FORMULATION AND CHARACTERIZATION OF FLOATING BEADS OF ANTIBIOTIC BY EMULSION GELATION TECHNIQUE

Objective: The study aims at formulation and characterization of floating hydrogel beads of cefdinir for improving its bioavailability. Methods: Cefdinir is broad-spectrum, oral, third-generation cephalosporin antimicrobial agent active against Gram-positive and Gram-negative bacteria. The floating hydrogel beads of cefdinir were formulated with polymers such as sodium alginate and sodium carboxymethyl cellulose by emulsion gelation technique using olive oil/castor oil. The beads were evaluated for surface morphology, bead size, entrapment efficiency, floating characteristics, in vitro swelling, in vitro drug release, and stability studies. Conclusion: From the findings, it may be concluded that cefdinir-loaded floating beads were successfully prepared and proved to be useful for the better bioavailability and patient compliance for enhanced antimicrobial activity.


INTRODUCTION
Oral delivery of drugs is by far the most preferable route of drug delivery due to the ease of administration, patient compliance, and flexibility in formulation [1]. From immediate release to site-specific delivery, oral dosage forms have really progressed [2]. However, it is a well-accepted fact that it is difficult to predict the real in vivo time of release with solid, oral controlled release dosage forms. Thus, drug absorption in the gastrointestinal tract (GIT) may be very short and highly variable in certain circumstances [3].
One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GIT is to control the gastric residence time. Dosage forms with a prolonged gastroretentive dosage forms will provide us with new and important therapeutic options [4].
Cefdinir is a broad-spectrum, oral, third-generation cephalosporin antimicrobial agent active against Gram-positive and Gram-negative bacteria. It is used in treatment of acute chronic bronchitis, rhinosinusitis, pharyngitis, etc. Cefdinir is having half-life of 1.5 h with oral bioavailability 20-30%. Cefdinir is better absorbed from the upper part of the GIT [9]. Therefore, in the present study, an attempt will be made to design and evaluate GRDDS of cefdinir with a view to enhance its bioavailability, duration of action, and convenience of administration in the form of hydrogel beads as floating system leading to improved patient compliance.

Materials
Cefdinir was purchased from Rajesh Chemicals, Mumbai (India), Sodium alginate, Sodium carboxy methyl cellulose (CMC), Calcium chloride, Aluminum chloride, Calcium Vegetable oil, mineral oil, (SD Fine Chem Ltd., Mumbai). All other chemicals were of analytical grade.
Nowadays, alginate gel beads become post-acceptable vehicle for drug delivery since it is cost-effective, biodegradable, simple process [5]. Floating is the most acceptable approach of gastroretentive drug delivery system (GRDDS). Floating approach is available in single as well as multiparticulate forms such as beads, microspheres, and pellets [6]. Beads spread out more uniformly in the GIT, thus avoiding exposure of the mucosa locally to high concentration of drug [7]. Beads are small, solid, and free-flowing particulate carriers containing dispersed drug particles either in solution or crystalline form. Spherical beads of approximately 2.5 mm in diameter [8].

Khalifa and Siraj
Each mixture with total volume of 100 ml (containing cefdinir 1 g and oil in two different concentrations 10 and 15%v/v) was stirred properly to prepare homogeneous mixtures. The mixture was extruded, using a 20-gauge syringe needle into 200 ml of gently agitated calcium chloride (1%) or aluminum chloride (2%) solution at room temperature. The resulting beads were allowed to stand in the solution for 24 h before being separated and washed twice with 500 ml distilled water. The beads were dried at room temperature for 48 h and were stored in desiccators [10,11].

Characterization of floating beads
Scanning electron microscopy (SEM) Morphological examination of the surface and internal structure of the dried calcium alginate beads was carried out using a SEM (JEOL JEM-1200 EX II, Japan) equipped with secondary electron detector at an accelerating voltage of 10 kV. The samples were coated with gold to a thickness of about 30 nm in a vacuum evaporator. The internal structure of beads was examined by cutting them with a steel blade [12].
Determination of bead diameter size Particle size of the prepared beads was determined using an optical microscope fitted with the stage and an ocular micrometer. Twenty dried beads were measured for calculating the mean diameter of beads. The result is expressed as the mean diameter (mm)±standard deviation [13].
Drug content and entrapment efficiency The drug content and entrapment efficiency of prepared beads were determined by the method of extraction of drug present in beads. The dried beads (100 mg) were taken and extracted in 100 mL of 0.1N HCl (pH 1.2) for 24 h. Then, the dispersion of beads was sonicated for 30 min and the solution was filtered through a 0.45 µm filter. The concentration of drug present in filtrate determined spectrophotometrically at 287 nm (UV-2450, Shimadzu, Japan). Each determination was made in triplicate. The drug content and entrapment efficiency of prepared beads were determined by putting value in the following formula [14].
Calculated drug content Drug content = ×100 Total amount of beads Calculated drug content Entrapment efficiency = ×100 Theoretical drug content In vitro buoyancy The time interval between the introduction of beads into the dissolution medium and its buoyancy to the top of dissolution medium was taken as floating lag time and floating time was observed visually. The floating abilities of the beads were determined using USP paddle apparatus (50 rpm, 37±0.2°C, 900 ml, 0.1 N HCl). 50 beads were placed in the medium; the time to float and duration of floating (floating time) were measured by visual observation. The percentage of floating pellets was calculated by the following equation: [15].
Floating beads (%) = Number of floating beads at the measure time ×100 Initial number of beads Swelling study Beads were studied for swelling characteristics. Sample from drug-loaded beads was taken, weighed, and placed in wire basket. Beads were studied for swelling characteristics. Sample from Vegetable oil  ----10  10  15  15  --10  15  Mineral oil  10  10  15  15  ----10 15

RESULTS AND DISCUSSION
The mean particle size of sodium alginate beads FB9-FB12 was between 1.58 mm and 1.99 mm. Sodium alginate beads were large when compared to sodium CMC due to molecular weight and viscosity. By increasing the oil concentration in the beads, an increase in size of the beads was observed.

Drug entrapment efficiency and floating study
The percentage yield of each batch was calculated on weight basis with respect to the weight of starting material. The percentage production yield of prepared beads was 81.98±0.32-96.10±0.08% for beads FB1-FB12 as shown in Table 4. drug-loaded beads was taken, weighed, and placed in wire basket of USP dissolution apparatus II. The basket containing beads was placed in a beaker containing 900 ml of HCl solution (pH 1.2) maintained at 37±0.5°C. After 12 h, the beads were removed from their respective swelling media and weighed after drying the water on the surface of the beads using filter paper. Then, the swelling index was calculated as percentage using the following formula [16][17][18][19].
Final wt. of beads -Initial wt. of beads Swelling index = ×100 Initial wt. of beads  In vitro drug release studies Release studies were performed in triplicate using the USP basket method at 100 rpm and 37±0.5°C in 1000 mL of test medium (i.e., SGF). Approximately, 50 beads were used for each experiment. The samples are withdrawn at specific time interval and assayed spectrophotometrically at the wavelength of maximum absorbance. The percentage of the drug release is calculated with respect to the drug content of the beads.
The drug content is expressed as the percentage of drug encapsulated in a unit weight of beads. The experiments are carried out in triplicate and the results were averaged [20][21][22][23][24].

SEM
The surface morphology of prepared beads was studied by SEM. External and internal surfaces of beads formulation FB12 are shown in Fig. 2. The sodium alginate and sodium CMC beads prepared with calcium chloride were spherical, and the beads prepared with aluminum chloride were spherical with tail. External surface was smooth with slightly rougher surface/shrinkage which could be due to drying. In the drug-loaded beads , the internal surface is slightly sponge like which is due to the drug and rate controlling polymer are uniformly dispersed in the polymer matrix. The internal surface of the oil-entrapped beads shows slightly sponge-like nature with little droplets of entrapped oil which imparts buoyancy to the beads. The surface layer of all beads was denser, and hence, in the preparation process, anionic polymer diffused from the droplet core toward the gelling solution (coagulation medium) to form more heterogeneous structure.

Khalifa and Siraj
In vitro swelling data of cefdinir beads The swelling index of sodium alginate beads containing vegetable oil (olive oil) as floating agent (FB1, FB2, FB3, and FB4)        The stability data are represented in Table 13, and the stability study was performed for selected formulation FB12 for 3 months, suggesting that FB12 the formulation were stable, with no physical change and also the floating ability, DEE and cumulative % drug release, was not significant changed.

CONCLUSION
Multiparticulate gastroretentive hydrogel beads of cefdinir were formulated with sodium alginate and sodium CMC by emulsion gelation method using olive oil/castor oil.