INTRODUCTION:

Oral route of administration is the most important and convenient route for drug delivery. The benefits of long-term delivery technology have not been fully realized for dosage forms designed for oral administration. This is mainly due to the fact that the extent of drug absorption from gastrointestinal tract is determined by gastrointestinal physiology; irrespective of the control release properties of the device prolonged gastric retention improves bioavailability¹.

Gastric retentive dosage forms are designed to be retained in the stomach and prolong the gastric residence time of the drugs. Prolonged gastric retention improves bioavailability, reduces drug waste and improves solubility for drugs that are less soluble in a high pH environment².

Based on the mechanism of flotation, delivery systems can be classified in two types. Effervescent floating drug delivery system and non-effervescent floating drug delivery system it release the drug from floating drug delivery system. These systems when reached to stomach, carbon dioxide is liberated by the acidity of gastric contents and is entrapped in the jellified Hydrocolloid.

This is prepared by swellable polymers such as HPMC, sodium alginate, carbopol 940 and PVP K30 and various effervescent components like sodium bicarbonate and citric acid mixtures may be used³.

Glipizide is a second generation sulfonylurea used in the treatment of hyperglycemia. It’s poorly soluble in acidic acid it absorbs rapidly and completely. However its absorption is erratic in diabetic patients due to the impaired gastric motility or gastric emptying to overcome the presence study gastric retentive controlled release dosage form of the drug in the form tablet was formulated with different polymers. The object of the present work is preparing floating tablets in controlled fashion. The gas generating agent sodium bicarbonate and citric acid were added in different concentrations with varying amount of retardation and investigated the release profile following USP type-II in vitro dissolution model⁴.

MATERIALS AND METHODS:

Materials:

Glipizide was received as gift sample from supra chemicals Mumbai. HPMC K100M as a gift sample from Wallace pharmaceutical goa. All other chemicals were of analytical grade.

Table 1: Composition of Gastroretentive Floating Tablets of Glipizide (F1 to F8)

Ingredients* (mg)	Formulation Code
Ingredients* (mg)	F1	F2	F3	F4	F5	F6	F7	F8
Glipizide	15	15	15	15	15	15	15	15
HPMC K100M	50	60	70	80	-	-	-	-
Sodium Alginate	-	-	-	-	50	55	60	65
Carbopol 940	50	40	30	20	50	45	40	35
PVP K30	10	10	10	10	10	10	10	10
Sodium Bicarbonate	90	90	90	90	90	90	90	90
Citric Acid	20	20	20	20	20	20	20	20
Aerosil	5	5	5	5	5	5	5	5
Talc	5	5	5	5	5	5	5	5
Mg. Stearate	5	5	5	5	5	5	5	5
Total	250	250	250	250	250	250	250	250

*All the ingredients are in mg. per tablet.

Methods:

Preparation of oral Floating tablet:

Floating tablets containing glipizide were prepared by direct compression technique using varying concentrations of different grades of polymers with sodium bicarbonate and citric acid.

All the powders were accurately weighed and passed though an 80 mesh sieve (180 micrometer size). 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 blend was compressed into tablets having average weight of 250mg using a single punch tablet machine (Proton, India) fitted with an 8mm round flat punches. The compositions of all formulations are given in (table 1) ^{5, 6, 7}.

Evaluation of tablet properties:

Determination of pre-compression parameters:

As per standard procedures, the preformulation studies including Bulk density, Tapped density, Compatibility study, Hausner’s ratio and Angle of repose was performed of the powder⁸.

Determination of post-compression parameters:

1. Hardness test

Pfizer hardness tester was used for the determination of hardness of tablets⁸.

2. Friability

Twenty tablets were accurately weighed and placed in the friabilator (Roche’s Friabilator) and operated for 100 revolutions. The tablets were dedusted and reweighed. The tablets that loose less than 1% weight were considered to be compliant⁹.

The % friability was then calculated by,

3. Weight variation

20 tablets were selected randomly from the lot and weighed individually to check for weight variation¹⁰.

4. Content uniformity test:

The Glipizide floating tablets were tested for their drug content. Five tablets were finely powdered; quantities of the powder equivalent to 15mg of Glipizide were accurately weighed and transferred to a 100 ml of volumetric flask. The flask was filled with 0.1N HCl (pH 1.2 buffers) solution and mixed thoroughly. The solution was made up to volume 100ml and filtered. Dilute 1 ml of the resulting solution to 10 ml with 0.1N HCl. The absorbance of the resulting solution was measured at 276 nm using a Shimadzu UV-visible spectrophotometer. The linearity equation obtained from calibration curve was used for estimation of Glipizide in the tablet formulations¹¹.

5. In vitro Buoyancy Studies:

The in vitro buoyancy was determined by floating lag time, as per the method described by Rosa et al. The tablets were placed in a 250 ml beaker, containing 200 ml of 0.1 N HCl. The time required for the tablet to rise to the surface and float was determined as Floating Lag Time (FLT) and the time period up to which the tablet remained buoyant is determined as Total Floating Time (TFT) ^{12, 13}.

6. Swelling Study:

The floating tablets were weighed individually (designated as W₀) and placed separately in glass beaker containing 200 ml of 0.1 N HCl and incubated at 37°C±1°C. At regular 1-h time intervals until 24 h, the floating tablets were removed from beaker, and the excess surface liquid was removed carefully using the tissue paper. The swollen floating tablets were then re-weighed (Wt), and % swelling index (SI) was calculated using the following formula^{14, 15}.

SI (%) = (Wt – W₀/ W₀) x 100

7. In vitro Dissolution Studies:

The In vitro dissolution study was performed by using a United States Pharmacopeia (USP) type II (paddle) apparatus at a rotational speed of 100 rpm. Exactly 900 ml of 0.1 N HCl was used as the dissolution medium and the temperature was maintained at 37^oC ± 0.5^oC.

Table 2: Pre-Compression Parameters of Designed Formulations (F1 to F8)

Formulation code	Pre-compression Evaluation Parameters
Formulation code	Bulk density(gm/ml) (n=3)Mean±SD	Tapped density(gm/ml) (n=3)Mean±SD	Carr’s Index (%)	Angle of repose (n=3) Mean±SD	Hausner Ratio
F1	0.4841±0.009	0.5796±0.010	16.47	20º41’±1.289	1.1972
F2	0.5246±0.009	0.6193±0.019	15.29	23º91’±2.188	1.1805
F3	0.5121±0.009	0.5998±0.015	14.62	24º51’±2.448	1.1712
F4	0.5094±0.004	0.5952±0.012	14.42	25º79’±1.102	1.1684
F5	0.5111±0.005	0.6012±0.013	14.98	23º69’±2.243	1.1762
F6	0.4894±0.007	0.5851±0.006	16.36	24º84’±1.327	1.1955
F7	0.5125±0.004	0.5901±0.006	13.15	26º59’±1.102	1.1514
F8	0.5113±0.005	0.6109±0.018	16.30	27º99’±1.944	1.1947

A sample (5ml) of the solution was withdrawn from the dissolution apparatus at specified time interval for 24 h and the same volume was replaced with pre -warmed fresh dissolution media. The samples were diluted to suitable concentration with 0.1 N HCl. Absorbance of these solutions was measured at 276nm using a UV spectrophotometer^{16, 17}.

8. Curve fitting analysis:

The mechanism of Glipizide release from the floating tablets was studied by fitting the dissolution data of optimized formulation in following models

1. Zero order

2. First order

3. Higuchi model

4. Korsemeyer and Peppas equation

Based on the slope and the R² values obtained from the above models the mechanism of drug release was decided¹⁸.

9. Stability studies:

The optimized formulation of Glipizide were packed in amber color bottle and aluminum foil laminated on the upper part of the bottle and these packed formulation was stored in ICH certified stability chambers maintained at 40^οC and 75% RH (zone III conditions as per ICH Q₁ guidelines) for 3 months. The samples were withdrawn periodically and evaluated for their content uniformity, in vitro buoyancy studies and for in vitro drug release¹⁹.

RESULT AND DISCUSSION:

Pre-compression parameters:

Results of the pre-compression parameters performed on the blend for batch F1 to F8 are tabulated in Table 2.

The bulk density and the tapped density for all the formulations varied from 0.4841±0.009 to 0.5246±0.009 g/ml and 0.5796±0.010 to 0.6193±0.019 g/ml respectively. The percentage compressibility of powder was determined using carr’s compressibility index. Carr’s index lies within the range of 13.15 to 16.47 %. All formulations show good compressibility. Angle of repose of all the formulations was found to be less than 30^o, which indicates a good flow property of the powders. The values were found to be in the range of 20º41’±1.289 to 27º99’±1.944. Hausner ratio was found to be in the range of 1.1514 to 1.1972.

Post-compression parameters:

The formulated tablets were subjected for post- compressional evaluation such as thickness, hardness, weight variation, friability, drug content, in vitro buoyancy studies, swelling studies, in vitro dissolution studies, and stability studies.

Tablet thickness (n=3) were almost uniform in all the formulations and values for tablets ranged from 3.1±0.114 to 4.15±0.048mm. The hardness of all formulations was in the range of 4.6±0.256 to 5.2±0.089 kg/cm², indicating satisfactory mechanical strength. The weight variation values of tablets ranged from 248.5±0.948 to 251.0±0.737 mg. All the tablets passed weight variation test as the % weight variation was within the Pharmacopoeias limits of ±7.5% of the weight. The friability values ranged from 0.281 to 0.369 %. All the values are below 1% indicating that the tablets of all formulations are having good compactness and showing enough resistance to the mechanical shock and abrasion. The percent drug content of tablets was found to be in between 95.16±0.842 to 98.21±0.812 % of glipizide, which was within the acceptable limits. Table 3 shows the results of physicochemical characters of glipizide tablets.

Table 3: Post-Compression Parameters of Designed Formulations (F1 to F8)

Formulation code	Post-compression Evaluation Parameters
Formulation code	Thickness (mm) (n=3) Mean±SD	Hardness Kg/cm² (n=3) Mean±SD	Weight Variation (mg) (n=20) Mean±SD	Friability (%) (n=10)	Drug Content (%) (n=3) Mean±SD
F1	4.11±0.033	5.2±0.089	248.9±0.948	0.289	98.21±0.812
F2	4.13±0.059	4.9±0.125	249.7±1.032	0.339	97.52±0.915
F3	4.09±0.039	5.1±0.195	249.9±0.823	0.281	97.96±0.652
F4	4.15±0.048	4.9±0.200	251.0±0.737	0.293	97.12±0.891
F5	3.1±0.145	4.7±0.200	250.6±0.918	0.352	96.52±0.959
F6	3.2±0.129	4.6±0.256	250.5±0.788	0.329	97.11±0.676
F7	3.1±0.125	4.9±0.152	248.5±0.948	0.369	97.84±0.681
F8	3.1±0.114	5.0±0.200	250.9±0.843	0.334	95.16±0.842

In vitro Buoyancy Studies:

In vitro buoyancy of the tablets from each formulation (F1 to F8) was evaluated and the results are mentioned in Table 4. Where, the highest and lowest floating lag time (FLT) was observed with the formulation F4 and F5 respectively. The concentration of the natural polymers increases the floating lag time also increases and total floating time (TFT) decreases.

Table 4: Floating Lag Time and Total Floating Time of Designed Formulations (F1 to F8)

Formulation Code	Floating lag time (sec.)(n=3) Mean ±SD	Total Floating Time (hrs.)
F1	81±1.325	> 16 hrs.
F2	93±1.402	> 20 hrs.
F3	102±1.759	> 20 hrs.
F4	109±1.665	> 24 hrs.
F5	68±1.294	> 24 hrs.
F6	79±1.196	> 20 hrs.
F7	81±1.789	> 20 hrs.
F8	94±1.546	> 16 hrs.

Swelling index:

The swelling index of the tablets from each formulation (F1 to F8) was evaluated and the results are mentioned in Table 5 and plot of % swelling index vs. time (hrs) is depicted in Figure 1. Where, the highest and lowest swelling was observed with the formulation F5 and F1 after 5 hrs respectively. The swelling index increases by increasing the contact time with pH 1.2 buffers as the polymer gradually absorbs buffer due to hydrophilic nature the polymer with resultant swelling.

In vitro Dissolution Studies:

In vitro dissolution studies of all the formulations of IGF tablets of glipizide were carried out in 0.1 N HCl. The study was performed for 24 hrs, and cumulative drug release was calculated at different time intervals. The in‐vitro drug release profiles for the formulations (F1-F8) were tabulated in Table 6.

The plot of cumulative percentage drug release V/s time (hr) for formulations (F1-F4) and (F5-F8) were plotted and depicted in Figure 2 and Figure 3 respectively. Effects of various ingredients and their concentration on drug release were studied. It was observed that the type of polymer influences the drug release pattern. The in vitro drug release was observed that as the concentration of polymer is increased in formulations (F5 to F8) the time of drug release was decreased.

Curve fitting analysis:

The data obtained from in vitro dissolution studies were fitted to zero-order, first-order, Higuchi and Korsemeyer–Peppas equations. The dissolution data obtained were plotted as Time versus cumulative percent drug released as zero order, Time versus log cumulative percent drug remaining as First order release kinetics, Square root of time versus cumulative percent drug released as Higuchi equation and Log time versus log cumulative percent drug released as per Korsemeyer-Peppas equation. The best fit with the highest determination R² coefficients was shown by both peppas and zero order models followed by Higuchi model which indicate the drug release via diffusion mechanism. Zero-order rate equation, which describe the system where release rate is independent of the concentration of the dissolved species. The Korsemeyer-peppas equation is used to analyze the release of pharmaceutical polymeric dosage forms, when the release mechanism is not well known or when more than one type of release phenomena could be involved. The values of n with regression coefficient of all the formulations are shown in Table 7. The value of n was in the range of 0.519 to 0.765, indicating non- Fickian diffusion. From the results it was confirmed that all the formulations are following zero order models followed by higuchi model which indicate the drug release via diffusion mechanism. The slope value from korsemeyer plots confirmed that the formulations are following non-fickian diffusion. The reason for showing zero order kinetics may be the presence of alkalizing agents in the formulation. The regression co-efficients for different drug release kinetics models were shown in Table 7.

Table 5: Swelling Index of Gastroretentive Floating Tablets of Glipizide

Formulation	Swelling Index (%)Time (hrs) (n=3) Mean±SD
Formulation	1 hrs	2 hrs	3 hrs	4 hrs	5 hrs
F1	81±1.289	129±0.991	147±1.038	161±1.069	179±1.211
F2	83±1.238	124±0.986	143±0.853	179±0.947	191±0.881
F3	79±1.229	127±0.826	147±1.059	183±0.929	198±0.989
F4	71±1.105	117±0.853	147±0.907	186±1.071	202±1.119
F5	88±1.196	124±0.851	163±1.101	191±0.793	210±1.212
F6	73±0.996	131±0.791	143±0.894	181±0.751	196±0.925
F7	74±0.899	127±1.009	147±1.047	171±1.078	183±1.213
F8	79±0.994	134±0.859	141±0.859	163±0.953	180±0.897

Figure 1: Swelling Index of Gastroretentive Floating Tablets of Glipizide

Table 6: In vitro Dissolution Data for Formulation F1 to F8

Time (hrs.)	Cumulative % Drug Release of Formulation F1 to F8(n=3) Mean±SD
Time (hrs.)	F1	F2	F3	F4	F5	F6	F7	F8
0.5	14.53±0.259	14.21±0.894	15.07±0.789	7.73±0.611	8.63±0.911	14.67±0.611	13.20±0.800	17.13±0.441
1	21.67±0.619	18.90 ±0.959	19.21 ±0.851	10.58±1.010	11.88±0.694	17.81±0.613	17.27±0.402	22.46±1.224
2	29.39 ± 0.659	22.84± 0.785	23.39± 0.695	13.79±1.012	15.50±0.944	23.83±0.614	21.70±1.746	29.84±0.814
3	35.85± 0.794	27.09± 1.399	28.19± 1.229	19.11±1.072	20.18±0.893	28.93±0.402	25.59±2.581	36.09±1.229
4	42.34± 0.238	33.76± 1.371	34.26± 1.331	23.94±1.490	25.95±1.091	36.56±0.802	31.34±3.830	41.92±1.064
6	51.26± 0.697	40.46± 2.034	41.16± 1.134	29.39±1.648	32.61±1.042	45.27±0.615	39.51±4.427	52.33±0.801
8	69.11± 1.451	48.91± 1.241	49.11± 1.131	36.79 ± 1.019	41.41±1.092	52.65±0.803	47.82±3.512	68.49±0.796
12	77.67± 2.226	59.14± 1.961	61.94± 1.769	43.44±1.418	56.96±1.490	65.49±0.804	62.93±1.634	79.65±0.235
16	91.51± 1.921	73.91± 1.984	75.61± 1.514	59.24±1.658	72.91±1.908	77.03±1.011	76.21±0.455	93.41±1.006
20	-	85.81±1.794	89.21±1.984	73.69±1.813	84.06±1.713	92.96±0.616	91.75±0.611	-
24	-	-	-	91.81±1.219	93.63±2.219	-	-	-

Figure 3: In vitro Drug Released Profile of Formulations F5 to F8

Table 7: Release Kinetics Data of All the Formulations

Formulation code	% CDR	Zero order	First order	Higuchi	Korsmeyer-peppas
Formulation code	% CDR	R²	R²	R²	n	R²
F1	91.51	0.929	0.971	0.993	0.527	0.983
F2	85.81	0.953	0.923	0.989	0.519	0.989
F3	89.21	0.977	0.855	0.926	0.594	0.961
F4	91.81	0.986	0.933	0.980	0.729	0.991
F5	93.63	0.990	0.909	0.961	0.765	0.994
F6	92.96	0.987	0.871	0.941	0.630	0.967
F7	91.75	0.964	0.937	0.986	0.547	0.986
F8	93.41	0.936	0.969	0.990	0.536	0.983

Stability studies:

The accelerated stability studies were carried out according to ICH guidelines. Optimized formulations F4 and F5 were packed in amber color bottle and aluminum foil laminated on the upper part of the bottle and these packed formulation was stored in ICH certified stability chambers maintained at 40^οC and 75% RH (zone III conditions as per ICH Q₁ guidelines) for 3 months. The samples were tested for any changes in physical appearance, drug content, in vitro buoyancy studies and in vitro drug release studies at monthly intervals. The results of stability studies did not show any significant change in the physical appearance, drug content, in vitro buoyancy studies and in-vitro dissolution studies of above four formulations as shown in the Table 8 and Table 9.

Table 8: Stability Study of Formulation F4

Time month	Drug content (%)	Floating behaviour		*In vitro* Drug Release at 24hr (%)
Time month	Drug content (%)	FLT (sec)	Total Floating Time (hrs)	*In vitro* Drug Release at 24hr (%)
Zero	97.12	109	> 24 hrs.	91.81
First	96.92	109	> 24 hrs.	91.23
Second	96.98	107	> 24 hrs.	91.08
Third	96.61	108	> 24 hrs.	90.83

Table 9: Stability Study of Formulation F5

Time (month)	Drug content (%)	Floating behaviour		*In vitro* Drug Release at 24hr (%)
Time (month)	Drug content (%)	FLT (sec)	Total Floating Time (hrs)	*In vitro* Drug Release at 24hr (%)
Zero	96.52	68	> 24 hrs.	93.63
First	96.11	69	> 24 hrs.	93.41
Second	95.89	68	> 24 hrs.	92.83
Third	95.62	67	> 24 hrs.	92.43

CONCLUSION:

Gastroretentive floating drug delivery Systems offers a simple and practical approach to achieve increased gastric residence and to modify drug release profiles essential for controlled, site specific and localized drug action. Lower values of angle of repose below 30 indicate good flow properties of blends. All the prepared tablets were found to be of circular shape with no cracks. Friability and hardness were within the standard limits thus showing good mechanical strength of tablets. The drug content was well within the Pharmacopoeial limits indicating uniform distribution of drug within the controlled release gastro-retentive dosage form. The drug release data were explored for the type of release mechanism followed. The best fit with the highest determination R² coefficients was shown by both of the models (Zero and Peppas) followed by Higuchi model which indicate the drug release via non-Fickian diffusion mechanism. Short-term stability studies of optimized formulations F4 and F5 indicate, that there are no significant changes in drug content and dissolution parameter values after 3 months storage at 40±2ºC.

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Received on 18.04.2012 Accepted on 22.05.2012

Asian J. Pharm. Tech. 2(2): April-June 2012; Page 67-73