa Y, Danjo K, Otsuka A and Iida K. Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity. Chem. Pharm Bull. 44(11): 21212127 (1996) Cohn JB and Rickels K. A pooled, double-blind comparison of the effects of buspirone, diazepam and placebo in women with chronic anxiety. Curr Med Res Opin. 11 (5): 304320 (1989). Fu Y, Yang S, Jeong SH, Kimura S and Park K. Orally fast disintegrating tablets: Development Technologies, TasteMasking and Clinical Studies. Crit Rev Ther Drug Carrier Sys 21(6): 433-475 (2004) Gohel M, Patel M, Amin A, Agrawal R, Dave R and Bariya N Formulation design and optimization of mouth dissolve tablets of nimesulide using vacuum drying technique. AAPS Pharm Sci Tech. 3:36 (2004) ISPCrospovidone-International http://www.ispcorp.com/ (2006) specialty products.
Conclusion
The orodispersible tablets of buspirone with sufficient mechanical strength and smaller disintegration time were achieved employing suitable superdisintegrants and other excepients at optimum concentration. Among three superdisintegrants PXL (crospovidone) showed better performance in disintegration time when compared to ADS (croscaremellose sodium) and EXT (sodium starch glycolate) as it exhibited the lowest disintegration time and a better dissolution profile. Based on the disintegration results freeze drying technique and direct compression techniques were more efficient than wet granulation technique. The formulations of Polyplasdone XL8 was found to be the best among buspirone formulations which were prepared by wet granulation, direct compression and freeze drying technique because it has exhibited faster disintegration time when compared to other formulations.
Kornblum SS and Stoopak SB. A new tablet disintegrating agent: Cross-linked polyvinylpyrrolidone. J. Pharm. Sci, 62(1): 43 49 (1973) Kuchekar BS, Badhan AC and Mahajan HS, Mouth Dissolving Tablets: A Novel Drug Delivery System, Pharma Times. 35: 7-9 (2003) Pharmeuropa, European directorate for the quality of medicines. 10(1): 547 (1998) Rowe RC, Sheskey PJ and Weller P.J. Handbook of pharmaceutical excipients 4th ed, London: Pharmaceutical Press, pp. 373377 (2003)