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 xanthan gum, guar gum, 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. All other chemicals were of analytical grade.

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 (table1) ^{5, 6, 7}.

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
Xanthan Gum	50	60	70	80	-	-	-	-
Guar Gum	-	-	-	-	50	60	70	80
Carbopol 940	40	40	30	25	40	40	30	25
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	15	5	5	5	15	5	5	5
Talc	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.

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.

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. 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 0.4918±0.008 to 0.5232±0.005 g/ml and 0.5600±0.029 to 0.6084±0.018 g/ml respectively. The percentage compressibility of powder was determined using carr’s compressibility index. Carr’s index lies within the range of 11.17 to 16.42 %. 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 19^o94’±2.093 to 26º86’±0.525. Hausner ratio was found to be in the range of 1.1258to 1.1964.

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 3.2±0.091to 3.2±0.194 mm. The hardness of all formulations was in the range of 4.9±0.208 to 5.3±0.200 kg/cm², indicating satisfactory mechanical strength. The weight variation values of tablets ranged from 249.1±0.737 to 251.1±0.738 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 0.203 to 0.365 %. 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 94.87±0.619 to 98.00±0.938 % of glipizide, which was within the acceptable limits. Table 3 shows the results of physicochemical characters of glipizide tablets.

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 F8 and F1 respectively. The concentration of the natural polymers increases the floating lag time also increases and total floating time (TFT) decreases.

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	0.4973±0.009	0.5883±0.011	15.46	19º94’±2.093	1.1829
F2	0.4974±0.012	0.5600±0.029	11.17	22º63’±1.402	1.1258
F3	0.5085±0.008	0.5927±0.023	14.20	23º90’±1.103	1.1655
F4	0.4918±0.008	0.5809±0.017	15.33	25º63’±0.802	1.1811
F5	0.5028±0.004	0.5806±0.006	13.40	22º42’±2.280	1.1548
F6	0.5232±0.005	0.5960±0.006	12.21	24º90’±1.589	1.1390
F7	0.5173±0.008	0.5921±0.006	12.63	25º46’±1.905	1.1446
F8	0.5085±0.008	0.6084±0.018	16.42	26º86’±0.525	1.1964

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

0.5

6.13±

0.611

8.93±

0.611

15.20±

0.400

15.73±

0.611

6.8±

0.800

10.53±

0.611

16.53±

0.611

15.87±

1.222

9.37±

1.010

12.58±

0.614

18.75±

0.613

22.89±

1.061

10.97±

1.011

13.39±

0.614

20.49±

0.803

22.75±

0.839

12.45±

0.806

15.94±

0.465

23.30±

1.446

28.53±

0.806

13.13±

1.410

17.81±

0.612

05±

0.458

29.86±

1.226

17.40±

1.011

20.35±

1.009

28.00±

0.931

34.56±

1.054

18.87±

1.608

21.97±

1.289

30.67±

1.224

34.70±

1.229

23.56±

1.012

23.71±

0.806

36.55±

0.804

41.39±

0.804

24.37±

0.620

25.32±

0.807

38.30±

0.839

41.53±

1.013

30.93±

1.606

28.53±

0.804

43.14±

0.837

53.03±

0.802

31.20±

1.807

30.54±

1.447

45.01±

0.696

52.50±

0.838

39.64±

1.414

34.16±

0.804

50.64±

1.204

69.23±

1.221

42.17±

1.610

36.30±

1.230

52.65±

0.803

68.16±

3.335

55.55±

1.412

44.99±

1.837

64.15±

1.229

79.05±

0.605

57.57±

1.813

43.13±

0.839

64.69±

0.798

78.78±

1.213

69.64±

1.812

59.32±

1.675

78.75±

0.802

93.10±

0.614

71.12±

2.410

56.64±

0.804

79.42±

0.614

92.97±

1.011

80.79±

1.610

77.13±

1.842

92.70±

0.614

81.46±

1.817

77.38±1.009

94.04±

0.397

94.58±

1.813

92.69±

1.675

93.78±

1.814

92.83±

0.806

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	94.58	0.991	0.910	0.965	0.764	0.993
F2	92.69	0.988	0.870	0.940	0.628	0.969
F3	92.70	0.964	0.937	0.986	0.547	0.986
F4	93.10	0.936	0.969	0.990	0.536	0.983
F5	93.78	0.986	0.935	0.970	0.727	0.987
F6	92.83	0.977	0.855	0.936	0.590	0.965
F7	94.04	0.956	0.921	0.988	0.517	0.987
F8	92.97	0.937	0.968	0.992	0.528	0.986

Figure 1: Swelling Index of Gastroretentive Floating Tablets of Glipizide

Figure 2: In vitro Drug Released Profile of Formulations F1 to F4

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 the time of drug release was decreased.

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

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 0.517 to 0.764, 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.

Stability studies:

The accelerated stability studies were carried out according to ICH guidelines. Optimized formulations F1 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 F1

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	97.80	93	> 24 hrs.	94.58
First	97.69	93	> 24 hrs.	94.21
Second	97.52	91	> 24 hrs.	94.09
Third	97.23	94	> 24 hrs.	94.29

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	97.13	109	> 24 hrs.	93.78
First	97.02	108	> 24 hrs.	93.51
Second	96.94	109	> 24 hrs.	93.59
Third	97.08	109	> 24 hrs.	93.21

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 F1 and F5 indicate, that there are no significant changes in drug content and dissolution parameter values after 3 months storage at 40±2ºC.

REFERENCES:

1. Kumar M, Selvi R, Perumal P, Chandra Sekhar Y, Zakir. Formulation and in vitro evaluation of gastroretentive floating tablets of glipizide. International Journal of Innovative Pharmaceutical Research. 2011; 2(3):151-155.

2. Sivabalan M, Vani T, Phaneendhar Reddy, Vasudevaiah, Anup Jose, Nigila G. Formulation and evaluation of gastroretentive glipizide floating tablets. International Journal of Comprehensive Pharmacy. 2011; 2(1):1-4.

3. Senthil A, Suresh Kumar P, Raju CH, Mohideen S. Formulation and evaluation of gastric oral floating tablet of glipizide. International Journal of Biological and Pharmaceutical Research. 2010; 1(2): 108-113.

4. Chien Y.W. Novel drug delivery systems. 2^nd ed. Marcel Dekker Inc; NY 1992.

5. Veerabrahma K, Bomma R, Naidu RAS, Yamsani MR. Development and evaluation of gastroretentive norfloxacin floating tablets. Acta Pharm. 2009; 59:211-221.

6. Patel JK, Raval JA, Li N, Patel MM. Ranitidine hydrochloride floating matrix tablets based on low density powder: effects of formulation and processing parameters on drug release. Asian J of Pharm Sci. 2007; 2(4):130-142.

7. Pare A, Yadav SK, Patil UK. Formulation and evaluation of effervescent floating tablet of amlodipine besylate. Research J. Pharm. And Tech. Oct.-Dec. 2008; 1(4):526-530.

8. Padmavathy J, Saravanan D, Rajesh D. Formulation and evaluation of ofloxacin floating tablets using HPMC. Int J of Pharmacy and Pharm Sci. 2011; 3(1):170-173.

9. Ziyaur R, Mushir A, Khar RK. Design and evaluation of bilayer floating tablets of captopril. Acta pharm. 2006; 56: 49-57.

10. Lachman L, Liberman HA, Kanig JL. The theory and practice of industrial pharmacy. 3^rd ed. Varghese publication house; 1991. pp. 300.

11. Krishnaiah YSR, Satyanarayan V, Kumar BD. In vitro drug release studies on guargum based colon targeted oral drug delivery systems of 5–fluorouracil. Eur. J. Pharm. Sci. 2002; 16:185-192.

12. Nama M, Gonugunta CSR, Veerareddy PR. Formulation and evaluation of gastroretentive dosage forms of clarithromycin. AAPS Pharm Sci Tech. March 2008; 9(1):231-237.

13 . Patel A, Modasiya M, Shah D, Patel V. Development and in vivo floating behavior of verapamil HCl intragastric floating tablets. AAPS Pharm Sci Tech. March 2009; 10(1):310-315.

14. Lodhiya DJ, Mukherjee DJ, Dholakiya RB, Akbari BV, Shiyani BG, Lathiya HN. Gastroretantive system of atenolol using HPMC k15. Int J of Pharm Tech Research. Oct-Dec 2009; 1(4):1616-1620.

15. Shishu, Gupta N, Aggarwal N. A gastroretentive floating delivery system for 5-fluorouracil. Asian J of Pharm Sci. 2007; 2(4):143-149.

16. Gambhir MN, Ambade KW, Kurmi SD, Kadam VJ, Jadhav KR. Development and in vitro evaluation of an oral floating matrix tablet formulation of diltiazem hydrochloride. AAPS Pharm Sci Tech. 2007; 8(3) Article 73:E1-E9.

17. Kavita K, Yadav SK, Tamizhamani T. Formulation and evaluation of floating tablets ofrhcl using natural and synthetic polymers. Int J of Pharm Tech Research. Apr-Jun 2010; 2(2):1513-1519.

18. Garg R, Gupta GD. Preparation and evaluation of gastroretentive floating tablets of Silymarin. Chem. Pharm. Bull. 2009; 57(6):545-549.

19. Stability studies in overview of ICH guidelines for drug products: Natalie Mc Clure, Matrix Pharmaceutical Inc; 1997 http://www.mcclurenet.com

Received on 30.08.2012 Accepted on 15.09.2012

Asian J. Pharm. Tech. 2(4): Oct. - Dec. 2012; Page 135-140

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	3.2±0.091	5.0±0.152	249.7±0.948	0.245	97.80±0.821
F2	3.2±0.160	5.2±0.251	250.7±0.948	0.247	98.00±0.938
F3	3.2±0.138	5.3±0.200	251.1±0.738	0.365	97.13±0.824
F4	3.2±0.194	4.9±0.305	250.5±1.269	0.244	95.80±1.009
F5	3.2±0.160	4.9±0.208	250.1±0.875	0.323	97.13±0.627
F6	3.2±0.189	5.0±0.264	249.1±0.737	0.243	96.20±0.783
F7	3.2±0.156	4.9±0.264	249.8±0.918	0.205	96.20±1.021
F8	3.2±0.169	5.0±0.264	251±0.674	0.203	94.87±0.619

Formulation Code	Floating lag time (sec.) (n=3) Mean±SD	Total Floating Time (hrs.)
F1	93±1.579	> 24 hrs.
F2	104±1.363	> 24 hrs.
F3	119±1.229	> 20 hrs.
F4	126±1.859	> 16 hrs.
F5	109±1.183	> 24 hrs.
F6	112±1.547	> 24 hrs.
F7	135±1.469	> 20 hrs.
F8	152±1.893	> 16 hrs.

Formulation	Swelling Index (%) Time (hrs) (n=3) Mean±SD
Formulation	1 hrs	2 hrs	3 hrs	4 hrs	5 hrs
F1	80±1.229	127±0.929	159±1.117	187±0.809	207±1.219
F2	87±0.951	129±0.869	153±0.698	189±1.193	205±1.003
F3	73±1.211	127±0.798	151±1.079	193±0.938	204±0.999
F4	77±0.996	116±1.011	141±0.859	163±0.953	180±0.897
F5	81±1.157	124±0.884	162±0.929	191±1.079	208±1.121
F6	85±0.989	127±0.761	155±1.119	187±1.009	203±0.989
F7	83±0.886	126±0.739	149±0.898	187±0.759	201±0.936
F8	81±0.987	127±0.847	147±1.047	171±1.078	183±1.213