Available online on www.ijarpb.com Research Article Received on 15/01/2013; Revised on 23/01/2013; Accepted on 27/01/2013; Fast Dissolving Tablets Of Pioglitazone Hydrochloride By Use Of Various Superdisintegrants Pavan K. Rawat*, Prakash B. Mote, Shailendra Singh K., Amarjit A. Salunke, Vivek B. Rajendra, Nityanand S. Zadbuke. 1 Shreya Life Sciences Pvt. Ltd. Aurangabad-431136 E-mail: prakashmote@gmail.com ABSTRACT The present investigations focus on formulation and evaluation of fast dissolving tablets (FDT) of Pioglitazone hydrochloride. To improve patient compliance, mouth dissolving tablets have emerged as an alternative to conventional dosage forms. Pioglitazone hydrochloride and Sulfonylurea are given in combination for treatment of type II Diabetes Mellitus for long term therapy. During this therapy, it is observed that there is uncontrolled increase of blood glucose level, and the drug undergoes hepatic metabolism. Therefore, fast dissolving tablets of Pioglitazone hydrochloride were prepared to overcome this unusual problem and to make use of the inherent advantages of the novel drug delivery system. The tablets were prepared by using direct compression method using superdisintegrants. Tablets containing Pioglitazone, croscarmellose, crospovidone, Indion 414. The tablets were evaluated for weight variation, hardness, % friability, wetting time, and disintegration time. KEYWORDS: Fast dissolving tablet, Pioglitazone, superdisintegrants. INTRODUCTION Diabetes mellitus is a chronic metabolic disorder characterized by high glucose concentration in blood, caused by Insulin deficiency, often combined with Insulin resistance. Pioglitazone hydrochloride is an oral hypoglycemic agent, which is a commonly prescribed drug for the treatment of patients with type II diabetes mellitus. Pioglitazone hydrochloride is a basic (pka = 12.06) which is practically insoluble in water and alkaline buffer solutions, but as per the Biopharmaceutical Classification System (BCS) Pioglitazone categorized as class II drug. The oral absorption is uniform, rapid and complete with a bioavailability of nearly 100% and an elimentation half-life of 3-7 hrs. Formulations for Pioglitazone hydrochloride for better control of blood glucose levels to prevent hypoglycemia enhance clinical efficacy and patient compliance. 1-2 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 (NDDS) aim to enhance safety and efficacy of drug molecules by formulating a convenient dosage form for administration and to achieve better patient compliance. One such approach is or dispersible tablet. Oral routes of drug 2011, IJARPB. All Rights Reserved 74
administration have wide acceptance up to 50-60% of total dosage forms. Solid dosage forms are popular because of ease of administration, accurate dosage, self-medication, pain avoidance and most importantly the patient compliance. One major drawback of this dosage forms for some patients, is the difficulty to swallow. Drinking Water plays an important role in swallowing of oral dosage forms. In absence of water there is inconvenience in swallowing conventional dosage forms such as tablet. For these reason, tablets that can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention. Fast dissolving tablets are also called as mouth dissolving tablets, melt-in mouth tablets, Orodispersible tablets, rapid melts, porous tablets, quick dissolving etc. Fast dissolving tablets are those when put on tongue disintegrate instantaneously releasing the drug which dissolves or disperses in the saliva the faster the drug into solution, quicker the absorption and onset of clinical effect. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than those observed from conventional tablets dosage form. The advantage of fast dissolving dosage forms are increasingly being recognized in both, industry and academics. 3 MATERIALS AND METHODS Table 1: Formulation of fast dissolving tablets of pioglitazone Hydrochloride Pioglitazone hydrochloride was received as a gift sample from Shreya Life Science Aurangabad. Croscarmellose Sodium, Crospovidone & Indion 414 were received as a gift sample from Hetero Pharma, Hyderabad. Pharmatose were received as a gift sample from Friesland food demo Ltd Mumbai. All other ingredients used were of research grade. PREPARATION OF PIOGLITAZONE HYDROCHLORIDE FAST DISSOLVING TABLETS Pioglitazone hydrochloride fast dissolving tablet was prepared by direct compression technique using varying concentration of superdisintegrants. Fast dissolving tablets were prepared using superdisintegrants addition. 4-5 Different ratio of Lactopress and Croscarmellose Sodium, Crospovidone & Indion 414 was used. The ratio giving the best disintegration time along with optimum hardness was chosen and tablets prepared by direct compression. The final formulations for preparation of fast dissolving tablet are given in table 1. All ingredients except Aerosil, Talc, Magnesium Stearate they are added in lubrication stage. Lubrication is done by adding aerosil-200, talc and magnesium stearate to dry mix followed by mixing for 5 min. Then the lubricated blend was compressed in 8 mm round flat punches. (Single station tablet compression machine, Cadmach, India) Sr. No Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 1 Pioglitazone HCl 30 30 30 30 30 30 30 30 30 2 Pharmatose (Lactose DCL 110) 70 75 80 70 75 80 70 75 80 3 Croscarmellose Sodium 15 10 5 - - - - - - 4 Crospovidone XL 10 - - - 15 10 5 - - - 5 Indion 414 - - - - - - 15 10 5 6 Aerosil 200 2 2 2 2 2 2 2 2 2 7 Magnesium Stearate 3 3 3 3 3 3 3 3 3 Total weight in mg 120 120 120 120 120 120 120 120 120 2011, IJARPB. All Rights Reserved 75
EVALUATION OF TABLETS 6-9 Hardness For each formulation, the hardness of 10 tablets was determined using the Monsanto hardness tester (Campbell Electronics, India). Thickness Tablet was selected at random from individual formulations and thickness was measured by using Vernier caliper scale, which permits accurate measurement. Tablet thickness should be controlled within a ± 0.5% variation of standard value. Weight variation test Weigh 20 tablets individually, calculate the average weight, and comparing the individual tablet weight to average weight. Not more than Calculation: 2 tablets are outside the percentage limit and if no more than two tablets are outside the percentage limit and if no tablet differs by more than two times the percentage limit then the test is passed. Friability Friability test is performed to assess the effect of friction and shocks, which may often cause tablet to chip cap or break. Roche friabilator was used for the Purpose. Preweighed sample of ten tablets were placed in the friabilator, which was then operated for 100 revolutions. After 100 revolutions the tablets were dedusted and reweighed. Calculate the percentage loss in weight as follows. (A-B) % Friability = x 100 % A Where, A = Initial weight of 20 tablets, B = Final weight of 20 tablets. Compressed tablets should not more than 1% of their weigh (USP-30 NF 2007). Disintegration Time The test was carried out on six tablets using water at 37 0 C ± 2 0 C as disintegration media and the time in second taken for complete disintegration of the tablet with no palable mass remaining in the apparatus were measured in seconds. Wetting time Five circular tissue paper of 10cm diameter were placed in a petridish with a 10cm diameter. 10 ml of simulated saliva ph (phosphate buffer ph 6.8) was poured into the tissue paper placed in the petridish. A tablet was placed carefully on the surface of the tissue paper. The time required for the solution to reach upper surface of the tablet was noted as the wetting time. Water absorption ratio The weight of the tablet before keeping in the petridish was noted (Wb). Fully wetted tablet from the petridish was taken and reweighed (Wa). The water absorption ratio R can be determined according to the following formula. R= (Wa Wb)/Wa x 100 In Vitro Dissolution Test: In vitro release studies were carried out using USP XXII dissolution test apparatus. Objectives in the development of in vitro dissolution tests were to observe, Release of the drug from the tablet is as close as possible upto 100% and Rate of drug release is uniform from batch to batch and is the same as the release rate from those proven to be bioavailable and clinically effective. RESULT AND DISSCUSSION In the present study, fast dissolving tablets of Pioglitazone Hydrochloride were prepared by using Pharmatose (Lactose DCL-110), 2011, IJARPB. All Rights Reserved 76
Croscarmellose sodium, Crospovidone & Indion 414 as superdisintegrants. These nine formulations were prepared by direct compression technique. The formulated granules were evaluated and the results are shown in the table 2. The angle of repose was in the range of 18.30±0.04 to 22.7±0.03 which was less than 25 indicating good flow property. The bulk density and tapped density was in the range of 0.51±0.01 to 0.59±0.01 gm/cc and 0.63±0.03 to 0.75±0.02 respectively. Carr s Index and Hausner ratio are lies in between 17.66 to 25.66 and 1.71±0.03 to 1.89±0.01 respectively. Table 2: Evaluation of Pioglitazone Hydrochloride Blend Formulation Angle of Bulk density Tapped Carr s Hausner Code Repose* (gm/cc)* density (gm/cc)* Index * Ratio* F1 20.5±0.01 0.54±0.02 0.74±0.03 21.42 1.81±0.02 F2 21.9±0.02 0.51±0.01 0.69±0.01 23.18 1.89±0.01 F3 22.5±0.02 0.54±0.02 0.75±0.01 21.12 1.78±0.02 F4 21.5±0.01 0.54±0.01 0.74±0.03 25.66 1.81±0.01 F5 22.7±0.03 0.59±0.01 0.73±0.01 21.12 1.78±0.03 F6 18.3±0.04 0.54±0.02 0.75±0.02 20.28 1.81±0.01 F7 20.9±0.01 0.54±0.01 0.71±0.01 19.44 1.71±0.03 F8 19.3±0.03 0.55±0.02 0.63±0.03 17.66 1.81±0.02 F9 22.6±0.01 0.56±0.02 0.65±0.01 25.00 1.85±0.01 * All value expressed as Mean ± S.D. (n=3) Table 3: Evaluation of Pioglitazone Hydrochloride fast dissolving tablets. Formulation Thickness(mm)* Hardness(kg/cm 2 ) Friability (%) Weight Variation Code (mg) F1 2.60±0.01 5.6 0.12 120 F2 2.50±0.02 5.6 0.25 120 F3 2.52±0.01 5.6 0.25 121 F4 2.60±0.02 5.6 0.30 122 F5 2.49±0.03 5.4 0.25 120 F6 2.49±0.01 5.4 0.30 121 F7 2.52±0.02 5.6 0.52 121 F8 2.52±0.01 5.6 0.60 122 F9 2.60±0.03 5.6 0.20 120 * All value expressed as Mean ± S.D. (n=3) Table 4: Evaluation of Disintegration Test, Wetting Time & Water Absorption Ratio Formulation Wetting Time* Disintegration Water Absorption Ratio % (Sec) time*(sec) F1 57±0.57 31.12 93±0.81 F2 64±1.15 29.97 102±0.47 F3 70±1.00 28.5 108±0.47 F4 54±0.50 26.68 70±0.81 F5 60±0.91 25.14 77±1.05 F6 64±1.15 23.31 86±0.81 F7 45±0.76 30.36 26±1.63 F8 52±0.85 28.97 38±0.94 F9 59±0.57 26.9 51±1.24 2011, IJARPB. All Rights Reserved 77
%Cumulative drug release Pavan K et al IJARPB: 2013, 3(2), 74-79 ISSN: 2277-6222 * All value expressed as Mean ± S.D. (n=3) Table 5: In vitro dissolution profile of formulation F1 to F9 % drug release F1 F2 F3 F4 F5 F6 F7 F8 F9 Time (min) 2 70.43 73.52 73.15 78.23 73.15 74.23 81.44 78.05 79.02 4 78.52 77.56 75.25 81.15 78.56 78.56 86.23 85.66 86.11 6 89.50 82.12 83.12 85.45 85.02 84.22 95.55 91.55 90.03 8 90.23 89.03 86.23 90.57 88.01 88.88 98.59 93.56 91.57 10 93.50 91.14 91.54 93.58 92.89 93.11 99.97 97.45 94.02 Cumulative % Drug Release of Pioglitazone HCl 100 80 60 40 20 0 0 2 4 6 8 10 Time (min) Fig. 1: Cumulative % Drug Release of Pioglitazone HCl F1 F2 F3 F4 F5 F6 F7 F8 F9 Precompression parameters like angle of repose, bulk density, tapped density; carr s index gave satisfactory results. Formulated Pioglitazone fast dissolving tablets gave desired results for various parameters such as hardness; friability indicated good mechanical strength of the all formulations. The formulated tablets showed compliance for various physiochemical parameters viz. tablet dimensions, weight variation, content uniformity and disintegration. Percentage of weight variations and drug content uniformity were found to be within the range (I.P) of all formulations. The in vitro studies revealed that formulation F7 showed maximum drug release as compared to other formulations. The water absorption ratio revealed that formulation F7 showed best wetting time results. On the basis of drug release disintegration and wetting studies it can be concluded that the formulation F7 is the optimum formulations. CONCLUSION In summary, it is concluded that the formulation of the Pioglitazone hydrochloride gives satisfactory results and by the use of superdisintegrants we achieved the Pioglitazone hydrochloride fast dissolving tablets. This study clearly demonstrated that one could develop fast dissolving tablets easily with superdisinegrants by using direct compression method. Tablets containing 2011, IJARPB. All Rights Reserved 78
Croscarmellose sodium, Crospovidone & Indion414 formulation F-7 had shown fastest disintegration. The study shows that the dissolution rate of pioglitazone can be enhanced to a great extent by combinations of superdisintegrants followed by direct compression technique. REFERENCES 1. C.Sadak Vali, Mohammad Rayees Ahmad1, Mitta Raghavendra. Formulation and evaluation of fast dissolving tablets of pioglitazone, Int.J.Adv.Pharm.Nano. 2011;1(2):60 63. 2. Indurwade NH, Rajyaguru TH, Nakhat PD. Novelapproach- fast dissolving tablets. Indian drugs, 39(8), 2002, 405-7. 3. Parul B. Patel Fast Dissolving Drug Delivery Systems: An Update, Pharmainfo.net 4(4), 2006. 4. Chang R, Guo X, Burnside B, Couch R. A review of fast dissolving tablets. Pharm Tech. (North America). June 2000;52-58. 5. In vitro Dissolution The united States Pharmacopoeia, United States Pharmacy convention. Asian edition, 2000, 1941-46. 6. Venkateswarlu BS, Margret Chandira R, Talele Ajay, Debjit Bhowmik, Chiranjib B. Jayakar, Sampath Kumar KP. Formulation Development and evaluation of Fast Dissolving Tablets of Carvedilol. J. Chem. Pharm. Res, 2(1), 2010, 196-210 196. 7. Suresh B, Rajendar KM, Ramesh G, Yamsani MR. Orodispersible tablets: an overview. Asian J Pharm. 2008;2:2.11. 8. Mizumoto T, Masuda Y, Kajiyama A, Yanagisawa M, Nyshadham JR. Tablets quickly disintegrating in the oral cavity and process for producing the same.2003 US Patent 6; 589.554. 9. Shirwaikar, Ramesh A. Fast disintegrating tablets of Atenolol by Dry Granulation method., IJPS. 2004; 66: 4, 422-426. 2011, IJARPB. All Rights Reserved 79