INTRODUCTION:

The oral route is considered as the most promising route of drug delivery. Effective oral drug delivery may depend upon the factors such as gastric emptying process, gastrointestinal transit time of dosage form, drug release from the dosage form and site of absorption of drugs. Most of the oral dosage forms possess several physiological limitations such as variable gastrointestinal transit, because of variable gastric emptying leading to non-uniform absorption profiles, incomplete drug release and shorter residence time of the dosage form in the stomach. This leads to incomplete absorption of drugs having absorption window especially in the upper part of the small intestine, as once the drug passes down the absorption site, the remaining quantity goes unabsorbed. The gastric emptying of dosage forms in humans is affected by several factors because of which wide inter- and intra-subject variations are observed. Since many drugs are well absorbed in the upper part of the gastrointestinal tract, such high variability may lead to non-uniform absorption and makes the bioavailability unpredictable.

Hence a beneficial delivery system would be one which possesses the ability to control and prolong the gastric emptying time and can deliver drugs in higher concentrations to the absorption site (i.e. upper part of the small intestine).

The identification of new diseases and the resistance shown towards the existing drugs called for the introduction of new therapeutic molecules. In response, a large number of chemical entities have been introduced, of which some have absorption all over the gastrointestinal tract (GIT), some have absorption windows (i.e. absorption sites, especially the upper part of the small intestine) and some drugs have poor solubility in intestinal media. The drugs belonging to the second and third categories, and the drugs which are required for local action in the stomach, require a specialized delivery system. All the above requirements can be met and effective delivery of the drugs to the absorption window, for local action and for the treatment of gastric disorders such as gastro-esophageal reflux, can be achieved by floating drug delivery systems (FDDS).

The hydrodynamic balanced system (HBS) also called Floating drug delivery system (FDDS) is an oral dosage form (capsule or tablet) designed to prolong the residence time of the dosage form within the GIT. It is a formulation of a drug with gel forming hydrocolloids meant to remain buoyant in the stomach contents. Drug dissolution and release from the dosage form retained in the stomach fluids occur at the pH of the stomach under fairly controlled conditions. The retentive characteristics of the dosage form are not significant for the drugs that:

· Are insoluble in intestinal fluids

· Act locally

· Exhibit site-specific absorption.

The formulation of the dosage form must comply with three major criteria for HBS.

· It must have sufficient structure to form a cohesive gel barrier.

· It must maintain an overall specific gravity less than that of gastric content.

· It should dissolve slowly enough to serve as a “Reservoir” for the delivery system^1-8.

Simvastatin is a hypolipidemic drug belonging to the class of pharmaceuticals called "statins". It is used to control hypercholesterolemia (elevated cholesterol levels) and to prevent cardiovascular disease. The half-life is 3 hours⁹. It is well adsorbed from the GIT. In the present work, an attempt has been made to formulate GFDDS of Simvastatin using hydroxyl propyl methyl cellulose of different viscosity grades in order to prolong the drug release, and to impart floating properties of the sustained release tablet formulations.

MATERIALS AND METHODS:

Simvastatin was obtaind as gift sample from Cipla Pharmaceuticals, Goa. b-Cyclodextrin were gift sample from SA Pharmachem Pvt. Ltd., Mumbai, Methanol were gift sample from Renkem,Ranbaxy chem.,S.A.S.Nagar. Dichloromethane were procured from Research Labs, Mumbai. Polyvinylpyrrolidone-K-30 was procured from West coast laboratories. Polyethylene glycol-4000 were procured from Genuine chemical Co., Mumbai and Hydroxypropylmethyl cellulose were procured from SD Fine chemical, Mumbai.

Procedure for preparation of HBS of Simvastatin:

All the ingredients were accurately weighed and pass through sieve No. 60. In order to mix the ingredients thoroughly, drug and polymer were blended in a mortar for 15 minutes, then Microcrystalline Cellulose (MCC), sodium bicarbonate, lactose, citric acid, talc and magnesium stearate were mixed one by one. After thoroughly mixing these ingredients, the powder blend was passed through sieve no. 44.

Tablets were compressed on a rotatory punching machine (Clit pilot press) using flat surfaced, round shaped punches of 9mm diameter. Hardness of the tablet was maintained around 4.3 to 5.0kg/cm².

Evaluation of HBS of Simvastatin:

Evaluation of Simvastatin granules:

The flow properties of granules (before compression) were characterized in terms of angle of repose⁹, tapped density, bulk density¹⁰, Carr’s index¹¹ and Hausner ratio.

Physical evaluation of Simvastatin floating tablets:

Hardness test: The crushing strength (Kg/cm²) of tablets was determined by using Monsanto hardness tester. In all the cases, means of six replicate determinations were taken. The results are given in table-4

Friability test: This was determined by weighing 10 tablets after dusting, placing them in the friabilator and rotating the plastic cylinder vertically at 25 rpm for 4 min. After dusting, the total remaining weight of the tablets was recorded and the percent friability was calculated.

The results are given in table-4.

Uniformity of weight: The weight (mg) of each of 20 individual tablets was determined by dusting each tablet off and placing it in an electronic balance. The weight data from the tablets were analyzed for sample mean and percent deviation. The results are summarized in table-4.

Uniformity of drug content: 5 tablets were powdered in a glass mortar and 100 mg of powder was placed in a 100 ml stoppered conical flask. The drug was extracted with 0.1N HC1 with vigorous shaking on a mechanical gyratory shaker (100 rpm) for 5 hour and filtered into 50 ml volumetric flask through cotton wool and filtrate was made up to the mark by passing more 0.1N HCI through filter, further appropriate dilution were made and absorbance was measured at nm 237.8nm against blank. The results are given in table-4.

Determination of swelling index:¹²

The swelling index of tablets was determined in 0.1N HCl (pH 1.2) at room temperature. The swollen weight of the tablet was determined at predefined time intervals over a period of 24 h. The swelling index (SI), expressed as a percentage, and was calculated from the following equation

SI = Weight of tablet at time (t) – Initial weight of tablet x 100

Initial weight of tablet

In vitro floating studies: In vitro floating studies were performed for all the fifteen formulations as per the method described by Rosa et al¹³. The randomly selected tablets from each formulation were kept in a 100ml beaker containing simulated gastric fluid, pH 1.2 as per USP. The time taken for the tablet to rise to the surface and float was taken as floating lag time (FLT). The duration of time the dosage form constantly remained on the surface of medium was determined as the total floating time (TFT). The results are given in table-5.

In vitro dissolution studies: In vitro dissolution studies of HBS of Simvastatin were carried out using USP XXIII tablet dissolution test apparatus-Il (Electrolab), employing a paddle stirrer at 50 rpm using 900m1 of 0.1N HC1 at 37±0.5°C as dissolution medium. One tablet was used in each test. At predetermined time intervals 5ml of the samples were withdrawn by means of a syringe fitted with a pre filter. The volume withdrawn at each interval was replaced with same quantity of fresh dissolution medium maintained at 37±0.5°C. The samples were analyzed for drug release by measuring the absorbance at 237.8 nm using UV-Visible spectrophotometer after suitable dilutions. All the studies were conducted in triplicate.

The results of in vitro release profiles obtained for all the HBS formulations were fitted into four models of data treatment as follows

1. Cumulative percent drug released versus time (zero-order kinetic model).¹⁴

2. Log cumulative percent drug remaining versus time. (first-order kinetic model).¹⁵

3. Cumulative percent drug released versus square root of time (Higuchi’s model).¹⁶

4. Log cumulative percent drug released versus log time (Korsmeyer-Peppas equation)^.17

Stability studies: Short-term stability studies were performed at a temperature of 45° ±1°C over a period of three weeks (21 days) on the promising HBS tablet formulation F10. Sufficient number of tablets (15) were packed in amber colored screw capped bottles and kept in hot air-oven maintained at 45°±1°C. Samples were taken at weekly intervals for drug content estimation. At the end of three weeks period, dissolution test and in vitro floating studies were performed to determine the drug release profiles, in vitro floating lag time and floating time.

RESULTS AND DISCUSSION:

In the present study, Hydrodynamically Balanced Systems of Simvastatin were prepared by using different viscosity grades of Hydroxy propyl methyl cellulose (HPMC), viz, K4M, K15M and K100M (4,000, 15,000 and 1,00,000cps respectively) at different drug to polymer ratio with or without gas generating agent like sodium bicarbonate and citric acid. Two different diluents used are lactose and MCC. (Table-1 and 2)

Drug – Polymer ratios for the preparation of HBS Simvastatin

Table-1: Preliminary Trial Formulation (for 1 tablet)

Ingredient (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
Simvastatin	10	10	10	10	10	10	10	10	10
HPMC K4M	95	120	153	-	-	-	-	-	-
HPMC K15M	-	-	-	95	120	153	-	-	-
HPMC K100M	-	-	-	-	-	-	95	120	153
MCC	50	50	-	50	50	-	50	50	-
Sodium bicarbonate	48	53	60	48	53	60	48	53	60
Lactose	-	-	50	-	-	50	-	-	50
Citric acid	-	-	-	-	-	-	-	-	-
Magnesium stearate	4	4	4	4	4	4	4	4	4
Talc	3	3	3	3	3	3	3	3	3

The weighed quantities of drug and polymers were mixed thoroughly in different ratios (1:9.5, 1:12 and 1:15.3) and HBS tablets were prepared by direct compression method. The prepared HBS tablets were evaluated. The prepared tablets of all the formulations were evaluated for precompression parameters like angle of repose, bulk and tapped density and compressibility index and physical characters like tablet hardness, friability, weight variation, buoyancy lag time, total floating time, Swelling index, in-vitro drug release.

Pre-compression parameters of Simvastatin granules

The formulations showed good flow property and compressibility index (Table 3). Angle of repose ranged from 20.48 to 26.40, Hausner ratio ranged from 1.11 to 1.16 and the compressibility index ranged from 10.52 to 14.04. The BD and TD of the prepared granules ranged from 0.39 to 0.55 and 0.49 to 0.64 respectively. The results of angle of repose indicates good flow property of the granules and the value of compressibility index further showed support for the flow property. Given in table 3.

Table-2: Final Formulation (for 1 tablet)

Ingredient (mg)	F10	F11	F12	F13	F14	F15
Simvastatin	10	10	10	10	10	10
HPMC K4M	153	153	153	153	153	153
HPMC K15M	-	-	-	-	-	-
HPMC K100M	-	-	-	-	-	-
MCC	-	50	50	50	50	50
Sodium Bicarbonate	80	60	80	60	80	60
Lactose	50	-	-	-	-	-
Citric acid	-	-	-	10	20	30
Magnesium stearate	4	4	4	4	4	4
Talc	2	2	2	2	2	2

Post compression parameters of Simvastatin tablets:

Hardness and friability: The hardness of the prepared HBS of Simvastatin was found to be in the range of 4.3 to 4.7 kg/cm² and is given in table 4. The friability of all the tablets was found to be less than 1% i.e. in the range of 0.57 to 0.93 given in table 4.

Uniformity of weight: All the prepared HBS were evaluated for weight variation and the results are given in tables 4. The percent deviation from the average weight was found to be within the prescribed official limits.

Uniformity of drug content: The low value of standard deviation indicates uniform drug content in the tablets prepared as observed from the data given in table 4.

Invitro floating studies: Invitro floating studies were performed by placing tablet in USP XXIII dissolution apparatus-II containing 0.1N HCl, maintained at temperature of 37±0.5°C. The floating lag time and floating time was noted visually. The results are given in table 5.

In the initial HBS formulations of Simvastatin, formulation containing drug and different viscosity grades of HPMC with gas generating agent (F1 to F9), the floating lag time was found to be in between 2 seconds to 12 seconds and remained under floating conditions for 24hours.

Formulations containing lactose along with a gas generating agent sodium bicarbonate at varying concentrations (F10 containing 50mg per tablet has shown a floating lag time of 10 seconds remained floating for 24 hours. HBS formulations containing MCC along with sodium bicarbonate at varying concentrations (F11, F12, F13, F14 and F15) the floating lag time was found to be in between 6 seconds to 24 seconds and remains under floating condition for 24 hours.

Table 3: Pre-compression flow properties of granules of Simvastatin

Formulation code	Angle of repose(θ) in degrees	Bulk density (gm/cm3)	Tapped density (gm/cm3)	Carr’s index (%)	Hausner ratio (HR)
F1	26.40	0.49	0.57	14.04	1.16
F2	25.06	0.48	0.55	12.72	1.14
F3	23.38	0.46	0.53	13.20	1.15
F4	22.72	0.43	0.49	12.24	1.14
F5	20.94	0.41	0.47	12.76	1.14
F6	20.48	0.39	0.44	11.36	1.12
F7	25.26	0.55	0.64	14.06	1.16
F8	24.74	0.53	0.61	13.11	1.15
F9	23.02	0.50	0.58	13.79	1.16
F10	22.51	0.49	0.56	12.50	1.14
F11	21.68	0.47	0.54	12.96	1.15
F12	20.82	0.46	0.53	13.20	1.15
F13	26.02	0.49	0.56	12.50	1.14
F14	24.07	0.49	0.55	10.90	1.12
F15	23.54	0.51	0.57	10.52	1.11

Table–4: Physical properties of HBS formulations F1 to F15

Formulation code	Diameter (mm)	Thickness (mm)	Hardness (kg/cm²)	Friability (%)	*Weight variatio (mg)**	Percent drug content^* ± SD
F1	9	2.65	4.6±0.5	0.59	204.95	98.49±0.001
F2	9	2.73	4.3±0.9	0.65	235.65	99.2±0.002
F3	9	2.87	4.9±0.3	0.70	274.70	99.36±0.01
F4	9	2.67	4.5±0.6	0.55	205.60	99.78±0.006
F5	9	2.77	4.5±0.8	0.71	236.55	99.92±0.017
F6	9	2.89	4.7±0.7	0.72	275.20	100.10±0.02
F7	9	2.64	4.6±0.3	0.58	205.25	100±0.46
F8	9	2.71	4.5±0.5	0.69	235.15	98.82±0.65
F9	9	2.86	4.8±0.9	0.57	275.25	99.68±0.75
F10	9	3.55	4.5±0.5	0.85	294.85	100±0.65
F11	9	3.68	4.5±0.2	0.75	274.70	99.28±0.53
F12	9	3.60	4.5±0.4	0.77	295.15	99.31±1.15
F13	9	3.70	4.6±0.3	0.91	286.40	99.78±0.77
F14	9	3.65	4.5±0.1	0.93	315.50	100±1.03
F15	9	3.76	4.5±0.4	0.86	306.65	100.17±0.83

The floating lag time was found to be more in the formulations which contains less gas generating agent (sodium bicarbonate) in the HBS formulations which may be due to delayed swelling of the polymer.

Table-5: In vitro floating of HBs of Simvastatin

Formulation code	Floating lag time (Seconds)	Floating time (hrs)
F1	10	24
F2	4.5	24
F3	2	24
F4	9	24
F5	6	24
F6	4	24
F7	8	24
F8	7	24
F9	5	24
F10	10	24
F11	11	24
F12	6	24
F13	24	24
F14	20	24
F15	15	24

It was observed that when an optimum concentration of sodium bicarbonate was used, there was a reduction in the floating lag time, where the dissolution medium was imbibed into the matrix, the interaction of acidic fluid with sodium bicarbonate resulted in the formation and entrapment of CO₂ gas within the swollen gel, thus causing floating as the matrix volume expanded and its density decreased.

Reduction in the floating lag time was observed by the addition of citric acid along with sodium bicarbonate. Formulations F13, F14 and F15 containing combinations of gas generating agents at varying concentrations exhibited a floating lag time of 24 seconds, 20 seconds and 15 seconds respectively which may be due to the immediate formation of CO₂gas that provides buoyancy.

Hence it can be concluded that optimum concentration of sodium bicarbonate (80 mg per tablet)

Swelling index studies: Tablets composed of polymeric matrices build a gel layer around the tablet core when they come in contact with water. This gel layer governs the drug release. Kinetics of swelling is important because the gel barrier is formed with water penetration. Swelling is also a vital factor to ensure floating and drug dissolution. To obtain floating, the balance between swelling and water acceptance must be restored^18-19. The swelling index of floating tablets of F1 to F15 is shown in Fig.1.

Figure-1: Swelling index studies of Simvastatin (F1 to F15)

The HPMC grade also affects the swelling and hydration with considerably higher swelling index for HPMC K4M than HPMC K15M and K100M. HPMC K15M and K100M exhibited low swelling index, but there was no decrease in swelling rate. The reason for this appeared to be its high viscosity and high water retention property. Further, no significant effect of effervescents on swelling indices was observed. Swelling index values start decreasing when polymer erosion starts in the medium.

Invitro dissolution studies: Invitro dissolution studies were performed for all the batches of HBS of simvastatin using USP XXIII dissolution test apparatus-II at 50rpm, 900ml of 0.1N HCl used as dissolution media. The invitro drug release data was given in tables 6 to 8 and drug release profiles are shown in figure-2 to 6.

Formulations F1, F2 and F3 containing drug : polymer ratio 1:9.5, 1:12 and 1:15.3 prepared with HPMC K4M exhibited 96.52, 93.46 and 90.36% of drug release in 10 hours respectively and the data is given in table 6 and drug release profiles are shown in figure-2.

Figure-2: Cumulative Percent Drug Released Vs Time Plots (Zero Order) of formulation F1, F2 and F3

Formulations F4, F5 and F6 containing drug : polymer ratio 1:9.5, 1:12 and 1:15.3 prepared with HPMC K15M exhibited 87.31, 85.63 and 86.47% of drug release in 10 hours respectively and the data is given in table 6-7 and drug release profiles are shown in figure-3.

Figure-3: Cumulative Percent Drug Released Vs Time Plots (Zero Order) of formulation F4, F5 and F6

Invitro drug release data for formulations F7, F8 and F9 are given in table 7 and drug release profiles are shown in figure-4. The formulations F7, F8 and F9 were prepared with HPMC K100M in drug polymer ratios 1:9.5, 1:12 and 1:15.3 exhibited 95.78, 85.07 and 84.64% drug release rates in 10 hours respectively.

Figure-4: Cumulative Percent Drug Released Vs Time Plots (Zero Order) of formulation F7, F8 and F9

In the above results, it was observed that as the concentration of the polymers increased, there is a decrease in the drug release rates. An increase in polymer concentration causes increase in viscosity of the gel as well as the gel layer with longer diffusional path. This could cause a decrease in effective diffusion coefficient of the drug and a reduction in drug release rate.

Formulations containing higher HPMC viscosity grades have slower drug release rates when compared to formulations with lower HPMC viscosity grades i.e. formulations F1, F2, F3 containing HPMC K4M have showed the fastest and formulations F7, F8, F9 containing HPMC K100M showed the slowest drug release rates. The amount of drug released for a particular drug polymer ratio was found to be in the order of K4M > K15M> K100M.

Among the three viscosity grades of HPMC studied, HPMC K4M with a drug-polymer ratio of 1:15.3 has been selected to study the influence of co-excipients lactose and MCC on drug release rates (F10, F11, F12 and F13).

Table-6: In Vitro release data of HBS of Simvastatin F1 to F5

Sl. No.	Time (Hrs)	F1	F2	F3	F4	F5
Sl. No.	Time (Hrs)	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD
1.	01	24.79±0.33	21.41±0.88	20.10±0.11	17.68±0.45	15.37±0.35
2.	02	44.32±0.76	33.31±0.41	35.73±0.35	27.89±0.33	24.36±0.22
3.	03	61.95±0.55	50.73±0.53	47.57±0.89	35.15±0.31	30.73±0.65
4.	04	77.62±0.72	52.27±0.98	56.84±0.51	41.36±0.85	45.10±0.95
5.	05	84.45±0.45	65.68±0.21	62.78±0.45	53.21±0.49	50.73±0.42
6.	06	85.52±0.63	72.15±0.35	70.26±0.49	64.10±0.53	61.21±0.48
7.	07	87.42±0.12	76.74±0.45	75.68±0.83	70.68±0.82	67.94±0.55
8.	08	90.76±0.53	81.91±0.59	80.05±0.77	75.89±0.73	74.68±0.22
9.	09	95.72±0.19	87.68±0.85	84.84±0.65	81.63±0.45	78.90±0.35
10.	10	96.52±0.46	93.46±0.18	90.36±0.81	87.31±0.78	85.63±0.95

*Average of three determinations

Table-7: In Vitro release data of HBS of Simvastatin F6 to F10

Sl. No.	Time (Hrs)	F6	F7	F8	F9	F10
Sl. No.	Time (Hrs)	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD
1.	1	20.10±0.96	28.94±0.40	25.05±0.71	21.54±1.15	28.21±0.86
2.	2	33.57±0.33	38.63±0.80	34.21±0.42	31.15±0.64	35.84±0.16
3.	3	42.63±0.59	43.78±0.75	43.47±0.67	39.36±0.38	50.21±0.18
4.	4	55.68±0.54	56.63±0.48	47.26±0.80	47.26±0.76	59.68±1.19
5.	5	59.26±0.97	60.73±1.33	51.10±0.66	51.71±0.33	65.31±0.51
6.	6	62.31±0.62	74.04±1.30	60.84±0.65	63.42±0.73	70.94±0.60
7.	7	72.73±0.60	80.36±0.80	71.64±0.71	66.26±0.65	78.42±0.53
8.	8	77.26±0.51	86.89±0.68	78.15±0.96	72.77±0.82	85.84±0.45
9.	9	81.26±0.33	90.57±0.71	81.42±0.63	78.17±0.33	93.36±0.71
10.	10	86.47±0.76	95.78±0.42	85.07±0.51	84.64±0.82	99.18±0.14

Table-8: In Vitro release data of HBS of Simvastatin F10 to F15

Sl. No.	Time (Hrs)	F11	F12	F13	F14	F15
Sl. No.	Time (Hrs)	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD	*Cumulative percent drug released** ±SD
1.	1	28.52±0.63	29.36±0.32	30.63±0.33	31.36±0.55	31.68±0.91
2.	2	38.31±1.20	33.57±0.83	39.15±0.39	35.05±0.48	45.63±0.85
3.	3	46.73±0.93	39.89±0.57	45.94±0.70	47.47±0.66	61.73±0.95
4.	4	60.52±0.94	46.63±0.34	60.26±0.40	55.26±0.70	69.15±0.67
5.	5	75.05±0.26	53.78±0.69	75.84±0.84	69.15±0.56	77.21±0.96
6.	6	81.42±0.80	60.42±0.69	80.36±0.74	78.68±0.58	83.16±0.18
7.	7	87.94±0.83	66.63±0.34	85.31±0.42	83.73±0.54	88.94±0.17
8.	8	90.52±0.58	73.47±0.93	90.52±0.69	87.84±0.31	93.89±0.20
9.	9	93.21±0.44	82.94±0.62	93.89±0.67	91.15±0.78	95.15±0.31
10.	10	97.05±0.32	94.52±0.59	95.21±0.53	96.84±0.34	97.57±0.33

*Average of three determinations

Figure-5: Cumulative Percent Drug Released Vs Time Plots (Zero Order) of formulation F10, F11 and F12

Formulation F10 containing lactose as diluent along with sodium bicarbonate exhibited 99.18% of drug release in 10 hours whereas formulation F11 and F12 containing MCC showed a drug release of 97.05 and 94.52% in 10 hours. It was observed that when Lactose was included along with HPMC K4M enhanced Simvastatin release from the HBS tablets when compared to same formulation with MCC. In the two excipients studied drug release was found to be faster in case of HBS containing MCC when compared to HBS with lactose (t₉₀for F10= 8.5 hours and F11= 8.0 hours, t₉₀for F12=9.7 hours and F13= 8.0 hours).

Invitro release data of formulations F13, F14 and F15 are given in tables 8 and dissolution profiles are shown in figure-6. These formulations containing drug and HPMC K4M along with MCC and a combination of gas generating agents sodium bicarbonate and citric acid exhibited a drug release of 95.21, 96.84 and 97.57% in 10 hours. The addition of citric acid in these formulations did not influence the drug release rates.

Figure-6: Cumulative Percent Drug Released Vs Time Plots (Zero Order) of formulation F13, F14 and F15

The dissolution t₅₀ and t₉₀ values for all the HBS formulations of Simvastatin is given in table 7. The comparative effect of two different diluents on the release profiles of Simvastatin from the HBS formulations in terms of dissolution t₅₀ and t₉₀values is shown in figure-7. It was observed that HBS containing MCC (T₉₀for F11= 8.0 hours) exhibited shorter dissolution times when compared to formulations containing lactose (t₉₀for F10= 8.5 hours).

Figure-7: Dissolution t₅₀ and t₉₀ values of HBS of Simvastatin

Drug release kinetics: The in vitro drug release data was subjected to goodness of fit test by linear regression analysis according to zero order, first order kinetic equations, Higuchi and Korsmeyer models to ascertain the mechanism of drug release.

When the regression coefficient ‘r’ value of zero order and first order plots were compared, it was observed that the ‘r’ values of zero order were in the range of 0.90 to 0.99 whereas the ‘r’ values of first order plots were found to be in the range of 0.93 to 0.99 indicating drug release from all the formulations were found to follow 1^st order kinetics.

The good fit of the Higuchi model to the dissolution profiles of all the formulations suggested that diffusion is the predominant mechanism limiting drug release since the ‘r’ values of Higuchis plots were nearer to unity.

The in vitro dissolution data as log cumulative percent drug release versus log time were fitted to Korsmeyer et al equation, values of the exponent ‘n’ was found to be in the range of 0.49 to 0.73 indicating that the drug release is by Non-Fickian diffusion mechanism.

Among the various formulations studied, HBS formulation F10 was considered as an ideal formulation which exhibited 90% of drug release in 8.5 hours (t₉₀) and floating lag time of 10 seconds with a floating time of 24 hours. Hence it is selected for further short term stability studies (Table-9).

Table–9: Dissolution t₅₀ and t₉₀ values of HBS of Simvastatin

Sl. No.	Formulation Code	t₅₀(hours)	t₉₀(hours)
1	F1	2.5	7.9
2	F2	3.0	9.4
3	F3	3.5	>10
4	F4	4.8	>10
5	F5	5.0	>10
6	F6	3.5	>10
7	F7	3.4	>10
8	F8	4.5	>10
9	F9	4.7	>10
10	F10	3.0	8.5
11	F11	3.4	8.0
12	F12	4.6	9.7
13	F13	3.3	8.0
14	F14	3.5	8.9
15	F15	3.3	7.6

Stability studies: Short term stability study was performed for formulation F10 at 45±1°C for 3 weeks (21 days). The samples were analysed for percent drug content, in vitro floating ability and in vitro drug release studies showing that there were no appreciable difference observed for the above parameters.

CONCLUSION:

The following conclusions can be drawn from the results obtained in this study:

Ø Hydrodynamically Balanced Systems offers a simple and practical approach to achieve increased gastric residence and to modify drug release profiles essential for sustained, site specific and localized drug action.

Ø The HBS of Simvastatin were developed by using different viscosity grades of HPMC by wet granulation technique. Lactose and MCC were used as diluents. Sodium bicarbonate and citric acid were used as gas generating agents either alone or in combination.

Ø All the prepared tablets prepared were found to be good without chipping, capping and sticking.

Ø The drug content was uniform and well within the accepted limits with low values of standard deviation indicating uniform distribution of drug within the HBS.

Ø The drug – polymer ratio, viscosity grades of HPMC, different diluents and gas generating agents were found to influence the release of drug and floating characteristics from the prepared HBS of Simvastatin.

Ø Polymer swelling is crucial in determining the drug release rate and is also important for flotation.

Ø The prepared HBS of Simvastatin showed excellent invitro floating properties. Addition of less quantity of gas generating agent sodium bicarbonate resulted in the reduction of floating lag time. Addition of citric acid to the HBS with sodium bicarbonate has produced a marked reduction in the floating lag time upto less than 15 seconds. All the HBS system have showed a floating time of 24 hours. The floating lag time is dependent upon the concentration of gas generating agent sodium bicarbonate and citric acid was found to achieve an optimum invitro floating.

Ø The invitro dissolution profiles of all the prepared HBS formulations of Simvastatin were found to extend the drug release over a period of 10 hours and the drug release decreased with increase in viscosity of polymer.

Ø Release of Simvastatin from most of the HBS formulations was found to follow zero order kinetics (0.93 to 0.99) and derived correlation coefficient ‘r’ (0.98) indicated good fit of Higuchi model suggesting that diffusion is the predominant mechanism controlling the drug release. When drug release data fitted to Korsmeyer equation, the values of slope ‘n’ (0.49 to 0.73) indicated that the drug release was by Non-Fickian mechanism.

Ø Among the various HBS formulations studied, formulation F10 containing drug-polymer ratio (1:15.3) prepared with HPMC K4M showed promising results releasing ≈ 90% of the drug in 8.5 hours (t₉₀) with a floating lag time of 10sec and floating time of 24 hours has been considered as an ideal formulation and subjected to further short term stability studies.

Ø Optimized HBS of Simvastatin (F10) was found to be stable at 45°C following a three week stability study.

Ø Finally, it may be concluded that this novel drug delivery system i.e HBS offers a valuable dosage form which delivers the drug at a controlled rate and at a specific site. The HBS of Simvastatin provides a better option for increasing the bio availability and reliability for hypertension and in benign prostatic hyperplasia to relieve symptoms of urinary obstruction by allowing a better control of fluctuations observed with conventional dosage forms.

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Received on 27.03.2010 Modified on 15.04.2010

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 1252-1259