Formulation and In Vitro Evaluation of Floating Matrix Tablets of Ofloxacin

 

Pramod Patil*, Someshwara Rao B, Suresh V Kulkarni, Basavaraj, Chetan Surpur and Anand Ammanage

Department of Pharmaceutics, Sree Siddaganga College of Pharmacy, B.H.Road, Tumkur-572102, Karnataka, India.

*Corresponding Author E-mail: pramodpatil86@yahoo.com

 

ABSTRACT:

The present study concerns the development of floating tablets of ofloxacin which were designed to prolong the gastric residence time after oral administration. Ofloxacin is a fluoroquinolone antibacterial agent which is highly effective against gram positive and gram negative bacteria. Ofloxacin floating tablets were prepared by wet granulation method incorporating natural polymer like guar gum, locust bean gum, either alone or in combination with HPMC K100M as swelling polymers, with sodium bicarbonate as gas generating agent and were evaluated for parameters such as Weight variation, Hardness, Friability, Drug content, Swelling index, in vitro buoyancy study, in vitro drug release study. All the formulation showed compliance with pharmacopieal standards. Based on the evaluation results, F3 and F6 formulations were selected as the best formulations and were checked for stability as per ICH guidelines. These results indicated that the selected formulations were stable. The drug release profile of the best formulations was well controlled and uniform throughout the dissolution studies. The drug release of optimized formulation follows the Higuchi kinetic model, and the mechanism is found to be non-Fickian/anomalous according to Korsmeyer–Peppas equation.

 

KEYWORDS: Floating tablets, Ofloxacin, Guar gum, Locust bean gum.

 


INTRODUCTION:

The primary aim of oral controlled drug delivery system is to deliver drugs for longer period of time to achieve better bioavailability, which should be predictable and reproducible. But this is difficult due to number of physiological problems such as fluctuation in the gastric emptying process, narrow absorption window and stability problem in the intestine1. To overcome these problems, different approaches have been proposed to retain dosage form in stomach. These include bioadhesive or mucoadhesive systems2, swelling and expanding systems3,4, floating systems5,6 and other delayed gastric emptying devices. The principle of floating preparation offers a simple and practical approach to achieve increased gastric residence time for the dosage form and sustained drug release7.

 

Floating drug delivery system also known as hydrodynamically balanced system, have a bulk density lower than gastric fluids and thus remain buoyant in the gastric fluids for a prolonged period of time without affecting the gastric emptying rate. While the system is floating on the gastric content, the drug is released slowly at desired rate from the system.8

 

Received on 18.02.2011          Accepted on 22.02.2011        

© Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 1(1): Jan.-Mar. 2011; Page 17-22

 

Hydrodynamically balanced drug delivery system, in either tablet or capsule form, is designed to prolong gastrointestinal (GI) residence time in an area of GI tract. It is prepared by incorporating a high level (20-70% w/w) of one or more gel forming hydrocolloids. On contact with gastric fluid hydrocolloid starts to become hydrate and build a gelled barrier around the device. This gel barrier controls the release of drug from the device9.

 

Ofloxacin is a fluoroquinolone antibacterial agent which is highly effective against gram positive and gram negative bacteria10. Ofloxacin exhibits pH dependent solubility. The solubility of ofloxacin in water is 60 mg/ml  at pH value ranging from 2 to 5, falls to 4 mg/ml at pH 7 (near isoelectric pH)11. Thus it is more soluble in acidic pH and slightly soluble at neutral or alkaline condition (intestinal environment). Hence, in the present study various natural polymers like guar gum, locust bean gum would be used either alone or in combination with synthetic polymer like HPMC K100M along with gas generating agent like sodium bicarbonate for the formulation of floating tablets of ofloxacin which would increase the bioavailability of ofloxacin and also to reduce frequency of administration, thereby improving patient compliance and therapeutic efficacy.

MATERIALS AND METHODS:

Materials:

Ofloxacin was obtained as gift sample from Blue Cross Laboratories Ltd, Mumbai. Guar gum was obtained from Himedia Mumbai, Locust bean gum was obtained from Research Lab Fine Chemical Industries Mumbai, HPMC K100M was obtained from Colorcorn Asia Pvt Ltd, Goa. All other ingredients used were of analytical grade.

 

Preparation of Floating tablets:

Floating tablets were prepared by conventional wet granulation. The powder mix was granulated with 5% w/w PVP-K30 in isopropyl alcohol. The wet mass was passed through sieve # 16 and the granules were dried at 60°C for 1 hr in a hot air oven. The dried granules were passed through sieve # 22 and lubricated with magnesium stearate and talc by further blending for 3 min. Tablets were compressed at 550 mg weight on a 10 station mini rotary tableting machine with 12 mm flat-shaped punches. Tablets of Batch F1 and F5 contain only single natural polymer, whereas Batch F2-F4 and F6-F8 contain HPMC K100M with increased concentration from 2.5 to 7.5% with corresponding decrease in concentration of natural polymer.

 

Evaluation of granules:

The angle of repose was measured by using funnel method12, which indicates the flow ability of the granules. Loose bulk density (LBD) and tapped bulk density (TBD)13 were measured using the formula: LBD= weight of the granules / volume of the packing. TBD= weight of the granules / tapped volume of the packing. Compressibility index14 of the granules was determined by using the formula:

CI (%) = [(TBD-LBD/TBD)] ×100.

 

Evaluation of tablets:

All prepared floating tablets were evaluated for its uniformity of weight, hardness, friability and thickness according to official methods.15 The weight variation was determined by taking 20 tablets using an electronic balance (type ER182A, Afcoset, Mumbai, India). Tablet hardness was determined using a Monsanto tablet hardness tester (MHT-20, Campbell Electronics, Mumbai, India). Friability was determined by testing 10 tablets in a friability tester (FTA-20, Campbell Electronics) for 4 minutes at 25 rpm.

 

Drug content:

Five tablets were powdered in a mortar. An accurately weighed quantity of powdered tablets (100 mg) was extracted with 0.1N HCl (pH 1.2 buffer) and the solution was filtered through 0.45 µ membranes. Each extract was suitably diluted and analyzed spectrophotometrically at 294 nm.

 

In vitro buoyancy study:

In Vitro buoyancy studies were performed for all formulations as per the method described by Rosa et al16 The randomly selected tablets from each formulation was 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. The overall floating time was calculated during the dissolution studies.

Swelling study of formulations17

Swelling study of individual batch was carried out using USP dissolution apparatus-II (rotating paddle), in 900 ml of 0.1N HCl which is maintained at 37±0.5°C, rotated at 50 rpm. Weight of individual tablet was taken prior to the swelling study (W1). The tablet was kept in a basket. The tablet was removed every one hour interval up to 12 hour and excess water removed carefully using filter paper. The swollen tablets were re-weighed (W2); Percent hydration (swelling index) was calculated as shown in table 5 using following formula,

% Swelling Index = {(W2) – (W1)/ (W1)} x 100

Where W1- initial weight of tablet, W2- weight of the swollen tablet.

 

In vitro drug release study:

In-vitro drug release studies were carried out using USP XXII dissolution apparatus type II (Electrolab, Mumbai, India) at 50 rpm. The dissolution medium consisted of 900 ml of 0.1N HCl (pH 1.2), maintained at 37 + 0.5ºC. The dissolution samples were collected at every 1 hour interval and replaced with an equal volume of 0.1N HCl to maintain the volume constant. The sample solution was diluted sufficiently and analyzed at 294nm using an UV spectrophotometer (Labindia, Mumbai, India). The study was performed in triplicate.

 

Drug release kinetics (Curve fitting analysis)

To analyze the mechanism of the drug release rate kinetics of the dosage form, the data obtained were fitted into zero order, first order Higuchi model and Korsmeyer’s equation release models.18, 19

 

Stability studies:

To assess the drug and formulation stability, stability studies were done according to ICH guidelines. 20 The optimized formulation was subjected to stability study at 40 ± 2ºC and 75 ± 5% RH for 90 days.  The samples were evaluated for physical changes, hardness, friability, drug content, buoyancy study and percentage drug release during the stability studies.

 

RESULTS:

FTIR spectroscopy:

The pure drug ofloxacin and the solid admixture of drug and various polymers used in the preparation of floating tablet formulations were characterized by FT-IR spectroscopy to know the compatibility. The spectra are shown in Fig 1-3.

 

 

Figure 1: FTIR Spectroscopy of pure drug


Table 1: Composition of different formulations

Ingredients

(mg /tablet)

Formulation

F1

F2

F3

F4

F5

F6

F7

F8

Ofloxacin

200

200

200

200

200

200

200

200

Guar gum

248

234

220

206

-

-

-

-

Locust bean gum

-

-

-

-

248

234

220

206

HPMC K100M

-

14

28

36

-

14

28

36

Sodium Bicarbonate

60

60

60

60

60

60

60

60

Magnesium stearate

11

11

11

11

11

11

11

11

Talc

5.5

5.5

5.5

5.5

5.5

5.5

5.5

5.5

MCC

13

13

13

13

13

13

13

13

PVP K30

12.5

12.5

12.5

12.5

12.5

12.5

12.5

12.5

Total weight of tablet-550mg

 

Table 2: Granules properties of formulations F1 to F8 of Ofloxacin floating tablets

Formulation

No.

Angle of repose*

Loose bulk density (LBD) * (g/ml)

Tapped bulk density (TBD) * (g/ml)

Compressibility index (%)*

F1

29.24 ± 0.78

0.4098 ± 0.006

0.4716 ± 0.011

13.10 ±  0.75

F2

27.47 ± 1.27

0.4032  ±0.007

0.4504 ± 0.010

10.47 ±  1.26

F3

26.56 ± 1.21

0.4132 ± 0.004

0.4761 ± 0.011

13.21 ± 1.63

F4

29.05 ± 1.08

0.3937 ± 0.004

0.4638 ± 0.014

15.11 ± 1.23

F5

27.40 ± 1.81

0.4201 ± 0.009

0.4761 ± 0.012

11.76 ± 1.35

F6

28.30 ± 1.57

0.4032 ±0.008

0.4504 ± 0.014

10.49 ± 0.49

F7

29.74 ± 0.73

0.3968 ± 0.007

0.4418 ± 0.013

11.97 ± 0.65

F8

27.47 ± 1.03

0.4065 ± 0.003

0.4761 ± 0.015

14.65 ± 0.71

* (n=3, ±S.D.)

 

Table 3: Tablet properties of formulations F1 to F8 of Ofloxacin floating tablets

Formulation No.

Hardness* (kg/cm2)

Thickness* (mm)

% Friability

Weight Variation*(mg)

% Drug content

F1

5.7±0.3

4.15±0.05

0.24

549.8±1.687

99.06

F2

5.6±0.2

4.17±0.05

0.30

550.2±1.370

97.89

F3

5.9±0.4

4.16±0.07

0.24

550.3±1.767

98.13

F4

6.1±0.3

4.15±0.08

0.52

548.9±2.132

99.68

F5

5.8±0.2

4.16±0.05

0.36

549.2±2.394

97.81

F6

6.1±0.3

4.17±0.02

0.31

550.3±1.494

99.37

F7

5.7±0.2

4.16±0.05

0.39

550.2±2.044

100.31

F8

5.9±0.4

4.15±0.03

0.18

548.5±2.251

98.50

* (n=3, ±S.D.)


 


 

Figure 2: FT-IR Spectroscopy of Formulation 3

 

Figure 3: FT-IR Spectroscopy of Formulation 6

 

 


Characterization of granules:

Granules prepared for compression of floating matrix tablets were evaluated for their flow properties like angle of repose, bulk density, tapped density and compressibility index. The results were shown in Tables 2. Angle of repose was in the range of 26.56 ± 1.21to 29.74 ± 0.73. The bulk density of the granules was in the range of 0.3937 ± 0.004 to 0.4201 ± 0.009 gm/ml; the tapped density was in the range of 0.4418 ± 0.013 to 0.4761 ± 0.015gm/ml, which indicates that the granules were not bulky. The Compressibility index was found to be in the range of 10.47 ± 1.26 to 15.11 ± 1.23.

 

Physicochemical evaluation of floating tablets:

The results of physicochemical characterizations are shown in Tables 3. The thicknesses of floating tablets were measured by vernier caliper and were ranged between 4.15±0.03 to 4.17±0.05 mm. The hardness of the floating tablets was measured by Monsanto tester and was controlled between 5.6±0.2 to 6.1±0.3 kg/cm2. The friability was below 1% for all the formulations. Weight variation for different formulations were found to be 548.5±2.251 to 550.3±1.767mg,. The percentage of drug content for F1 to F9 was found to be in between 97.81% to 100.37% of ofloxacin it complies with official specifications.

 

 

Table 4:  Buoyancy studies of formulations F1-F8

Formulation code

Floating lag time (min)

Floating duration

F1

7.83

Disintegrated after 8 hrs.

F2

5.71

Disintegrated after 10 hrs.

F3

3.32

>12 hrs

F4

2.45

>12 hrs

F5

5.05

>12 hrs

F6

2.45

>12 hrs

F7

1.66

>12 hrs

F8

1.07

>12 hrs

 

Buoyancy Studies:

The floating lag time determined by keeping tablet in 100ml beaker containing 0.1N HCl. Whereas total floating duration determined during dissolution studies. The results are shown in table 4.

 

Swelling index:

Swelling index for all the formulations was carried out in the 0.1N HCl. Graphical representation swelling index of all the batches were shown in figure 5.

 

Figure 4: Swelling Index of floating tablets F1-F8

 

 

Figure 5: Drug release profile of floating tablets F1-F8


Table 5: Swelling Index of floating tablets F1-F8

Time in ‘hrs’

Swelling index (%) Formulation code

F1

F2

F3

F4

F5

F6

F7

F8

0

0

0

0

0

0

0

0

0

1

86.18

110.36

119.9

150.36

80.61

95.98

103.81

120.87

2

119.6

148.54

175.73

219.2

112.18

120.25

127.81

153.72

3

148.18

180.90

234.18

265.8

133.8

145.43

152.72

186.20

4

180.18

203.27

275.8

302.5

140.76

176.64

186.36

215.78

5

124.0

225.63

304.9

343.8

164.45

197.0

209.40

241.01

6

84.36

250.45

315.4

378.36

186.59

216.9

231.81

263.70

7

 

203.81

330.4

400.36

209.05

239.23

248.72

284.02

8

 

160.18

350.5

417.27

226.26

262.59

270.72

300.72

9

 

108.18

341.1

429.0

208.87

284.12

292.54

316.87

10

 

 

330.4

418.3

193.84

268.24

285.0

331.39

11

 

 

320.6

407.8

178.07

252.73

279.09

333.75

12

 

 

309.0

399.09

164.13

237.59

267.81

340.65

 

Table 6: Kinetic values obtained from different plots of formulations F1 to F8

Formulations

 

Zero order plots◘

First order plots▪

Higuchi’s plots●

Korsmeyer et al’s plots□

R2

R2

R2

R2

Slope(n)

F1

0.858

0.635

0.991

0.990

0.48

F2

0.902

0.857

0.998

0.992

0.45

F3

0.948

0.889

0.998

0.997

0.57

F4

0.960

0.952

0.997

0.998

0.604

F5

0.896

0.817

0.993

0.995

0.46

F6

0.948

0.896

0.995

0.989

0.569

F7

0.965

0.947

0.990

0.985

0.60

F8

0.969

0.983

0.995

0.997

0.67

◘Zero order equation, C=K0 t, First order equation, Log C=log Cₒ-Kt/2.303, ●Higuchi’s equation, Q= Kt½, □Korsmeyer et al’s equation, Mt/= Ktn

 


In vitro release study

In vitro dissolution studies were performed for all the formulations using USPXXII Tablet dissolution tester employing paddle type at 50 rpm using 900 ml of 0.1N HCl as dissolution medium. The samples withdrawn were analyzed by using UV spectrophotometer. As per the results of dissolution study formulations F1, F2, F3, F4, F5, F6, F7, F8 showed 99.98%, 98.91%, 97.8%, 92.27%, 99.59%, 97.33%, 92.2%, and 86.12% respectively. This showed that the drug release from the tablet was sustained for 8 to 12hr. Graphical representation drug release profile of all the batches were shown in figure 5.

 

Drug Release Kinetics:

The drug release data were fitted to models representing zero order (cumulative amount of drug released vs. time), first order (log percentage of drug unreleased vs. time), Higuchi’s (cumulative percentage of drug released vs. square root of time), and Korsmeyer’s equation (log cumulative percentage of drug released vs. time) kinetics to know the release mechanisms. The results were shown in table 6.

 

DISCUSSION:

The present study was aimed to make the formulation remain in the stomach for longer period of time, gastro retentive dosage form was designed, to release the drug in sustained manner in gastric fluid.

 

FT-IR study were carried out to know the compatibility As shown in figure 1-3, there was no significant difference or the characteristic peaks of pure drug were unchanged in spectrum of optimized formulation. The granules of different formulations were evaluated for angle of repose, LBD, TBD, compressibility index. The results of angle of repose  indicate reasonably good flow property of granules. The results of bulk and tapped density which indicates that the granules were not bulky. The Compressibility index results, indicating compressibility of the tablet blend is good. The resuts of Granular properties of formulation F1-F8 were shown in table 2.

 

The ofloxacin floating tablets were off-white, smooth, and flat shaped in appearance. According to table 3 the results of hardness and friability were an indication of good mechanical resistance of the tablets.  The weight variation test showing satisfactory results as per Indian Pharmacopoeia (IP) limit. Good uniformity in drug content was found among different formulation of the tablets.

 

For buoyancy gas generating agent plays important role, the gas generating agents immediately evolves carbon dioxide in presence of HCl solution generating sufficient porosity which helped the dosage unit to float. Formulation F1 prepared with guar gum started floating after 7.83min and remains buoyant for 8 hr till they were completely eroded. On the other hand, formulation F2-F4 prepared with combination of guar gum and HPMC K100M show decrease in floating lag time and increased floating duration time. This might be due to high viscosity polymer HPMC K100M maintains the integrity of the tablets for longer duration by reducing the effect of erosion thus resulting in increase in floating time. Similar results were obtained with batches prepared from locust bean gum. The selected formulations F3 and F6 shows floating lag time 3.32min and 2.45min respectively with floating duration time >12 hrs. the results for buoyancy study were shown in table 4.

According to table 5 F4 and F8 showed maximum swelling in 12 hr with sharp increase up to 8 hr, this may due to increased concentration of HPMC K100M which retains water and form thick swollen mass. The selected formulations F3 and F6 show maximum swelling up to 8 hr followed by decrease in swelling index. Reason behind this may be erosion process initiation at the end of 8 hr attributing gradual decrease in percent swelling after 8hr.

Formulations F3 and F6 (97.8% and 97.33% in 12 hr) show reasonable drug release when compared to other formulations. Also all other parameters like hardness, thickness, friability, drug content and weight variation for these formulations were within the range. So, formulations F3 and F6 were selected as the optimized formulations. It is evident from the in vitro dissolution data  that increase in HPMC K100M concentration decreases  the release rate this might be due to increase in diffusional path length, which the drug molecule may have to travel. Comparative dissolution profile is presented in fig 5.

 

As per table 6 all the formulations in this investigation could be best expressed by Higuchi’s classical diffusion equation, as the plots showed high linearity (R2 : 0.990 to 0.998) indicates that the drug release follows diffusion mechanism. To confirm the diffusion mechanism, the data were fitted into Korsmeyer–Peppas equation. All the formulations showed values ranging from 0.45 to 0.67, indicating that non-Fickian/anomalous diffusion (If the exponent n=0.45, then the drug release follows the Fickian diffusion, and if 0.45 < n < 0.89, then it is said to be non-Fickian or anomalous release).

 

CONCLUSION:

Floating matrix tablets containing ofloxacin can be prepared successfully by using wet granulation technique. Tablets were subjected to various evaluation parameters such as Weight variation, Hardness, Friability, Drug content, Swelling index, in vitro drug release study, in vitro buoyancy study. It was revealed that tablets of all batches had acceptable physical parameters. FT-IR studies revealed that there was no interaction between ofloxacin and other excipients used in the tablets.  It was found that increase in the HPMC K10M concentration will decrease floating lag time and increases floating duration but decrease drug release. Tablets of batch F3 and F6 have considerable in vitro drug release, and also showing good floating lag time. The drug release kinetics follows Higuchi model and the mechanism was found to be non Fickian/anomalous. The stability studies were carried out according to ICH guideline which indicates that the selected formulation was stable.

 

ACKNOWLEDGEMENT

The authors are thankful to the Management, Sree Siddaganga College of Pharmacy Tumkur for providing necessary facilities to carry out this work.

 

REFERENCES:

1.        Gangadharappa HV, Pramod Kumar TM, Shiva Kumar HG. Gastric floating drug delivery systems: A review. Indian J Pharm Educ Res 2007; 41(4): 295-303.

2.        Santus G, Lazzarini G, Bottoni G. An in vitro-in vivo investigation of oral bioadhesive controlled release furosemide formulations. Eur J Pharm Biopharm 1997; 44: 39-52.

3.        Deshpande AA, Rhodes CT, Shah NH, Malick AW. Controlled-release drug delivery systems for prolonged gastric residence: An overview. Drug Dev Ind Pharm 1996; 22: 531-9.

4.        Deshpande AA, Rhodes CT, Shah NH, Malick AW. Development of a novel Controlled-release drug delivery systems for gastric retention. Pharm Res 1997; 14: 815-9

5.        Menon A, Ritshel WA, Sakr A. Devlopement and evaluation of a monolithic floating dosage form for furosemide. J Pharm Sci 1994; 83: 239-45.

6.        Whitehead L, Fell JT, Collett JH, Sharma HL, Smith AM. Floating dosage forms: An in vivo study demonstrating prolonged gastric retention. J Control Rel 1998; 55: 3-12.

7.        Patel DM, Patel NM, Pandya NM, Jogani PD. Formulation and optimization of carbamazepine floating tablets. Indian J Pharm Sci 2007; 69(6): 763-7.

8.        Prabhu P, Harish NM, Gulzar AM, Yadav B, Narayana CR, Satyanarayana D et al. Formulation and in vitro evaluation of gastric oral floating tablets of glipizide. Indian J Pharm Educ Res 2008; 42(2): 174-83.

9.        Chien YW. Novel drug delivery systems. 2nd ed.  New York: Informa Healthcare USA; 2009. p. 164.

10.     Tang X, Cui Y, Zhang Y. In vitro and in vivo evaluation of ofloxacin sustained release pellets. Int J Pharm 2008; 360(1): 47-52.

11.     Block JH, Beale JM, editors. Wilson and Gisvold’s textbook of organic medicinal and   pharmaceutical chemistry. 11th ed. Philadelphia: Lippincott Williams and Wilkins; 2004. p. 248.

12.     Cooper J and gunn G. Powder flow and compaction, In; Tutorial pharmacy (carter SJ; Eds.) New Delhi. India; CBS Publishers and distributers; 1986. p. 211-233.

13.     Shah DY, Rampadhan M. Development and evaluation of controlled release diltiazem hydrochloride microparticles using cross-linked polymer (vinyl alcohol). Drug Dev. Ind. Pharm. 1997; 23 (6): L 567-574.

14.     Aulton ME, and well TI. Pharmaceutics: The Sciences of Dosage form Design, London, England; Churchill Livingstone; 1998.

15.     Hadjiioannou TP, Christian GD, koupparis MA. Quantitative calculations in pharmaceutical practices and Research New Dehli, NY: VCH publishers INC; 1993: 345-48.

16.     Rosa M, Zia H, Rhodes T. Dosing and testing in vitro of a bioadhesive and floating drug delivery system fororal application, Int. J Pharm., 1994; 105: 65-70.

17.     Lalla JK, Gurnancy RA. Polymers for mucosal delivery-swelling and mucoadhesive delivery. Indian Drugs 2002; 39: 270-276

18.     Higuchi T. Mechanism of sustained action medication. Theoretical analysis of rate releaseof solid drugs dispersed in solid matrices. J Pharm Sci. 1963; 52: 1145-1149.

19.     Korsmeyer RW, Gunny R, Peppas NA. Mechanism of solute release from porous hydrophilic polymers. Int J Pharmaceutics. 1983; 15: 25-35.

20.     Cartensen J T. Drug Stability: Principle and Practices, Marcel Dakker, New Work, 2nd Ed, 1995, p. 538-50.

 

 

 

 

Received on 17.01.2011  Accepted on 20.02.2011            

© Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 1(1): Jan.-Mar. 2011; Page 09-16