INTRODUCTION:

Effervescent floating drug delivery systems generate gas (CO₂), thus reduce the density of the system and remain buoyant in the stomach for a prolonged period of time and released the drug slowly at a desired rate.^1,2,3 Amlodipine is long acting calcium channel blocker and used in the treatment of hypertension, and chronic stable angina. In hypertension or angina, initially 5 mg. one daily and adjusted to maximum dose 10 mg one daily dose of Amlodipine is given orally.⁴ Amlodipine has maximum solubility in acidic pH. Amlodipine has some adverse effect such as nausea, abdominal pain. Effervescent floating tablet of Amlodipine besylate retain in stomach improves solubility, bioavailability, reduces drug waste and decrease side effect such as gastric irritation and nausea.^{5, 6}

In present work, effervescent floating tablets of different formulation were developed with an objective of achieving 24 hrs floating and drug release time and the effervescent floating tablet was compared with marketed formulation of Amlodipine besylate for drug released time.

Experimental

Materials

Amlodipine besylate was procured from Signa Pharma Pvt. Ltd. Kanpur. HPMC K100 M, HPMC K15 M, Carbapol 934 p, Sodium biacarbonate, Citric acid, poly vinyl pyrrolidine and Talc were obtained from Colorcon Asia Pvt. Ltd and Loba chemicals. Amlosafe 10 (marketed brand of Amlodipine besylate) tablets were purchased from local market.

Methods

Effervescent Floating tablets containing Amlodipine besylate were prepared by direct compression technique using varying concentrations of different grades of polymers with Sodium bicarbonate and citric acid. All the ingredients were accurately weighed and passed through different mesh sieves accordingly. Then, except Magnesium stearate all other ingredients were blended uniformly in glass mortar After sufficient mixing of drug as well as other components, Magnesium stearate was added, as post lubricant, and further mixed for additional 2-3 minutes. The tablets were compressed using rotary tablet machine. The weights of the tablets were kept constant for all formulation.

Evaluation of effervescent floating tablet formulations

Hardness of the tablets was tested using a Monosanto hardness tester. Friability of tablets was determined in Roche friabilator. Ten tablets were selected randomly from each batch and weighed individually to check for weight variation. The results are given in table no. 2

Figure 1: In-vitro dissolution profile of formulations F 1 to F 9

Figure 2: In-vitro dissolution profile of optimized formulation (F 10)

Figure 3: Plot of cumulative percentage drug released vs. time of optimized formulation (F10) [Zero Order]

The buoyancy lag time (BLT) and total floating time (TFT)⁷

On immersion of tablets of different formulations in 0.1N HCl solution at 37±5°C, the tablets floated, and remained buoyant without disintegration, the results of the buoyancy lag time (BLT) and total floating time (TFT) were shown in Table 3.

Estimation of Amlodipine besylate⁸

Amlodipine besylate content in the tablets was estimated by using UV spectrophotometric method based on the measurement of absorbance at λ _max 239

Figure 4: Plot of log cumulative percentage drug retained vs. time of optimized formulation (F10) [First order]

Figure 5: Plot of cumulative percentage drug released vs. root time of optimized Formulation (F10) [Higuchi Matrix]

Figure 6: Plot of log cumulative percentage drug released vs. log time of optimized formulation (F10) [Korsmeyer and Peppas Model]

nm in phosphate buffer 7.4. Amlodipine besylate content of the tablets are given in Table 4.

Drug release study

In vitro release studies of F1 to F10 formulations and one brand of Amlodipine besylate were carried out in the dissolution test apparatus (USP Type II). The tests were carried out in 900 ml of dissolution media 7.4 pH buffers for 24 hrs at 50 rpm at 37±0.5°C 10 ml of the aliquot were withdrawn at different predetermined time intervals (0.5, 1,

Table 1: Composition of all the Formulations (F1 –F10)

Ingredient	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10
Amlodipine	10	10	10	10	10	10	10	10	10	10
HPMC K100M	---	100	---	50	---	100	100	100	110	125
HPMC K15M	100	---	---	100	100	---	50	50	40	40
Carbopol 934P	---	---	100	---	50	50	---	50	50	40
MCC	100	100	100	50	50	50	50	---	---	---
Sodium Bicarbonate	60	60	60	60	60	60	60	60	60	60
Citric Acid	30	30	30	30	30	30	30	30	30	30
Poly vinyl Pyrrolidine K30	10	10	10	10	10	10	10	10	10	10
Magnesium Stearate	10	10	10	10	10	10	10	10	10	5
Talc	5	5	5	5	5	5	5	5	5	5
Aerosil	5	5	5	5	5	5	5	5	5	5
Total weight	330	330	330	330	330	330	330	330	330	330

*All the quantities are in mg

Table 2: Hardness, Friability, Weight variation of tablets of different formulation F1 to F10

Formulation	Hardness (Kg/cm²)	Friability (%)	Weight Variation (mg)
F1	4.5 ±0.47	0.96	334±5%
F2	4.4 ±0.32	0.72	331±5%
F3	4.4 ±0.54	0.91	328±5%
F4	4.3 ±0.42	0.86	329±5%
F5	4.5 ±0.35	0.79	327±5%
F6	4.5 ±0.54	0.97	334±5%
F7	4.5 ±0.54	0.72	333±5%
F8	4.3 ±0.42	0.72	327±5%
F9	4.4 ±0.32	0.72	332±5%
F10	4.4 ±0.32	0.86	329±5%

*Values are mean± S.D

2, 4, 6, 8, 10, 12, 16, 20, 24 hr) and filtered. The required dilutions were made with and the solution was analyzed for the drug content by using UV detector detecting at λ _max 239 nm 10 ml of sample was replaced in the vessel after each withdrawal to maintain sink condition. From this percentage drug release was calculated and this was plotted against function of time to study the pattern of drug release. The in-vitro drug release profiles of tablet from each batch (F1 to F10) were shown in Table 5. The plot of cumulative percentage drug release versus time (hr) was plotted and depicted as shown in Figure 1 and 2

Analysis of release mechanism

In order to examine the release mechanism of Amlodipine besylate from the prepared floating tablets of the optimized formulation (F10), the results of the dissolution study was examined in accordance to the kinetic models. The regression coefficient R²value nearer to 1 indicated the model fitting of the release mechanism. The results are shown in Table 6 and Figure 3 to 6.

Comparison with marketed product:

The promising formulation (F10) as found by evaluation studies was compared with marketed product Amlosafe (Amlodipine besylate). The evaluation parameters tested and compared were drug content uniformity and in-vitro dissolution profile. The values of comparative in-vitro dissolution study of optimized formulation (F10) and marketed product are recorded in Table 7 and the result had come that the F10 formulation was sustained released as compare with Amlosafe tablet.

Figure 7: Plot of Comparative dissolution profile of optimized formulation (F10)

and marked product

Results and discussion:

Amlodipine is a potent drug for the treatment of angina, hypertension and also suitable in the treatment diabetic hypertension. Amlodipine had maximum solubility in acidic pH. Amlodipine has some adverse effect such as headache, nausea, abdominal pain. Prolonged gastric retention improves bioavailability, reduces drug waste and improves solubility for drugs that are less soluble in high pH environment. Effervescence production, decrease the several local GIT side effect, such as gastric irritation, nausea and gastritis.

The effervescent floating tablets of Amlodipine besylate were formulated in ten different batches F1 toF10 by using hydrophilic polymers HPMC K100M, HPMC K15M and hydrophobic polymer carbopol 934P along with effervescing agent sodium bicarbonate and citric acid. It was found that carbopol has a negative effect on floating behavior but it was used only for the drug release retardant characteristics. All the formulations were prepared by direct compression method. The prepared tablets of all the formulations were evaluated for physical characters like tablet hardness, friability, weight variation buoyancy lag time, total floating time, assay, in-vitro drug release. The main aim was to optimize the formulation for 24 hours in-vitro release and total floating time to more than 24 hours.

Table 3: Buoyancy Lag Time, Total Floating Time of formulations (F1toF10)

Formulation

Buoyancy Lag Time (Sec)

Total Floating Time (hrs)

F10

133 sec

130 sec

Fail

120 sec

102 sec

150sec

140sec

141sec

138sec

110sec

>12 hrs

>14 hrs

Fail

>16 hrs

>20hrs

>24hrs

The measured hardness of tablets of each formulation ranged between 4.1 to 4.5 kg/cm². The % friability was less than 1% in all the formulations ensuring that the tablets were mechanically stable. All the tablets passed weight variation test as the % weight variation was within the Pharmacopoeial limits of ±5% of the weight.

Buoyancy lag time (BLT) and total floating time (TFT) of different formulation were noted, where F1 BLT of 133 sec and TFT of >12 hours, F2 BLT of 130 sec and TFT of >14 hours, F3 fails to buoyancy because of absence of H P M C polymers, F4 BLT of 120sec and TFT of >16 hours, F5 BLT of 102 sec and TFT of >16 hours, F6 BLT of 150 sec and TFT of >20 hours, F7 BLT of 140 sec and TFT of >20 hours, F8 BLT of 141 sec and TFT of >24 hours, F9 BLT of 138 sec and TFT of >24 hours, F10 BLT of 110 sec and TFT of >24 hours, With reference to buoyancy studies results it can be concluded that the batch containing HPMC polymers showed good buoyancy lag time (BLT) and total floating time (TFT). Formulation F10 containing HPMC K15M, HPMC K100M and carbopol 934P showed good BLT of 110 sec and TFT of more than 24 hrs.

Amlodipine besylate release from the effervescent floating tablets was studied in phosphate buffer pH 7.4. The release profile of various formulations are shown in table no. Figure no. 1 and 2. Formulation F1 released 98.4% of the drug in 12 hours. Formulation F2 released 98.4% of the drug in 16 hours. Formulation F3 released 96.2% of the drug in 8 hours. Formulation F4 released 98.3% of the drug in 16 hours Formulation F5 released 98.7% of the drug in 16 hours Formulation F6 released 98.4% of the drug in 16hours.Formulation F7 released 98.3% of the drug in 16 hours. Formulation F8 released 98.8% of the drug in 20 hours. Formulation F9 released 98.4% of the drug in 20 hours. F10 released 98.6 % of drug in 24 hours. Thus F10 formulation was said to be optimized formulation.

Table 4: Drug Content Uniformity of Tablets of Batch F1 to F10

Batches	Drug content uniformity (%)
F1	97.01
F2	99.51
F3	98.01
F4	97.42
F5	98.41
F6	99.05
F7	99.05
F8	98.46
F9	98.45
F10	99.82

Optimized formulation F10 was subjected to curve fitting analysis, zero order, and first order, Higuhi Kinetics, Korsmeyer and Peppas model. The slope and r² are shown in Table 6 and graphs in Figure 3 to 6. Optimized formulation F10 fitted best for Korsemeyer – Peppas equation with R² value of 0.9959.

Comparison study with marketed product of Amlodipine besylate10mg (Amlodipine 10) showed that the optimized formulation F10 has better control over release rate in comparison to the commercial product. The marketed product released the drug 98.3% in 12 hours whereas the optimized formulation F10 released the drug 72.1% in 12hrs. And the optimized formulation F10 remained floatable in the stomach for 24 hours .and give the maximum released 98.6 at 24^th hours.

It is, thus concluded that effervescent floating tablet containing Amlodipine besylate (F10 formulation) gave slow and complete drug release spread over 24 hours.

Acknowledgment:

The authors are grateful to Centre for development action and community research (CDACR) for help in literature survey and procurement of drug sample.

Table 5: In-vitro drug release profile of tablets of F1 to F10

Time (hr)	Cumulative Percentage Drug Release
Time (hr)	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10
0.5	18.5	15.8	20.2	15.3	13.5	12.8	13.6	10.7	10.2	7.3
1.0	30.2	27.3	32.5	26.8	28.2	27.4	22.3	15.8	16.1	11.7
2.0	42.8	39.8	45.2	37.1	39.8	38.3	35.2	24.6	23.5	19.4
3.0	55.2	51.5	57.3	49.9	51.5	50.2	48.4	32.4	30.3	25.9
4.0	68.5	61.9	69.8	60.8	62.9	61.1	59.2	42.7	41.6	32.1
6.0	76.8	72.7	88.5	71.8	73.7	72.4	69.3	55.2	53.1	43.2
8.0	89.6	81.5	96.2	83.1	84.9	84.1	78.8	70.8	68.7	52.8
12.0	98.4	96.2		93.2	95.3	94.5	89.2	84.7	79.8	72.1
16.0		98.4		98.3	98.7	98.4	98.3	96.2	95.5	85.8
20.0								98.8	98.9	96.8
24.0										98.6

Table 6: Kinetic Release Data of Different Model for Optimized Formulation (F10)

Model	Slope	R²value
Zero order	4.2369	0.9528
First order	-0.729	0.9475
Higuchi	23.761	0.9924
Korsemeyer-Peppas model	0.6901	0.9959

Table 7: Comparative dissolution profile of optimized formulation (F10) and marketed product.

Time (hr)	Cumulative percentage drug release
Time (hr)	F10	Marketed product
0.5	7.3	15
1.0	11.7	25.01
2.0	19.4	40.3
3.0	25.9	65.42
4.0	32.1	66.04
6.0	43.2	70.8
8.0	52.8	92.0
12.0	72.1	98.3
16.0	85.8	-
20.0	96.8	-
24.0	98.6	-

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Received on 20.07.2008 Modified on 23.08.2008

Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008;Page 526-530

Figure 1: In-vitro dissolution profile of formulations F 1 to F 9

Ingredient

Total weight

Formulation

Table 3: Buoyancy Lag Time, Total Floating Time of formulations (F1toF10)

Batches

Table 5: In-vitro drug release profile of tablets of F1 to F10