INTRODUCTION:

Gastroretentive systems can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste and improves solubility for drugs that are less soluble in a high pH environment¹. Gastro retentive drug delivery ensures maximum utilization of drugs with minimum side effects and better patient compliance. Several approaches have been developed to achieve extended gastric residence time of the oral drug delivery systems such as bio-adhesive system, swelling and expanding systems, floating systems and delayed gastric emptying devices. Amongst these methods, floating drug delivery system is preferred one that offers a simple and practical approach to achieve gastro retention². Ofloxacin is an antibacterial antibiotic.

The mechanism by which it exerts this effect is by binding to and inhibiting topoisomerase II (DNA gyrase) and topoisomerase IV. These bacterial enzymes are responsible for the coiling and uncoiling of DNA, which is needed for bacterial cell repair and ofloxacin exhibits pH-dependent solubility³. Ofloxacin is readily soluble in gastric environment, but it has poor absorption from the lower part of the intestine. The absorption site for the ofloxacin is the upper part of gastrointestinal tract⁴. To overcome the above drawbacks, gastro retentive floating tablets of ofloxacin were developed, which will improve the bioavailability of the drug and increase the retention time of the dosage form within acidic medium with controlled release of drug for the prolonged period of time. The natural polymers always have unique properties which make them distinct from the synthetic polymers and tamarind seed polysaccharide is also not an exemption from this, as it shows a wide range of properties making it a potent polymer not only in the field of food industries but also in the field of pharmaceutical industries⁵. Pectin has promising pharmaceutical uses such as in controlled release dosage forms and also having very safe toxicity profile, which makes pectin an interesting and promising excipient for the pharmaceutical industry⁶. Hence the present study was conducted with an aim to formulate and evaluate the gastro retentive floating tablets of ofloxacin using natural polymers and to improve the bioavailability.

MATERIALS AND METHODS:

Materials:

Ofloxacin was procured from Waksman Selman Pharmaceuticals, Pvt. Ltd., Anantapur, Andhrapradesh, India and Tamarind seeds were purchased from local market of Anantapur. Pectin was purchased from SD Fine Chemicals, Mumbai, India. Sodium bicarbonate and tartaric acid were purchased from Thermo Fishers scientific, Mumbai, India. All chemicals used were of analytical grade.

Drug excipients compatibility studies:

FT-IR Studies:

Infrared spectra of pure drug and mixture of drug and excipients were recorded by Fourier Transform Infrared Spectrophotometer (Shimadzu, Japan). In the present study, drug and excipients were taken in 1:1 ratio in a mortar and mixed with KBr and compressed into pellets⁷. The Samples were analyzed in the scanning range of 4000-400 cm^-1.

DSC Analysis:

The drug and natural polymers were taken in a small amount in a aluminium pan and this pan is sealed by crimping. The sample were analysed using a differential scanning calorimeter (Perkin Elmer, USA) with a heating rate of 10˚c/min with nitrogen pure gas at a flow rate of 20ml/min⁸.

Isolation of Tamarind Seed Polysaccharide:

The seeds of tamarindus indica were washed thoroughly with water to remove the adhering materials. The seeds were heated in the sand in the ratio of 1:4 (Seed: Sand) to remove the testa and were crushed lightly. The crushed seeds were soaked in water for 24 h and then boiled for 1 h and kept aside for 2 h for the release of mucilage into water. The soaked seeds were taken and squeezed in a muslin bag to remove marc from the filtrate. To precipitate the mucilage equal quantity of acetone was added and mucilage was separated. The separated mucilage was dried at 50°C, powdered and passed through sieve number 80 and stored in airtight container at room temperature⁹.

Formulation of ofloxacin floating tablets:

The ofloxacin floating tablets were prepared by wet granulation method. Six formulations were developed and coded as F1, F2, F3, F4, F5, F6. The drug, polymer and excipients were weighed according to the composition tabulated in (Table 1) and were passed through sieve 60 and mixed well. The above mass was granulated with 10% solution of PVP K30 in IPA (Isopropyl alcohol). The wet mass was passed through sieve 10 and dried at 45°C for 2 h using tray dryer. Dried granules were passed through sieve 22 and mixed with magnesium stearate, talc¹⁰and compressed by using rotary compression machine (Rimek mini press).

Table 1: Composition of Ofloxacin floating tablets

Ingredients(mg)	F1	F2	F3	F4	F5	F6
Ofloxacin	200	200	200	200	200	200
Pectin	-	-	-	60	120	180
Tamarindseed polysaccharide	60	120	180	-	-	-
Sodium Bicarbonate	120	120	120	120	120	120
Tartaric acid	60	60	60	60	60	60
Magnesium stearate	6	6	6	6	6	6
Talc	6	6	6	6	6	6
Lactose	148	88	28	148	88	28
PVP	Qs	Qs	Qs	Qs	Qs	Qs
Total weight	600	600	600	600	600	600

Evaluation of precompression parameters:

Bulk density:

It is the ratio of total mass of powder to the bulk volume of the powder. It is estimated by pouring the known weight of powder into a measuring cylinder and volume was noted. This is called the bulk volume¹¹.It is expressed as gm/ml and is given by

Bulk density = mass of powder (w) / bulk volume

Tapped density:

The tapped density was estimated by using tapped density apparatus (Electro lab). Weighed quantity of sample was taken into 250 ml measuring cylinder and the cylinder was kept on cylinder holder and allowed to tap for 500 times and the tapped volume was noted¹².The tapped density was determined by using the following formula

Tapped density = mass of powder / tapped volume.

Angle of repose:

A glass funnel was held in place with a clamp on a ring support over a tile. Approximately 100g of powder was transferred into funnel through a mesh size no. 20 keeping the orifice of the funnel blocked by the thumb. When the powder was emptied from the funnel, the angle of the heap to horizontal plane was measured with a scale. The height of the pile (h) and the radius of the base was measured with a ruler¹³.

θ=tan-1h/r Where

θ=angle of repose, h=height of pile, r=radius of base if pile

Carr’s index:

It is measured by using the bulk density and tapped density¹⁴.

Tapped density – Bulk density

Carr’s index = –––––––––––––––––––––––––– × 100

Bulk density

Hausner’s ratio:

It is the ratio of tapped density to the bulk density¹⁵. It is calculated by using the formula

Hausner’s ratio = Tapped density / Bulk density

Evaluation of post compression parameters:

Hardness:

The hardness of each batch of tablets was estimated using Monsanto hardness tester¹⁶. The hardness was measured in terms of kg/cm².

Thickness:

Thickness was estimated by using vernier callipers. Randomly tablets were taken and kept in between the two upper jaws and thickness was measured¹⁷.

Friability:

The friability of floating tablets was measured using a friability tester (Electrolab) by operating at 25 rpm for 4 min. The tablets were removed, dedusted, accurately weighed and the percent weight loss was calculated¹⁸.

Weight variation:

Twenty tablets from each formulation were selected randomly and weighed individually and average weight was determined. Individual tablets weights were then compared with average weight¹⁹.

Drug content:

10 tablets were collected randomly and crushed in a mortar to form powder and weighed samples of tablet powder equivalent to dose were taken. The samples were diluted with 0.1N HCl in a 100ml volumetric flask. The contents were shaken for a time frame and then filtered in Whatmann paper and absorbance was estimated at 294nm using 0.1N HCl²⁰.

Swelling index:

The swelling index of tablets was determined by using 0.1 N HCl at room temperature. The swollen weight of the tablets was determined at predefined time intervals. The Swelling characteristics were expressed in terms of percentage water uptake (WU %) according to the equation²¹.

% WU = (Wt‐Wo/Wo) ×100

Where

WU – Water uptake

Wt – Weight of tablet at time t

Wo – Weight of tablet before immersion

Floating lag time and total floating time:

In vitro buoyancy was determined by floating lag time and total floating time. The tablets were placed in a 100 ml beaker containing 0.1N HCl. The time required for the tablet to rise to the surface of the liquid and the duration of the time it remained floating were noted as floating lag time and total floating time respectively²².

In vitro drug release study:

The in vitro release of ofloxacin floating tablets was determined using the USP dissolution apparatus II. 900ml of 0.1N HCl was used as the dissolution medium. The test was performed at 37±0.5°C with 50rpm. At suitable intervals of time, required amount of samples were collected and replaced with fresh medium. These samples were filtered and filtrates were analyzed by using UV Spectrophotometer at 294 nm²³.

Drug release kinetics:

In vitro dissolution data was fitted to mathematical models like Zero order, First order, Higuchi plots, and koresmeyer peppas plots to determine the order of drug release mechanism²⁴.

RESULTS AND DISCUSSION:

Floating tablets were prepared by utilizing the polymers like TSP and Pectin. The FT-IR studies demonstrated that no major shift of peaks in drug and excipients that are used in the formulation and shown in (Figure 1). The thermograms in the DSC studies showed that there is no major interaction between drug and excipients and shown in (Figure 2) respectively.

Fig.1: A) FT-IR spectrum of Ofloxacin B) FT-IR spectrum of Ofloxacin and TSP C) FT-IR spectrum of Ofloxacin and Pectin

A B C

Fig.2: A) DSC thermogram of Ofloxacin B) DSC thermogram of Ofloxacin and TSP C) DSC thermogram Ofloxacin and Pectin

Table 2: Evaluation of flow properties of the formulations F1-F6

Formulation	Bulk density (gm/ml)±SD*	Tapped density (gm/ml)±SD*	Angleof repose(º) ±SD*	Carr’s index(%) ±SD*	Hausner’s ratio ±SD*
F1	0.438±0.03	0.487±0.02	23.5±0.12	10.06±0.22	1.11±0.11
F2	0.527±0.01	0.591±0.01	23.62±0.06	11.86±0.01	1.13±0.02
F3	0.442±0.13	0.492±0.03	24.57±0.08	10.16±0.12	1.11±0.06
F4	0.545±0.15	0.617±0.04	24.01±0.10	11.40±0.18	1.13±0.09
F5	0.561±0.12	0.635±0.02	25.01±0.09	11.65±0.14	1.04±0.04
F6	0.500±0.17	0.561±0.05	24.7±1.14	10.87±0.01	1.12±0.05

* All values are expressed as mean ± SD (n=3)

Table 3: Post compression parameters of formulations F1-F6

Formulation	*Hardness (kg/cm²) ±SD(n=5)*	*Friability ±SD(n=10)*	*Average weight ±SD(n=20)*	*Drug content ±SD(n=10)*
F1	5.1±0.10	033±0.10	598±0.02	93.2±0.41
F2	5.5±0.21	0.10±0.12	602±0.04	99.1±0.21
F3	5.4±0.26	0.40±0.16	599±0.01	92.4±0.54
F4	5.9±0.32	0.32±0.21	597±0.03	95.5±0.44
F5	5.2±0.38	0.37±0.28	600±0.02	94.3±0.38
F6	5.0±0.42	0.44±0.33	599±0.05	97.6±0.43

*(All values are expressed as mean ± SD)

Evaluation of post compression parameters:

Hardness of each batch of the tablets were found to be within the range of 5.0-5.9kg/cm². It ensures the good characteristics for all formulations. Percentage friability was less than 0.5% for all the formulations, ensuring that all the tablets are mechanically stable and found to be within the range of 0.1-0.4%. All the formulations passed the weight variation test and were within the standard limits of ± 5% of weight. All the results were tabulated in (Table 3). The drug content and was found to be in the range of 92.4- 99.1%. The formulation F2 showed the drug content of 99.1%.

Evaluation of precompression parameters:

The angles of repose of all formulations were found to be in the range of 23.5º-25.01º. The formulation F2 shown an angle of repose of 23.92º, which indicates that the flow property was excellent. Carr’s indexes of all formulations were found to be in the range of 10.06% - 11.86%. Formulation F2 showed Carr’s index 11.86% which indicates that the flow property was excellent. Hausner’s ratio of all formulations were found to be in the range of 1.04 - 1.13. Formulation F2 showed Hausner’s ratio of 1.13 which indicates that flow property was good. The results were represented in (Table 2).

In vitro buoyancy studies:

The formulations F1, F2 and F3 prepared with TSP shown the floating lag time of 68 sec, 45 sec, and 71 sec and exhibited the total floating time of 11 h, 12 h, and 12 h. An increase in the polymer concentration in the formulations F2 and F3 increased the total floating time²⁵. The formulations F4, F5, F6 prepared with pectin shown the floating lag time of 90 sec, 85 sec, 74 sec and exhibited the total floating time of 11 h, 12 h, 12 h and were tabulated in (Table 4).

Table 4: Floating lag time and Total floating time of formulations F1-F6

Formulation	Floating lag time(sec)	Total floating time (h)
F1	68	11
F2	45	12
F3	71	12
F4	90	11
F5	85	12
F6	74	12

Swelling index:

The prepared tablets were evaluated for swelling index. Formulation F2 showed the swelling index of 75% as presented in (Table 4). Enhanced swelling index was observed with an increase in the polymer concentration. This could be due to the hydrophilic property of the polymer²⁶ and the results were represented in (Table 5).

Table 5: Swelling index of formulations F1-F6

Formulations	Swelling index (%) ± SD*
Formulations	2h	4h	6h	8h
F1	26 ±0.02	44 ±0.07	53 ±0.03	62 ±0.89
F2	27 ±0.06	52 ±0.23	64 ±0.19	75 ±0.01
F3	23 ±0.09	47 ±0.74	56 ±0.54	76 ±0.54
F4	20 ±0.05	38 ±0.65	53 ±0.45	66 ±0.62
F5	22 ±0.08	47 ±0.75	54 ±0.64	68 ±0.94
F6	26 ±0.01	51 ±0.98	59 ±0.73	70 ±0.87

* All values are expressed as mean ± SD (n=3)

In vitro dissolution study of ofloxacin floating tablets:

Formulation F1 containing 10% TSP could not able to float upto 12 h and showed only 75.5% of drug release at the end of 11 h. The formulation F2 containing 20% TSP showed the higher drug release of 95.4% at the end of 12 h. Formulation F4 containing 10% Pectin as polymer has showed drug release of 72.8% at the end of 11 h. The Formulation F6 containing 30 % pectin polymer showed the drug release of 89.2% at the end of 12 h. The results clearly indicate that an increase in concentration of polymer can able to release the drug release up to 12 h ²⁷.

Fig. 3: Drug release profile of formulations F1-F6

In vitro drug release kinetics:

The dissolution data was fitted to various kinetic models like zero order, first order, higuchi, korsemeyer peppas. R²values of zero order kinetics of F2 formulation was found to be 0.995. R² values of first order kinetics of F2 formulation was found to be 0.866. The n-value of the F2 formulation was observed as 0.987 and the mechanism of drug release was found to be non-fickian²⁸.

CONCLUSION:

The gastroretentive ofloxacin floating tablets were prepared successfully by using wet granulation method. Among all the formulations, formulation F2 containing 20% tamarind polysaccharide showed 95.4% drug release at end of 12 h with floating lag time of 45sec and can be considered as the promising formulation. The formulation F2 follows zero order kinetics and the mechanism of drug release was found to be non-fickian.

ACKNOWLEDGEMENT:

The authors are thankful to DST-FIST facility of Raghavendra Institute of Pharmaceutical Education and Research (RIPER) - Autonomous, Anantapur, AP, India for the provided support experimental part.

CONFLICT OF INTEREST:

None.

REFERENCES:

1. Shweta A, Javed A, Alka A. Floating drug delivery systems: A review. AAPS Pharm Sci Tech. 2005; 6(1):372-390.

2. Rajani S, Panna T, Ranendra N. In vitro and in vivo evaluation of gastro retentive floating drug delivery system of ofloxacin. Asian Journal of Pharmaceutical Sciences 2013; 8:191-198.

3. Gangurde HH et al. Formulation and evaluation of sustained release bioadhesive tablets of ofloxacin using 3² factorial design. Int J Pharm Investig. 2011; 1:148–156.

4. Prabhakar Reddy V, Spandana B. Formulation and evaluation of gastroretentive dosage form of ofloxacin. S. J. Pharm. Sci 2011; 4: 09-18.

5. Joseph J, Kanchalochana S. Tamarind seed polysaccharide: A promising natural excipient for pharmaceuticals. Int J Green Pharm. 2012; 6:270-278.

6. Poonam Y, Parijat P, Sonia P. Pectin as Natural Polymer: An overview. Research J. Pharm. and Tech. 2017; 10: 1225-1229.

7. Haranath C et al. Formulation and in vitro evaluation of fast dissolving tablets of Lacosamide using natural super disintegrants. Int J Pharm Sci and Res. 2019; 10: 2769-76.

8. Vijay D, Suparna S. Development and evaluation of ofloxacin floating tablets using natural polymer: sterculia foetida Linn. gum. Int J Pharm Pharm Sci. 2016; 8:356-360.

9. Rashmi M, Arora SC. Tamarind Seed Polysaccharide and its modifications. Int J Pharma. 2014; 6: 412-420.

10. Niraj G, Shrivastava VK. Prepare and evaluate floating gastro retentive tablets of Ofloxacin. Int J of Scientific Research. 2016; 2:29-34.

11. Syam Prasad B et al. Evaluation of different synthetic and natural polymers as protective layer on highly soluble and high dose drug metoprolol succinate for manufacturing of control release multi unit pellets tablets. Int J App Pharm. 2018; 10: 69-76.

12. Shajan A et al. Formulation and evaluation of gastro-retentive drug delivery system containing a combination of glipizide and metformin hydrochloride. Asian J Pharm Clin Res. 2016; 9:235-40.

13. Abdulahad H, Pradeepkumar B, Haranath C. Fabrication and evaluation of glimepiride Cordia dichotoma G. Forst fruit mucilage sustained release matrix tablets. International Journal of Chemical Sciences. 2009; 7: 2555-60.

14. Arunachalam A, Mazumder A. The outcome of formulation and in vitro release studies of levothyroxine sodium tablets. Asian Journal of Pharmaceutical Science and Technology. 2011;1:33-39.

15. Ramu, B Shanmuga P. Formulation and evaluation of floating osmotic tablets of nizatidine. J App Pharm. 2015; 8: 1-7.

16. Vivek D, Vandana A. Formulation and evaluation of effervescent floating tablets of amlodipine besylate with natural polymer chitosan. Journal of Pharmaceutical and Scientific Innovation. 2012; 1: 13-18.

17. Atul Mansing K et al. Formulation and evaluation of anti-ulcer floating tablet using swellable polymers. International Journal of Drug Delivery. 2014; 6: 244-253.

18. Prasanthi S, Vidyavathi M. Optimization of valsartan floating tablets by 3² factorial design. Asian Journal of Pharmaceutics. 2017; 11: 625-634.

19. Lokesh K, Virendra S. Formulation and evaluation of gastro retentive floating tablets of Terbutaline sulphate. International Journal of Pharma Sciences and Research. 2014; 5: 639-645.

20. Saigeethika S, Singhvi G. Formulation and evaluation of floating tablets of ofloxacin. Int J Pharm Sci Res. 2012; 3: 4291-4296.

21. Manoj kumar S et al. Formulation, optimization and evaluation of floating tablets clarithromycin. Int J Pharm Pharm Sci. 2014; 7: 320-326.

22. Suresh K et al. Design and evaluation of an oral floating matrix tablet of salbutamol sulphate. Trop J Pharm Res. 2012; 11: 569-576.

23. Padmavathy J, Saravanan D. Formulation and evaluation of ofloxacin floating tablets using HPMC. Int J Pharm Pharm Sci. 2011; 3: 170-173.

24. Saritha D et al. Formulation and evaluation of gastroretentive floating tablets of domperidone maleate. Journal of Applied Pharmaceutical Science. 2012; 2: 68-73.

25. Haranath C et al. Formulation and in vitro evaluation of floating tablets of dicloxacillin sodium using different polymers. J Young Pharm. 2019; 11: 248-53.

26. Navjot K et al. Preparation and evaluation of floating tablets of pregabalin. Drug Dev Ind Pharm. 2015; 1: 1-7.

27. Anilkumar J et al. Formulation and evaluation of an oral floating tablet of cephalexin. Indian J. Pharm. Edu. Res. 2010; 44: 1-10.

28. Bansod YB et al. Quality by design approach for development of verapamil hydrochloride floating matrix tablet. American Journal of Pharm Tech Research. 2014; 4:890-904.

Received on 27.01.2020 Modified on 01.03.2020

Research J. Pharm. and Tech. 2021; 14(2):851-856.

DOI: 10.5958/0974-360X.2021.00151.7