International Journal of Drug Development and Research

Keywords

Ofloxacin, effervescent floating tablets, psyllium husk

INTRODUCTION

The real challenge in the development of oral controlled release dosage forms is not just to prolong the delivery of drugs for more than 12 hours, but to prolong the presence of the dosage forms in the stomach or upper gastrointestinal tract until all the drug is released for the desire period of time1. Rapid gastrointestinal transit could result in incomplete drug release from the drug delivery device in the absorption zone leading to diminished efficacy of the administered dose2. Therefore, various attempts have been made to retain the dosage form in the stomach as a way of increasing the retention time. These attempts include floating system3 (gas generating systems), Swelling and expanding systems4&5, Mucoadhesive systems6&7, High density systems8, Modified shape systems9&10, Gastric emptying delaying devices and co-administration of gastric delaying drugs. 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 environment11. Based on the mechanism of buoyancy, two types of technologies are developed in the floating systems. They are non effervescent and effervescent systems. Non effervescent systems prepared by using polyacrylate, polycarbonate, polystyrene as excipients swells unrestrained via inhibition of gastric fluid to an extent which will prevent their exit from stomach12. Effervescent system utilizes matrices prepared by using swellable polymers like methocel, polysaccharides and effervescent compounds like sodium bicarbonate, citric acid or tartaric acid13. Ofloxacin is a fluoroquinolone antibacterial agent which is highly effective against gram positive and gram negative bacteria14. 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). Thus it is more soluble in acidic pH environment and slightly soluble at neutral or alkaline condition15 (intestinal environment). The tablet form of Ofloxacin has bioavailability approximately 98% following oral administration reaching maximum serum concentrations within one to two hours. Between 65% and 80% of an administered oral dose of Ofloxacin is excreted unchanged via the kidneys within 48 hours of dosing. Therefore, elimination is mainly by renal excretion. Plasma elimination half-life is approximately 4 to 5 hours in patients. Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control the emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms, it is widely acknowledged that the extent of gastrointestinal tract drug absorption is related to contact time with the small intestinal mucosa16. The objective of present study was to develop matrix floating tablets of Ofloxacin using HPMC K4M and HPMC K100M alone and combination with Psyllium husk and Xanthan gum and evaluating the prepared tablets for physicochemical properties, floating lag time, total floating time, swelling index, dissolution study and FT-IR studies.

MATERIALS AND METHODS:

Materials:

Ofloxacin was obtained as a gift sample from Dr. Reddy’s Pharmaceuticals, Hyderabad, HPMC K4M and HPMC K100M were obtained from Aurobindo Pharma Pvt, Ltd, Hyderabad, Psyllium husk was obtained from Cambridge Health Care Ltd, Gujarat and Xanthan gum was obtained from Himedia Laboratories, Mumbai.

Preparation of Floating tablets:

Floating tablets were prepared by conventional wet granulation method. Ofloxacin (200 mg) , required amount of polymers and other excipients were accurately weighed. Ofloxacin was well mixed with weighed quantity of polymer and then mixed with remaining ingredients i.e., sodium bicarbonate, citric acid and microcrystalline cellulose in geometric proportions. All the excipients were passed through # 60 mesh, mixed and granulated with 5% solution of PVP K30 in isopropyl alcohol. The wet mass passed through # 16 mesh and dried at 60°C for 1 hour. Dried granules were passed through # 24 mesh and mixed with magnesium stearate and talc. Granules were compressed in to tablets on a sixteen station rotary tablet punching machine using 12 mm circular standard caplet shaped punches.

EVALUATION OF FLOATING TABLETS OF OFLOXACIN

Pre-Compression of Ofloxacin granules Angle of repose

Angle of repose for prepared granules was determined by fixed funnel method. A funnel was fixed with its tip at a given height (h), above a flat horizontal surface to which a graph paper was placed. The granules were carefully poured through a funnel till the apex of the conical pile just touches the tip of the funnel. The angle of repose was then calculated using the formula17, θ= tan-1 (h/r) Where, ‘ ’ is the angle of repose ‘h’ is height of pile, ‘r’ is radius of base of the pile

Bulk density

Loose bulk density (LBD) and Tapped bulk density (TBD) were determined for the prepared granules. LBD and TBD was calculated using the formula, LBD = Wt of Powder / Vol. of Powder TBD = Wt of Powder / Tapped Vol. of Powder

Compressibility Index

Carr’s Compressibility Index18 for the prepared granules was determined by the equation, Carr’s Index (%) = TBD – LBD/TBD x 100

Hausner’s ratio

Hausner ratio is an indirect index of ease of measuring the powder flow. It is calculated by the following formula19. Hausner’s ratio = Tapped density / Bulk density

Post-Compression parameters of Ofloxacin Floating tablets

Thickness

Thickness of 10 tablets randomly selected were measured using vernier calipers and expressed in millimeters.

Hardness Test

The crushing strength kg/cm2 of prepared tablets was determined for tablets of each batch by Pfizer tablet hardness tester. Hardness indicates the ability of a tablet to withstand mechanical shocks while handling.

Friability Test

The friability of tablets was determined using Roche friabilator. It is expressed in percentage (%). Ten tablets randomly selected were initially weighed (W0 initial) and transferred into friabilator. The friabilator was operated at 25 rpm for 4 minutes or run up to 100 revolutions. The tablets were weighed again (W final). The percentage friability (%F) was then calculated by

%F = (1 - W/W0 ) x 100

Where, W0 = weight of tablet before test,

W = weight of tablet after test.

Weight Variation Test

Twenty tablets were selected randomly from each batch and weighed individually using electronic balance to check for weight variation20. Pharmacopoeial limits are shows in below Table 1.

In vitro Buoyancy Studies

The in vitro buoyancy was determined by floating lag time. The tablets were placed in a 100 ml beaker containing 0.1 N HCl. The time required for the tablet to rise to the surface for floating 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)21.

Determination of Swelling Index

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 5 h. The swelling index (SI), expressed as a percentage, and was calculated from the following equation

Where, Wt = Weight of the tablet at time t. Wo = Initial weight of tablet.

Drug Content Estimation

The drug content in each formulation was determined by triturating 20 tablets and powder equivalent to average weight was added in 100ml of 0.1N hydrochloric acid, followed by stirring for 30 minutes. The solution was filtered, diluted suitably and the absorbance of resultant solution was measured spectrophotometrically at 294nm using 0.1N HCl as blank22

In vitro Drug Release Studies

The release rate of Floating tablets of Ofloxacin was determined using USP Type 2 Apparatus. The dissolution test was performed in triplicate, using 900ml of 0.1 N HCl at 37± 0.5°C at 50 rpm for 12 hrs. A 5ml sample was withdrawn from the dissolution apparatus at specified time points and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45-μm membrane filter and diluted if necessary. Absorbance of these solutions was measured at 294nm using a U.V-Visible Spectrophotometer. Cumulative drug release was calculated from the developed methods.

Drug release kinetics:

Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release rate kinetics of the dosage form, the obtained data were fitted into zero-order23, first order24, Higuchi25 and Korsmeyer-Peppas26 release model.

Fourier Transform Infrared (FTIR) Spectroscopy

Fourier transform Infra red analysis (FT-IR) measurements of pure drug, polymers and drug loaded floating tablets formulations were obtained using a model name BX- Perkinelmer System 200 FT-IR Spectrophotometer. The pellets were prepared on KBr press under hydraulic pressure of 150 kg /cm2, the spectra were scanned over the wave number range of 4000- 500 cm-1 at an ambient temperature27.

RESULTS AND DISCUSSION

Pre-compression parameters of Ofloxacin granules:

Results of the pre-compression parameters performed for the granules of Ofloxacin formulations F1 to F14 are tabulated in Table 4. The bulk density and the tapped density for all the formulations varied from 0.32±0.01 to 0.40±0.02 g/ml and 0.37±0.02 to 0.52±0.02 g/ml respectively. The percentage compressibility of granules was determined using Carr’s index. Carr’s index lies within the range of 12.19±0.84 to 21.73±0.56 %. All formulations show good compressibility. Angle of repose of all the formulations found to be less than 27.86° which indicates a good flow property of the granules. The values were found to be in the range of 22.43°±0.05 to 27.86°±1.03. Hausner ratio was found to be in the range of 1.14±0.06 to 1.30±0.03.

Post-compression parameters of Ofloxacin floating tablets:

All of the Ofloxacin formulations were tested for Physical parameters like Hardness, Thickness, Weight Variation, Friability drug content. The results of the tests were tabulated in Table 5. The Hardness of the tablets was found in the range of 5±0.05 - 5.7±0.11 Kg/cm2 indicating satisfactory mechanical strength. The thickness of the tablets was found to be between 4.20±0.03 and 4.40±0.04 mm. The variation in weight was within the range ±5% complying with pharmacopoeial specifications. The friability was below 1% for all the formulations, which is an indication of good mechanical resistance of the tablet. Assay of the prepared matrix tablets was found in the range of 98-100% clearly indicating the good content uniformity. This study indicated that all the prepared formulations were good.

The results of the physical tests of many of the formulations were within the limits and comply with the standards.

In vitro Buoyancy studies:

In vitro buoyancy of the tablets from each formulation (F1 to F14) was evaluated and the results are mentioned in Table 6. Where, the highest and lowest floating lag time (FLT) was observed with the formulation F1 and F8 respectively. The concentration of the naturalpolymers increases the floating lag time also increases and total floating time observed for all the formulations was >12 hours.

Swelling index:

The swelling index of the formulations (F5, F7, F8, and F10) was evaluated and the results are mentioned in Table 7 and plot of % swelling index vs. time (hrs) is depicted in Fig.2. Where, the highest and lowest swelling was observed with the formulation F7 and F10 after 5 hrs respectively. The swelling index increases by increasing the contact time with pH 1.2 buffer, as the polymer gradually absorbs buffer due to hydrophilic nature of the polymer, resultant swelling of the tablets is also observed.

In vitro release studies

In vitro dissolution studies of all the floating tablets formulations of Ofloxacin were carried out in 0.1N HCl. The study was performed for 12 hours and cumulative drug release was calculated at every one hour time interval. In vitro dissolution studies of all the formulations are shown in Fig 3 & 4. The different polymers like HPMC K4M, HPMC K100M, Psyllium husk and Xanthan gum table 2 & 3 were used to prepare floating tablets. It was observed that the type of polymer influences the drug release pattern. HPMC K4M and HPMC K100M are hydrophilic polymers, upon contact with aqueous fluid is able to form quite viscous gel, and hence retard the drug release from hydrophilic matrix. The concentration of the polymers like HPMC K100M and HPMC K4M increased, slow drug release was observed. The formulation containing HPMC K100M (F8) gave the best results, which retarded the drug release 92.31% for 12 hours and hence it was considered as the optimized formulation.

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 of all formulation were shown in table 8. The release profile of optimized formulation F8, fitted best to Zero order kinetics with R2 value of 0.9514. As the n value for the Korsmeyer-Peppas model was found to be greater than 0.45 it follows Non-Fickian diffusion mechanism, while all other formulations also follows Zero order kinetics and Non-Fickian diffusion mechanism.

Fourier Transform Infrared (FTIR) Spectroscopy:

Potential chemical interaction between drug and polymer may change the therapeutic efficacy of the drug. To investigate the possibility of chemical interaction between drug and polymer FTIR spectra of pure Ofloxacin, pure polymers and optimised formulations were analyzed over the range 4000–500 cm−1. The peaks obtained in the spectrum of formulation correlated with the peak of drug spectrum and there were no significant extra peaks. This indicates that the drug was compatible with the formulation components. The spectra of pure drug and drug with excipients are shown in Fig 5 & 6.

CONCLUSION

The present study was aimed at developing an oral floating system for Ofloxacin with the use of different polymers such as HPMC K100M, HPMC K4M individually and combination with other polymers such as Psyllium husk and Xanthan gum, as it released the drug in a controlled manner for extended period of time by maintaining the buoyancy. This formulation may overcome the problem of poor solubility and its associated problems. Since the formulation showed sufficient release for prolonged period, the dose can be reduced and possible incomplete absorption of the drug can be avoided

ACKNOWLEDGEMENT

I express my deep sense of gratitude and sincere thanks to my esteemed guide, Mohammed Asif Hussain Blue Birds college of Pharmacy, Bheemaram, Warangal, who has been a constant source of inspiration to me with his scholastic guidance, valuable suggestions, and constructive criticism at all stages of my work. It was one of the golden opportunities to work under him.

Figures at a glance

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

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