Research Paper Preparation and Evaluation of Rapidly Disintegrating Glimepiride Tablets

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1 122 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 211 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January March 211 Research Paper Preparation and Evaluation of Rapidly Disintegrating Glimepiride Tablets Adel M. Aly 1, Bassam I. Amro 2 and Feras D. El Hajji College of Pharmacy, King Khalid University, Abha, Saudi Arabia. 2 Faculty of Pharmacy, University of Jordan, Amman, Jordan. ABSTRACT: The objective of this work was to prepare Glimepiride (1 mg) rapidly disintegrating tablets (RDT) by direct compression, and also, to evaluate Pharmaburst as a newly introduced diluent for this type of tablets, either alone or in combination with other well known tablet excipients. Another goal was to study the stability, as well as, the in vivo effects of selected formulations. Orange flavor was the most preferred flavor for the prepared rapidly disintegrating tablets containing Pharmaburst as a single diluent. Pharmaburst alone is sufficient to produce rapidly (orally) disintegrating tablets of Glimepiride with good physical characteristics, better compactability and shorter in-vivo and in-vitro disintegration time. The prepared Glimepiride RDT were found to have faster onset of action than the conventional Glimepiride tablets. Also, they were effective in lowering fasting blood glucose levels (FBG) in rabbits. Glimepiride RDT containing Pharmaburst alone were found to be stable when subjected to accelerated stability conditions (4 C / 75 % relative humidity) for at least 3 months. Packaging the prepared Glimepiride RDT in 4 CC high density polyethylene (HDPE) bottles with 2 grams silica gel desiccant canisters and rayon had provided sufficient protection for the tablets. The used packaging system is believed to be very practical and convenient for elderly diabetic patients. It is also assumed to be preferred by the manufacturers. KEYWORDS: Glimepiride; Pharmaburst; Superdisintegrant; Rapidly disintegrating tablets Introduction With the increase in the average human life, drug administration for elderly patients has become more important. Due to a decline in swallowing ability with age, a great many elderly patients complain that it is difficult to take medication in the form of tablets (Mallet, Sugihara and Ito et.al.). Recently, useful dosage forms, such as rapidly disintegrating or dissolving tablets have been developed and applied clinically (Sallam et.al1998., Ishikawa et.al., 1999, Shu et.al., 22, Aly, 23, Abdelbary, 24, 25, Aly et.al., 25, and Oshima,et.al.,). This dosage form can also improve compliance in children (Fukmi et.al., 26), as well as, for local action within oral cavity as local anesthetics for toothache, cold sore, or teething product. Rapidly disintegrating tablets (RDT) may also be another option in emergency (Chue et.al., 24). Camphor sublimation method (Aly et.al., 25 Koizumi 1997) has been proved to be effective for the production of tablets of higher porosity. * For correspondence: Adel M. Aly, Tel: amaly5@yahoo.com. Taste is the deciding factor regarding compliance to this dosage form. Usually, low-compression force is applied to form a rapidly disintegrating tablets containing all or some of the following components: taste-masked active ingredient; if the drug has an unpleasant taste, diluents, sweetener, disintegrating agent, lubricant, glidant, flavor and coloring agent (Rathbone, et.al., 23). Presence of water-soluble materials improves taste and texture of the disintegrating tablets (Ishikawa, et.al., 1999, and Sunada, et.al., 22). Spray dried excipient base of mannitol and a superdisintegrant can be prepared for compression with the drug for faster disintegration time (Mishra, et.al., 26). Pharmaburst is a newly introduced polyols and mainly co-processed sugar alcohols (carbohydrates), with other materials (SPI Pharma newsletter, 22; Pharmaburst C1 COA, 23). Glimepiride is approved by the Food and Drug Administration (FDA) for once-daily use as monotherapy or in combination with insulin to lower blood glucose in diabetes mellitus by binding to β-cell ATP dependent potassium channel. It has a long duration of effect with a half-life of about 5 hours, allowing once daily dosing and therapy improving compliance (Katzung, 21). 122

2 Adel M. Aly et.al. : Preparation and Evaluation of Rapidly Disintegrating Glimepiride Tablets 1221 The main objective of this work was to prepare Glimepiride (1mg) rapidly disintegrating tablets by direct compression, and to evaluate Pharmaburst as a newly introduced diluent for this type of tablets, either alone or in combination with other well known diluent. Also, to study the physical properties of the prepared tablet formulations to select the most suitable formula for stability, as well as, in vivo study. Experimental Materials Glimepiride (USV Limited, India), Pharmaburst (polyols and mainly co-processed sugar alcohols,carbohydrates) C-1 (SPI Pharma), Mannitol (Mannogem ), Lactose monohydrate fast-flow, Lactose DCL 21, Sorbitol DC, Magnesium stearate, Aspartame, Crospovidone (Polyplasdone-XL and Polyplasdone-XL 1 ), Sodium starch glycolate (Primogel ), Croscarmellose sodium (AcDiSol ), Polacrilin potassium (Amberlite), lemon flavor, tutti-frutti flavor, orange flavor, golden syrup flavor, banana flavor, cherry flavor and strawberry flavor, and also, the packaging materials consisting of 4 CC high-density polyethylene (HDPE) bottles, 33 mm child resistant caps (CRC), rayon and 1 g silica gel canisters, as well as, Glorion 1mg tablets, were kindly obtained from Hikma Pharmaceuticals, Amman, Jordan. All other materials used in this study were of analytical grade. Methods Preparation of Glimepiride Tablets with Pharmaburst Aiming for the production of Glimepiride (1mg) tablets with acceptable taste and oral rapidly disintegrating properties seven flavors, namely; lemon, tutti-frutti, orange, cherry, strawberry, golden syrup, and banana flavors were tested for tablets including Pharmaburst as the single diluents. Glimepiride (1%) was mixed manually for two minutes with Pharmaburst and then sifted through 85μm mesh sieve. Aspartame (4%), magnesium stearate (2%) and flavor (2%) (seven formulas each contains one of the mentioned above flavours) were mixed for 1 minutes in a double cone blender (Erweka AR4, Germany), sifted through 85 μm mesh sieve and compressed into 1mg tablets on a rotary tablet press (Cadmach 16 stations, India) fitted with an octagon shape flat punch (8.6 X 6.1 mm). Glimepiride is an odorless drug, and was found tasteless at the used concentration (1 mg/tablet). Twenty five subjects (11 females and 14 males, 2 to 61 years old) examined the taste of each formula. For safety issues Glimepiride was substituted with 1 mg of the diluents in each formula. Evaluation scale was by describing the taste as excellent, good, acceptable, and bad (Table1). Another five tablet formulations containing the same ingredients but using different water-soluble diluents, 91%, namely; Sorbitol DC (A2), lactose monohydrate fast-flow (A3), lactose DCL 21 (A4), and mannitol (A5) in comparison with the previously prepared formula that includes Pharmaburst C-1 (A1). Orange flavor (2%) was added as it was the best according to the results of the taste examination performed. Moreover, another Glimepiride 1mg tablet formulae including Pharmaburst (76%) with different well known disintegrants (15%) namely; AcDiSol (B1), Primojel (B2), Polyplasdone XL (B3), Polyplasdone XL-1 (B4), or Amberlite (B5), were prepared applying the same previous procedures, in order to study the effect of their inclusion on the disintegration time. Table 1 The results of taste evaluation for Glimperide (1mg) tablets containing Pharmaburst Flavor Taste result Excellent Good Acceptable Bad Golden syrup Cherry Orange Banana Tutti-frutti Strawberry Lemon

3 1222 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 211 Evaluation of the Prepared Tablets Uniformity of Weight Twenty tablets taken randomly were weighed individually and the average weight, the standard deviation, and the coefficient of variation percent, C.V. %, were calculated according to the USP. The thickness of the prepared tablets was measured using thickness caliper (Mitutoyo CD- 15B, England) for 1 randomly selected tablets. Hardness and Friability The crushing strength (hardness) for randomly selected 1 tablets was measured by the hardness tester (Dr. Schleunger Pharmatron, Switzerland). The plunger speed was 2 mm/minute. It was aimed to fix the hardness of all tablets to be around 25 N. The friability test was performed for 2 tablets at 25 rpm for 4 minutes (European Pharmacopoeia, 26) using a friabilator (Erweka TA1, Germany), Disintegration Time Disintegration Time in the Oral Cavity The time required for complete disintegration of a tablet in the oral cavity, over the tongue (without allowing the tongue to move), was collected from six healthy volunteers administered each formula at 24 hours intervals. The end point is the exact time required for complete disintegration of the tested tablet (Abdelbary, et.al., 25). For safety issues Glimepiride was substituted with 1 mg of the diluent in each formula. Disintegration Time in the Disintegration time apparatus The test was performed by the disintegration time apparatus (Erweka ZT52, Germany) at 37 C, 8 ml water, on 6 tablets, separately. Wetting Time and Water Absorption Ratio A piece of tissue paper (Whatman number 1 filter paper 1.75 X 12. mm) folded twice was placed in small culture dish containing 6 ml of water. A tablet was placed on the paper and the time for complete wetting was measured. The tablet was weighed before and after wetting. Water absorption ratio was calculated using equation 1: R = 1(Wa-Wb) / Wb..(1) Where (Wb) and (Wa) are the weight before and after water absorption, respectively. The test was performed separately on 6 tablets of each formula. Drug Content Uniformity Tests Standard solution (.2 mg/ml) was prepared by accurately weighing 2 mg of Glimepiride dissolved in 1 ml solvent (Acetonitrile in water in 8: 2 ratio) by sonication for 15 minutes. Each sample solution (.2 mg/ml) was prepared by shacking 1 tablets individually with 5 ml solvent for 1 minutes then sonicated for 15 minutes then passing through.45 μm PTFE membrane filter. Each of the standard and sample solutions were injected to the HPLC system, using column (Venusil XBP) C18 1 A (25 X 4.6 mm), 5 μm. The flow rate was 1. ml/min; with a wavelength of 228 nm; and injection volume of 2 μm. The Mobile phase was prepared by mixing phosphate buffer solution (monobasic sodium phosphate (NaH 2 PO 4 ) and ortho-phosphoric acid) with equal volume of acetonitrile, and then ph was adjusted to 2.2 ±.5 with phosphoric acid. System suitability: The relative standard deviation (RSD) for five replicate injections of Glimepiride standard solution was not more than 2. %. Tailing factor for Glimepiride peak was not more than 2. The % concentration of glimipride was calculated according to the following equation 2: Assay (%) = Peak area of sample Concentration of standard 1% Peak area of standard Concentration of sample For content uniformity test the difference was only in sample solution preparation step. Assay linearity: Different concentrations of the standard were prepared and tested for HPLC peak area. Considering.2 mg/ml concentration of the standard sample of Glimepiride to be 1 %, other concentrations represent 25 %, 5 %, 75 %, and 2 % of standard. Each concentration point was correlated with its specific peak area, and linear correlation equals 1 was resulted, which prove the assay linearity. Stability Study The stability study of the prepared Glimepiride tablets was performed by exposing to accelerated stability conditions and detecting the physical and chemical changes on tablets. In addition, the suitability of the packaging system can be evaluated by filling 1 tablets per 4 CC HDPE bottle, and 2 g silica gel canisters were added to each bottle as desiccant. The neck space of the bottle was occupied by rayon to minimize mechanical stress on tablets during handling. Each bottle was then thermally sealed and capped by a 33 mm CRC cap. The bottles were charged into a stability chamber (Votsch, Germany) at 4 ± 2 C and 75 ± 5 % relative humidity. Samples were withdrawn after 1 and 3 months exposure. Tablets were evaluated physically by all the previously mentioned tests. In-vivo Study Experimental animals: French rabbits weighing between 1. and 2. Kg were involved in the study. The rabbits were maintained on commercial diet (with free water).

4 Adel M. Aly et.al. : Preparation and Evaluation of Rapidly Disintegrating Glimepiride Tablets 1223 They were acclimated to the laboratory conditions before carrying out any experimental work. The aim of the in-vivo study is to compare the glucose lowering (hypoglycemic) effect of the following three Glimepiride tablet formulations: 1. Glimepiride 1mg rapidly disintegrating tablet.. (Test). 2. Glimepiride 1mg conventional tablet (Glorion 1mg Hikma Pharmaceuticals) (Reference). 3. Placebo orally disintegrating tablet (Substituting the 1 mg Glimepiride in the test tablet with 1 mg Pharmaburst ).(Control). Study design: Twelve rabbits were involved in the experiment for each period. Three way cross-over study, consisting of 3 dosing periods, with 7 days washing out period between each were applied. They were randomly classified in into 3 groups, and each group includes 4 rabbits. Each group will administer different tablet every dosing period. Rabbits were fasted (with free water) for 12 hours before dosing. Half an hour before dosing, initial ( time) FBG was measured as an average of two readings. Dosing had always started at 8: AM. Tablet administration was carried out either by ingesting the whole reference tablet followed by 1 ml water, or by keeping the whole test or control tablet in the oral cavity of the rabbit, keeping the mouth closed with continuous checking till the tablet had completely disappeared (disintegrated / dissolved). Sampling time intervals were: 1:, 1:3, 2:, 2:2, 2:4, 3:, 3:3, 4:, 5:, and 6: hour after administration. Blood samples were taken from marginal ear vein of the rabbit, and blood glucose level (BGL) was determined by glucose dehydrogenase instrumental biochemical reaction (Accu-Check Active, Roche Diagnostics GmbH, Germany). Results and Discussion Taste Evaluation for Glimperide (1mg) Tablets Containing Pharmaburst Glimepiride is an odorless drug, and was found tasteless in the used amount (1 mg/tablet) and may not have an effect the tablets taste. Thus, it was preferred to exclude Glimepiride and perform the study on placebo tablets for the safety of the volunteers. The evaluation scale was from excellent to bad, passing through good and acceptable. According to the results represented in table1, orange flavor was considered excellent by 64 % of the volunteers, and it is the highest excellent result among other flavors, so, orange flavor is the most preferred flavor by the volunteers. The other flavors included in this survey can be arranged according to taste preference as follows: orange > strawberry > cherry > golden syrup > lemon, tutti-frutti > banana. Therefore, orange flavor will be used for the production of tablets for this study. Physical Properties Results of Glimepiride 1mg Tablets Containing Water Soluble Diluents The average thickness of the compressed tablets of formulae from A1 to A5 lies within the range of 1.97 to 2.29 mm (Table 2). The thickness of the prepared tablets were found to be thin and flat which are preferred for rapidly disintegrating tablet, to enable fast wetting by saliva and short disintegration time. Friability results showed that only tablets with Pharmaburst (A1) and tablets with Mannitol (A5) were acceptable while tablets of formulae A2, A3, and A4 were friable. Two approaches were followed to measure the disintegration time; the in-vivo (oral) disintegration time is the actual time during which the tablet disintegrates in the oral cavity, and the conventional disintegration time apparatus. The disintegration time results obtained for the five formulae (Figure 1) clearly indicate that formula A1 (with Pharmaburst) revealed the shortest disintegration time. Oral disintegration time is within the recommended time for this type of tablets (< 6 second). Tablets of A3 formula (with lactose fast-flow) also have disintegration time less than 6 seconds, but the time is longer than A1. Disintegration time results for the rest formulae (A2, A4, and A5) exceeded the 6 seconds limit for the two methods. Tablets of A4 (lactose DCL21) showed the longest disintegration time. This means that tablets with Pharmaburst are superior in disintegration time compared to the other tablet formulations. The relation between the oral disintegration time and the wetting time for tablets of group (A) is expressed in Figure 2. The wetting time for all tablets is always longer than oral cavity disintegration time. Tablets of A1 have the shortest wetting time, which means that Pharmaburst presents better hydrophilic and porous properties. Wetting time for Sorbitol tablets (A2) is extremely high, and also very high for lactose DCL21 tablets (A4). An inverse relationship could be observed between the oral disintegration time and water absorption ratio (Figure 2). It could be also, observed that tablets containing Pharmaburst (A1) showed the highest water absorption ratio with the most rapid disintegration time. This means that A1 tablets have comparatively the highest swelling capacity and are the most porous tablets. Glimepiride 1mg Tablets Containing Pharmaburst alone and with other Disintegrants The thickness values, represented in Table 2, were in the range of 2.12 to 2.38 mm thickness and also considered thin, i.e. promotes very rapid disintegration when in contact with water. Friability results show that tablets containing Pharmaburst and AcDiSol (B1), as well as,

5 1224 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 211 those of Pharmaburst and Amberlite (B5) were friable, while the others B2, B3, and B4 tablets are acceptable. Disintegration Time Results The used disintegrants, AcDiSol, primojel, polyplasdone XL and polyplasdone XL1 are considered superdisintegrants. Amberlite (polacrilin potassium) is considered a resin with good disintegration behavior (Sunada, et.al., 22). The relation between disintegration time results by each method of measurement for A1 and B1 to B5 formulae is presented in Figure 3. Disintegration time in the oral cavity for all tablets containing Pharmaburst is below 6 seconds. No significant improvement had occurred to oral disintegration time after inclusion of disintegrants. Disintegration time of B3 and B5 is slightly faster than A1, however, it was longer with B4, and the longest with B1 and B2 by about 2 seconds than A1. According to the oral disintegration time results, tablets can be arranged from the shortest to the longest time as: B5 < B3 < A1 < B4 < B1 < B2. Wetting time is longer than oral cavity disintegration time for all tablet formulations. The relation between the oral disintegration time and the wetting time is expressed in Figure 4. Table 2 Physical properties of Gliperide (1mg) tablets prepared with single diluents. Parameter Pharmaburst (A1) Sorbitol DC (A2) Lactose fastflow (A3) Lactose- DCL21 (A4) Mannitol (A5) Weight (mg ± SD) 98.6 ± ± ± ± ± 2.6 Thickness (mm ± SD) 2.21 ± ± ± ± ±.2 Hardness (N ± SD) 26.2 ± ± ± ± ± 3.9 Friability (%) Disintegration time in oral cavity (second ± SD) 23 ± 1 16 ± ± ± ± 7 In-vitro disintegration time(second ± SD) 1 ± 4 12 ± 1 51 ± ± ± 15 Wetting time (second ± SD) 75 ± 5 1,35 ± ± ± ± 2 Water absorption ratio (% ± SD) ± ± ± ± ± Disintegration time (second) Oral In vitro A1 A2 A3 A4 A5 Fig. 1 Disintegration time results for tablets containing Pharmaburst (A1), Sorbitol (A2), Lactose fast-flow (A3), Lactose DCL21 (A4), or Mannitol (A5).

6 Adel M. Aly et.al. : Preparation and Evaluation of Rapidly Disintegrating Glimepiride Tablets Oral disintegration time Wetting time Time (second) A1 A2 A3 A4 A5 Fig. 2 Oral disintegration time versus wetting time for formulae containing Pharmaburst (A1), Sorbitol (A2), Lactose fast-flow (A3), Lactose DCL21 (A4), or Mannitol (A5). Disintegration time (second) water absorption ratio (%) A1 A2 A3 A4 A5 Oral disintegration time Water absorption ratio Fig. 3 Oral disintegration time versus water absorption ratio for tablets containing Pharmaburst, (A1), Sorbitol (A2), Lactose fast-flow (A3), Lactose DCL21 (A4), or Mannitol (A5). 6 Disintegration time (second) Oral In vitro A1 B1 B2 B3 B4 B5 Fig. 4 Disintegration time results of tablets containing Pharmaburst alone (A1), with AcDiSol (B1), Primojel (B2), Polyplasdone XL(B3), Polyplasdone XL1 (B4), or with Amberlite (B5).

7 1226 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 211 Tablets containing highly swellable disintegrants (AcDiSol and primojel in B1 and B2 respectively) have the highest water absorption ratio. These results can give an explanation about disintegration action of Pharmaburst. It may suggest that Pharmaburst has a good disintegrating capacity by mainly two mechanisms: swelling and wicking action. From physical evaluation results for tablets with Pharmaburst and a disintegrating agent compared to tablets with Pharmaburst only, it seems that addition of disintegrants to aid lowering oral disintegration of Glimperide tablets containing Pharmaburst is of no significant advantage. Thus, formulating Glimepiride rapidly disintegrating tablets with Pharmaburst alone with no additional disintegrants are preferred, since powder compactability is almost the best, cost would be lower, and processing would be more practical. Chemical Evaluation Chemical evaluation was performed on Glimepiride 1 mg rapidly disintegrating tablets (with Pharmaburst, A1), and Glimepiride 1 mg oral conventional immediate release tablets- Glorion 1 mg tablets. Content Uniformity Test Assay results for content uniformity of rapidly disintegrating tablets was 1.2% (with RSD of 2.2). but for conventional tablets was 99.8% (with RSD of 1.7). The two formulations were acceptable (within the 9 11 %). Stability Study The stability of Glimepiride rapidly disintegrating tablets (containing Pharmaburst as single diluent A1) was studied in high density polyethylene (HDPE) bottles final package. Physico-chemical evaluation of the samples was performed. Chemical evaluation can assess the stability of Glimepiride active material in this dosage form that containing Pharmaburst. Packaging Glimepiride 1mg RDT in bottles is very practical and convenient. Filling tablets into bottles is the most preferred packaging process, because it is time saving and less expensive than others. Since the mechanical strength for the tablets studied for stability (A1) is very satisfactory, so filling the tablets in bottles would be easily applicable. For further mechanical protection on handling or transportation, rayon coil was added to fill the space over the tablets. Protection from moisture is generally very critical for drugs, especially for RDT. If high percent of moisture was absorbed by the RDT, this will lead to physical spoilage as tablet softening or disintegration, and chemical spoilage for the drug as enhanced degradation and decrease in assay. As a precaution, silica gel desiccants were added in the bottles to protect the tablets from moisture during shelf-life, and even after opening the bottle. More moisture protection is attained by sealing the bottle thermally. Taking into consideration that Glimepiride is an antidiabetic medicine, it is surely harmful for children. The child resistant cap used with this packaging system is assumed to provide avoidance of misuse of the drug by children. Physical Evaluation Physical results are summarized in Table 3. Upon studying the weight and thickness values for stability samples, it could be observed that results are very close and there is almost no change. Since the tablets did not gain weight upon exposure to the accelerated stability conditions, this means that the tablets did not absorb humidity. This is aided also by the unchanged thickness values. Hardness and friability results also are considered more or less the same as initial results. Thus, it could be concluded that the physical strength of Glimepiride RDT were kept upon exposure to the accelerated stability conditions up to 3 months. Table 3 Physical properties of Gliperide (1mg) tablets containing Pharmaburst with disintegrants. AcDiSol Primojel Polyplasdone Polyplasdone Amberlite Parameter (B1) (B2) XL (B3) XL1 (B4) (B5) Weight (mg ± SD) 11.2 ± ± ± ± ± 2.1 Thickness (mm ± SD) 2.26 ± ± ± ± ±.2 Hardness (N ± SD) 25.4 ± ± ± ± ± 4.5 Friability (%) Disintegration time in Oral cavity (second ± SD) 4 ± 5 46 ± 6 18 ± 5 33 ± 7 16 ± 2 In-vitro disintegration time (second ± SD) 17 ± 4 19 ± 3 11 ± 2 8 ± 3 1 ± 2 Wetting time (second ± SD) 25 ± ± ± 3 82 ± ± 16 Water absorption ratio (% ± SD) ± ± ± ± ± 7.4

8 Adel M. Aly et.al. : Preparation and Evaluation of Rapidly Disintegrating Glimepiride Tablets 1227 Figure 5 represents the relationship between the invitro disintegration, and the wetting time for the tablets initially and after stability study. For initial, 1 month and 3 months stability tablets, results are very close and no significant changes could be detected. Results of in-vitro conventional disintegration and wetting time are directly related to disintegration time in the oral cavity. Since no change had occurred to results of the tested parameters, oral disintegration time is not supposed to change. Hence, about 23 seconds is the expected disintegration time for Glimepiride 1 mg rapidly disintegrating tablet exposed to 4 C / 75 % relative humidity in its final package. The above prediction for oral disintegration time is also aided by the unchanged water absorption ratio for tablets after stability. Chemical Evaluation Chemical evaluation includes assay test and dissolution. Assay results for the one and three months stability tablets were 13.1 % and 98.7 %, respectively. There is no decrease in assay values for the glimepiride in the rapidly disintegrating tablets compared to initial reading (97.9 %). These results indicate that glimepiride is stable during three months of exposure to accelerated conditions. In-vivo Study Glimepiride 1mg was tested for in-vivo release from the prepared rapidly disintegrating tablet, conventional (Glorion 1mg) tablet and control (placebo tablets). The blood glucose concentration in rabbits was measured as an indication of the efficacy of Glimepiride tablets. Results of blood glucose values are presented in tables 4 and Figure 6. Analysis of variance (ANOVA) calculated (p-values) comparing the prepared Glimepiride RDT with the reference commercial (Glorion 1mg) for each time interval are mentioned in Table Oral disintegration time Wetting time Time (second) A1 B1 B2 B3 B4 B5 Fig. 5 The relation between oral disintegration time and wetting time of tablets containing Pharmaburst alone (A1) or with AcDiSol (B1), Primojel (B2), Polyplasdone XL(B3), Polyplasdone XL1 (B4), or with Amberlite (B5). Table 4 Physical properties of tablets containing Pharmaburst alone (A1) Time Parameter Initial (A1) 1 Month 3 Months Weight (mg ± SD) 98.6 ± ± ± 3.4 Thickness (mm ± SD) 2.21 ± ± ±.7 Hardness (N ± SD) 26.2 ± ± ± 5.8 Friability (%) In-vitro disintegration time 1 ± 4 1 ± 4 14 ± 3 Wetting time (second ± SD) 75 ± 5 74 ± 8 73 ± 16 Water absorption ratio (% ± SD) ± ± ± 1.4

9 1228 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 211 Blood Glucose Concentration (m g/dl) Test Reference Control Time (hour) Fig. 6 Rabbits blood glucose concentration in mg/dl for test, reference, and control, vs. time. Table 5 Blood glucose concentration (mg/dl) for the tested Glimepiride 1 mg tablet formulation Time (hr). Glimepiride with Pharmaburst tablets (1) Mean (mg/dl) SD Glimepiride (Glorion 1mg) tablet (2) Mean (mg/dl) SD Control (placebo) Mean (mg/dl) Tablets (3) SD p-values between (1) and (2) : a : b :3 64. c : d : d : c : 4.42 c : a : b : 36.92c : 36.8 c Considerable reduction in blood glucose levels for both the prepared and reference formula after 1 hour with p-values of.7 reduced to.3 after.5hour and nearly less than.5 at all the tested time intervals. This indicates that significant difference between the prepared and the commercial conventional tablets. Thus, it could be concluded that the prepared Glimepiride rapidly disintegrating tablets is considerably more efficient in lowering blood glucose than reference (conventional tablets) especially during the first two hours. The faster disintegration of the Glimepiride RDT may be the actual reason for faster onset of action and more effective in lowering fasting blood glucose levels (FBG) in rabbits.

10 Adel M. Aly et.al. : Preparation and Evaluation of Rapidly Disintegrating Glimepiride Tablets 1229 Conclusion Glimepiride RDT containing Pharmaburst alone were found to have faster onset of action than the conventional Glimepiride tablets. Also, they were effective in lowering fasting blood glucose levels (FBG) in rabbits. The prepared Glimepiride RDT were found to be stable when subjected to accelerated stability conditions (4 C / 75 % relative humidity) for at least 3 months. Packaging the prepared Glimepiride RDT in 4 CC HDPE bottles with 2 g silica gel desiccant canisters and rayon had provided sufficient protection for the prepared Glimepiride RDT tablets. Acknowledgments The authors wish to thank Hikma Pharmaceuticals, Amman, Jordan for the supplying of most of the utilized materials and reagents. References Abdelbary, G., Eouani, C., Prinderre, P., Joachiom, J., Reynier, J. P., and Piccerelle, P., Determination of the in vitro disintegration profile of rapidly disintegrating tablets and correlation with oral disintegration. International Journal of Pharmaceutics. 292, 29-41(25). Abdelbary, G., Prinderre, P., Eouani, C., Joachiom, J., Reynier, J. P., and Piccerelle, P., The preparation of orally disintegrating tablets using a hydrophilic waxy binder. International Journal of Pharmaceutics. 278, (24). Aly AM, Semreen M., and. Qato MK. Superdisintegrants for Solid Dispersion to produce Rapidly Disintegrating Tenoxicam Tablets via Camphor Sublimation; Pharmaceutical Technology,29(1):68-75,(25). Aly AM., Preparation of Rapidly Disintegrating Ketorolac Tromethamine Tablets by Direct compression and Lyophilizaion, Arab Journal of Pharmaceutical Sciences, 2 (4):47-6 (23). Chue P., Welch R., and Binder C., Acceptability and disintegration rates of orally disintegrating Risperidone tablets in patients with Schizophrenia or Schizoeffective disorder. Canadian Journal of Psychiatry. 49 (1): 71-73(24). Fukami J., Yonemochi E., Yoshihashi Y., and Terada K., Evaluation of rapidly disintegrating tablets containing glycine and carboxymethylcellulose, International Journal of Pharmaceutics, 31 (1):11-19(26). Ishikawa T., Watanabey Y., Utoguchi N.and Matsumoto M. Preparation and evaluation of tablets rapidly disintegrating in saliva containing bitter-taste-masked granules by the compression method. Chem Pharm Bull, 47(1): (1999). Ito A. and Sugihara M. Development of oral dosage form for elderly patients: use of agar as base of rapidly disintegrating oral tablets. Chem Pharm Bull, 44(11): (1996). Katzung BG., Basic & Clinical Pharmacology. Eighth edition (International edition). New York: Lange Medical Books / McGraw-Hill Companies, Inc., Medical Publishing Division. (21). Koizumi KI., Watanabe Y., Morita K., Utoguchi N., and Matsumoto M..New method of preparing high- porosity rapidly saliva soluble compressed tablets using mannitol with camphor, a subliming material. International Journal of Pharmaceutics, 152: (1997). Mallet L. Caring for the elderly patient. J Am Pharm Assoc, 36(11): 628 (1996). Mishra DN, Bindal M., Singh SK., and Vijaya Kumar SG., Spray Dried Excipient Base: A Novel Technique for the tion of Orally Disintegrating Tablets. Chemical and Pharmaceutical Bulletin. 54 (1):99 12 (26). Oshima T., Sonoda R., Ohkuma M., Sunada H. Preparation of rapidly disintegrating tablets containing itraconazole solid dispersions. Chemical & pharmaceutical bulletin, 55 (11): (27). Rathbone M., Hadgraft J., and Robert M., Modified-release Drug Delivery Technology. Marcel Dekker Inc., New York and Basel (23). Sallam E., Ibrahim H.,. Dahab RA, Shubair M., and Khalil E. Evaluation of fast disintegrants in terfenadine tablets containing a gas-evolving disintegrant. Drug Dev Ind Pharm, 24(6):51-57 (1998). Shu T., Suzuki H., Hironaka K., and Ito K. Studies of rapidly disintegrating tablets in the oral cavity using co-ground mixtures of mannitol with crospovidone. Chemical & pharmaceutical bulletin, 5 (2): (22). Sugihara M.. New oral dosage form for elderly patient. Chem Pharm Bull, 43(12): (1995). Sunada H.., and Bi Y., Preparation, evaluation and optimization of rapidly disintegrating tablets. Powder Technology. 122: (22)