PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES DEVELOPMENT AND CHARACTERIZATION OF TASTE

Transcription

1 PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES DEVELOPMENT AND CHARACTERIZATION OF TASTE MASKED, ORALLY DISINTEGRATING TABLET OF PIROXICAM Bhupendra G. Prajapati*, Rakesh P. Patel and Bhaskar C. Patel S.K.Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva , Mehsana, Gujarat State, INDIA. ABSTRACT Piroxicam is a Non-steroidal anti inflammatory, analgesic and anti-pyretic drug which is widely used in Musculo-skeletal disorder like osteoarthritis. Piroxicam has bad taste, half life of 30 hrs and poor water solubility. In the present work to develop taste masked orally disintegrating tablets of piroxicam, preformulation parameters like solubility, particle size, tapped density, bulk density,hausner ratio, Carr s compressibility index, angle of repose, and Differential scanning calorimetry study were performed. Out of twelve formulations (F-1 to F-12), F-11 formulation containing crospovidone XL 10 %, drug: polymer 1:0.35, aspartame 6% and sodium lauryl sulphate 0.5%, showed optimum characteristics of orodispersible tablet (ODT) of piroxicam with sufficient crushing strength (5.5 to 6.5 kp), friability (0.18%), wetting time (28 sec) and disintegration time (22 sec). In-vitro dissolution profile studies revealed that 82.3% drug was released within 5 min. The study concluded that crospovidone XL and Eudragit EPO can successfully be used as superdisintegrant and taste masking excipient respectively. Key words: Piroxicam, Orally disintegrating tablet, Eudragit EPO Crospovidone XL. INTRODUCTION Over a decade, the demand for development of orally disintegrating tablets (ODTs) has enormously increased as it has significant impact on the patient compliance. Orally disintegrating tablets offer an advantage for populations who have difficulty in swallowing. It has been reported that dysphagia [1] (difficulty in swallowing) common among all age groups and more specific with pediatric, geriatric population along with institutionalized patients and patients with nausea, vomiting, and motion sickness complications. [2] Recently, European Pharmacopoeia has used the term orodispersible 35

2 tablet for tablets that disperses readily and within 3 minutes in mouth before swallowing. [3] United States Food and Drug Administration (FDA) defined orally disintegrating tablet as A solid dosage form containing medicinal substance or active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon the tongue. Moreover, drug candidates that undergo pre-gastric absorption when formulated as orally disintegrating tablets may show increased oral bioavailability. [4] The key parameters that are to be considered in the process of formulating an orally disintegrating tablet are taste and the disintegration time. [5] Both of these are related either directly or indirectly to the oral cavity. Of the total oral mucosa, 15% of it consists of specialized mucosa, which is present on the dorsum of the tongue. It is mainly involved in identifying the taste of the formulation [6]. Saliva is mainly constituted by water (99.5% w/v) and the remaining 0.5% w/v is constituted by dissolved compounds [7]. The principal components of saliva are inorganic electrolytes (0.2% w/v), gases (CO 2, N 2, and O 2 ), nitrogen products, such as urea and ammonia, vitamin C, creatinine, and mucins. The accepted range of normal salivary flow is comprised from about 0.1 to 0.2 ml/min and reaches 7 ml/min upon stimulation [8]. Motion sickness is the uncomfortable dizziness, nausea, and vomiting that people experience when their sense of balance and equilibrium is disturbed by constant motion. Riding in a car, aboard a ship or boat, or riding on a swing all cause stimulation [9, 10, 11] of the vestibular system and visual stimulation that often leads to discomfort. EXPERIMENTAL Material Piroxicam was gifted from the Sifavittor, Italy. Mannitol, Sodium starch glycolate was purchased from the Roqutte pharma, Nasik India. Sodium lauryl sulphate was purchased from S.D. fine chemicals, Mumbai. Cross carmellose sodium was gifted from the FMC biopolymer, Shangai, China. Crospovidine XL was gifted from the ISP petrochemicals. Aspartame Fine grade, Nutra sweet, India and Magnesium stearate were gifted from the Dr. paul Lohman. Pipermint flavour was purchased from the Colorcon Pvt Ltd. Compatibility study (Differential Scanning Calorimetry analysis) 36

3 DSC study was carried out using DSC-60 instrument (M/s Shimadzu, Japan) to check the compatibility of ingredients. DSC thermo grams of pure drug (piroxicam), superdisintegrants Sodium starch glycolate, croscarmelllose sodium and crospovidone XL, Aspartame, mannitol and magnesium stearate were individually taken for their identical endothermic reaction. Finally physical mixture of all above ingredients was scanned for DSC. Formulation of ODT Sift all intragranular ingredients through 30#. Aspartame and magnesium stearate, extragranular ingredients, were passed through 30# and 60# respectively. Granulation was carried out with ethanol water mixture (80:20) for batches F6 to F12 and with methylene-chloride for batch F3. Purified water and ethanol were used for granulation in the batches as mentioned in Table 1. Granules were dried at 60 to 65 0 c for 20 to 30 minute for aqueous granulation and at room temperature for non-aqueous granulation. Dried Granules were sifted through 30#. Crospovidone XL and aspartame was added in dried granules and mixed. For batch F9 to F12, piroxicam and Eudragit EPO was properly mixed for partially coating of Eudragit EPO on drug. Magnesium stearate was added to above blend and mixed. The powder blend was compressed using 8mm 4mm breakline capsule shaped FFBE (flate faced beaveled edges) punch. Typical composition of formulations showed in Table 1. Evaluation parameters of prepared piroxicam ODT Evaluation of ODTs Uniformity of weight The weights of 20 tablets as well as individual tablet was carried out using mettler toledo PG-403 S. Crushing Strength A significant strength of ODT is difficult to achieve due to the specialized processes and ingredients used in the manufacturing. The limit of crushing strength for an ODT is usually kept in a lower range to facilitate early disintegration in the mouth. The crushing strength of the tablet may be measured using conventional hardness testers. 37

4 The crushing strength of the tablets was measured using Dr. Schleuniger pharmatron model SY hardness tester. [12] Friability Friability of the tablet was determined using Roche friabilator (Electrolab USP friabilator). This device subjects the tablet to the combined effect of abrasion and shock in a plastic chamber revolving at 25rpm and dropping a tablet at l height of 6 inches in each revolution. Preweighted sample of tablets was placed in the friabilator and were subjected to the 100 revolutions. Tablets were de-dusted using a soft muslin cloth and reweighed. The friability (F) is given by the formula. [12] % Friability W W W (1) Where, Wo is initial weight of tablets and W is weight after 100 revolutions. Table 1: Composition of Orally Disintegrating Tablets of Piroxicam * All ingredients are in milligram 38

5 Wetting time For measurement of wetting time five circular tissue papers of 10 cm diameter are placed in a petridish with a 10 cm diameter. Ten millimeters of water-containing Eosin, a water-soluble dye, is added to petridish. A tablet is carefully placed on the surface of the tissue paper. The time required for water to reach upper surface of the tablet is noted as a wetting time. [12] Modified disintegration test A petridish (10 cm diameter) was filled with 10 ml of water. The tablet was carefully put in the center of petridish and the time for the tablet to completely disintegrate into fine particles was noted. [13] In- vitro dissolution test Kancke proposed USP 2 Paddle apparatus, which is the most suitable and common choice for ODTs, with a paddle speed of 50 rpm. The release rate of piroxicam from orally disintegrating tablets was determined using USP dissolution testing apparatus 2 (paddle method, Electrolab, TDT-06T, Mumbai, India). The dissolution test was performed using 900 ml of 0.1 N HCl ( P H=1.2), at 37 ± 0.5 C and 50 rpm. A sample (10 ml) of the solution was withdrawn from the dissolution apparatus at 5, 10, 15, 20, 30, 45 and 60min. The samples were replaced with fresh dissolution medium of same quantity. The samples were filtered through a 0.45 µ membrane filter. Absorbance of these solutions was measured at 333 nm using a Shimadzu UV-1700 UV/Vis double beam spectrophotometer. Cumulative percentage of drug release was calculated using an equation obtained from a standard curve. [14] Taste Evaluation of ODT Taste evaluation was done using the time intensity method on 11 healthy human volunteers from whom informed consent was first obtained. The various Drug: polymer complexes (DPC) equivalent of 20 mg of Piroxicam was held in the mouth until complete disintegration, and 1 ODT (containing 20 mg Piroxicam) was held in the mouth until complete disintegration. Bitterness was recorded immediately and at several intervals for 15 minutes according to the bitterness intensity scale from 0 to 3 where 0, 0.5, 1, 2, and 3 indicate no, threshold, slight, moderate, and strong bitterness. [14] 39

6 RESULT AND DISCUSSION DSC curves obtained for pure piroxicam, SSG, croscarmellose sodium, crospovidone, mannitol, Aspartame, SLS, magnesium stearate and physical mixture of all ingredients were shown in Figure 1. Pure powdered piroxicam showed a sharp melting endotherm at C. DSC scan of mannitol, Aspartame, SLS showed sharp endotherm at C, C & C, C & C respectively due to melting whereas during scanning of SSG, croscarmellose sodium, crospovidone and magnesium stearate, melting endotherm at C, C, C, C and C were observed respectively. DSC thermograms of physical mixture of drug and excipients showed the melting peak of the drug at C and broad endothermic peak at C. Physical mixture of all above ingredients showed their identical peaks at defined temperature range. Presence of all peaks indicates that all ingredients are compatible with drug means there is no incompatibility between the selected ingredients. Figure 1 DSC thermograms of A-piroxicam, B-Crospovidone-XL, C-Mg.stearate, D-S.S.G, E- Croscarmellose sodium, F-Mannitol, G-Sodium lauryl sulphate, H-Aspartame, I-Physical mixture. 40

7 Genertal tablet evalaution parameter compiled in Table II and other evaluation parameters like disintegration time, wetting time, hardness, friability and % drug released and Avg.wt have shown in Table III. A (Initial) B (After Disintegration) Figure 2 Disintegration of piroxicam ODT. TABLE 2: RESULT OF EVALUATION OF TABLET BLEND OF BATCHES F1 TO F12 Powder Angle of Loose Tapped Bulk Carr s Hausner s blend Repose ( 0 ) Bulk Density Density(g/ml) Index (%) Ratio F1 31.3±0.01 (g/ml) 0.54± ± ± ±0.01 F2 33.0± ± ± ± ±0.02 F3 28.8± ± ± ± ±0.03 F ± ± ± ± ±0.02 F ± ± ± ± ±0.01 F ± ± ± ± ±0.02 F ± ± ± ± ±0.03 F ± ± ± ± ±0.03 F ± ± ± ± ±0.02 F ± ± ± ± ±0.01 F ± ± ± ± ±0.01 F ± ± ± ± ±0.01 * Mean ± SD and n=3 (in triplicate) 41

8 TABLE 3: EVALUATION PARAMETERS OF BATCHES F1 TO F12 Wetting Disintegration Hardness Friability Batch time time (sec) (kp) (%) (sec) Q 5 (%drug released) Avg.wt (mg) F1 10±1 12± ± ±1 60.3±1 F2 25±2 30± ± ±1 60.0±3 F3 30±1 35± ± ±2 60.1±1 F4 37±2 46± ± ±1 59.9±2 F5 42±3 51± ± ±3 61.0±1 F6 25±1 32± ± ±3 69.8±3 F7 28±2 35± ± ±2 70.4±1 F8 23±3 30± ± ±1 70.1±2 F9 120±1 150± ± ±2 80.1±2 F10 29±2 35± ± ±2 81.0±1 F11 25±1 31± ± ±1 80.4±2 F12 22±1 28± ± ± ±1 * Mean ± SD and n=3 (in triplicate) The power blends was evaluated for angle of repose, loose bulk density, tapped density, carr s index and hausner s ratio, which suggested the flow property of blend was found good. The optimization of formulation done based on trial and error method. Starting formulation composition was selected based on literature survey. Crospovidone XL was selected as superdisintegrant at 7%. The results of batch F1 showed disintegration time, 10 seconds and drug release 36.6±1% in 5 minutes period. To improve dissolution of formulation, next two batches was taken using, wet granulation method by changing the solvents like ethanol and methylene chloride (batch F2 and F3) respectively. Batch F2 and F3 showed improvement in drug release to almost double, 65.1% and 51.3% 42

9 respectively in 5 minutes (Table 3). This may because of recrystallization of drug in solvent taken for granulation. Further study was conducted using release modifier, 0.25% and 0.5% sodium lauryl sulphate in the formulation of batch F4 and F5 respectively. The results showed improvement in drug release to 71.5% and 87.6% at Q5 respectively, but there was a problem of disintegration time which was found to 37 sec and 42 sec respectively at same hardness of 4kp. Increase in the disintegration time may be due to SLS itself having high wetting time. SLS could not allow the tablet to disintegrate or break immediately. To overcome this problem, 3% crospovidone XL was added intragranularlly in rest of formulations. Along with this to get pleasant taste aspartame was added 1%, 3%, 4% intragranular and extragranular for next batches (F6 to F8). This modification had shown the improvement of disintegration time as well as taste. There was improvement in taste with 6% concentration of aspartame but concentration more than 6% was giving bitter after taste. Figure 3 Dissolution Comparison of Piroxicam ODT tablets batches F1 to F

10 Figure 4 Dissolution Comparison of Piroxicam ODT tablets of batches F6 to F8 Figure 5 Dissolution Comparison of Piroxicam ODT tablets batches F9 to F

11 The results of F5 batch showed disintegration time of 42sec and after addition of 3% crospovidone XL intragranular in batch F6, the disintegration time decreased to 25 second. The percentage of crospovidone XL was optimized as 3% intra and 7% extragranular, along with 6% aspartame for taste. The study of taste masking done on human volunteers who showed, formulation still persist bitter taste. Further study was done for taste masking using Eudragit EPO as taste masking agent. In this study, different ratio of drug:polymer have been selected 1:0.5, 1:0.25, 1:0.35, 1:0.35 for batch F9, F10, F11 and F12 respectively. Batch F11 and F12 contains the same ratio but both s weight are different. Batch F9 contains drug:polymer ratio of 1:0.5 had shown good results of taste evaluation by 11 healthy volunteers with comparision of other ratio of drug:polymer but it was having higher disintegration time of 120 second due to the excess coating of drug:polymer. So in next batchf10, drug:polymer ratio has been reduced to 1:0.25. The result shown that disitegration time was comparable but within this ratio satisficatory taste masking was not obtained. So, further study was carried out by using drug:polymer ratio 1:0.35 which showed acceptable evaluation of taste and desired disintegration time below 30 second (Table 3). The weight of formulatoin was increased to 100 mg from 80mg. All parameters were evaluated indicating no change even after dilution. CONCLUSION The present work concluded that orally disintegrating tablets can be formulated using superdisintegrants properly distributed in intragranular and extragranular part with suitable solvents used for granulation. Eudragit EPO was found to be a good candidate to mask the taste of bitter drug. A drug:eudragit EPO ratio (1:0.35) and optimum concentratin of disintegrant masks the bitter taste of the drug. REFERENCES 1. Lindgren S, Janzon L. Dysphagia: Prevalence of swallowing complaints and clinical finding: Med Clin North Am 1993; 77: Sastry SV, Nyshadham JR, Fix JA: Recent technological advances in oral drug delivery: A review. Pharm Sci Technol Today 2000; 3:

12 3. Fu Y, Yang S, Jeong SH, Kimura S, Park K: orally fast disintegrating tablets: Developments, technologies, taste-masking and clinical studies. Crit Rev Ther Drug Carrier Sys 2004; 21: Virely, P., & Yarwood, R: Zydis-a novel, fast dissolving dosage forms. Maniac. Chem. 1990; S.K.Battu, Michael A. Repka, Madhusudan Rao Y: Formulation and Evaluation of Rapidly Disintegrating Fenoverine Tablets Effect of Superdisintegrants, Drug Development and Industrial Pharmacy 2007; 33: Song, Y., Wang, Y., Thakur, R., Meidan, V. M., & Michniak, B: mucosal drug delivery: Membranes, methodologies, and applications. Crit. Rev. Ther. Drug Carrier Syst 2004; 21(3): Saracco G, C. E. In Dobrosielski-Vergogna (Ed.): Biology of the salivary glands Boca Raton: CRC Press. 1993; Rossi, S., Sandri, G., & Caramella, C: Buccal drug delivery: A challenge already won? Drug Discovery Today: Technologies 2005; 2(1): Lack, F. O: Maternal Susceptibility to Nausea and Vomiting of Pregnancy: Is the Vestibular System Involved?: American Journal of Obstetrics and Gynecology 2002; Supplement 5, 185:S204-S J. E., W. Bles, and B. de Graaf: Eye Movements to Yaw, Pitch, and Roll About Vertical and Horizontal Axes: Adaptation and Motion Sickness. Aviation, Space, and Environmental Medicine 2002; 73: Hamid, Mohamed and Nicholas Lorenzo: Dizziness, Vertigo, and Imbalance. emedicine 2002; September

13 12. Suresh Bandari, Rajendar Kumar Mittapalli, Ramesh Gannu and Yamsani Madhusudan Rao: Orodispersible tablets: An overview. asian journal of pharmaceutics. 2008; 2(1): Jyotsana Madan, AK Sharma, Ramnik Singh: Fast Dissolving Tablets of Aloe Vera Gel. Tropical Journal of Pharmaceutical Research 2009; 8(1): Shagufta Khan, Prashant Kataria, Premchand Nakhat, and Pramod Yeole: Taste Masking of Ondansetron Hydrochloride by Polymer Carrier System and Formulation of Rapid-Disintegrating Tablets. AAPS PharmSciTech 2007; 8(2): Article 46. For Correspondence: Bhupendra G Prajapati Assistant Professor, Department of Pharmaceutics and Pharmaceutical Technology, S.K. Patel College of Pharmaceutical Education & Research, Ganpat Vidyanagar, Kherva, Mehsana. bhupen_27@yahoo.co.in Phone and Fax No.: