1. INTRODUCTION:

Microspheres are considered one of the most prominent and potential buoyant systems. They exhibitthe exclusive advantages of multiple unit systems and better-floating properties due to the central hollow space inside the microsphere. The techniques involved in their preparation include simple solvent evaporation, solvent diffusion and evaporation methods. In the preparation of hollow microspheres, polycarbonate, eudragit S, cellulose acetate, calcium alginate, agar, and low methoxylated pectin are commonly used polymers. Buoyancy and drug release are dependent on the quantity and quality of polymer, the plasticizer–polymer ratio, and the solvent system used.

Gentamicin is an example of an aminoglycoside antibiotic, which is composed of a mixture of related gentamicin components and its fractions. It is a regular choice of drug for bacterial infections, chiefly those caused by Gram-negative organisms. Still, gentamicin is not used for Neisseria meningitides, Neisseria gonorrhoeae, or Legionella pneumophila¹.

Clinically, Gentamicin is ototoxic and nephrotoxic-with this toxicity;it shows major problems in clinical use. Gentamicin is a bactericidal antibiotic that interrupts protein synthesis by binding with the 30S subunit of the bacterial ribosome².

Gentamicin is highly water-soluble and shows poor oral absorption and poor protein binding. It is distributed well in body fluids but poorly in many tissues; thus, it is only effective at treating aerobic bacteria. It is also absorbed well from denuded skin and the peritoneum, pleural cavity, and joints. The drug is eliminated unchanged^3-4.

2. MATERIAL AND METHOD:

The following materials were used in the study: chitosan (polymer), sodium lauryl sulfate (SLS), sodium tripolyphosphate (TPP) cross-linking agent, all obtained from Central drug house Pvt. Ltd, India. Gentamicin sulfate wasobtained from Cipla Healthcare Pvt. Ltd, Ahmedabad, India, as a gift sample.

2.1 Preparation of gentamicin floating microsphere:

Chitosan microspheres containing Gentamicin Sulphate were prepared by a capillary extrusion procedure⁵. Briefly, GS (100mg) was dispersed in 20ml 1% v/v acetic acid solution having different concentrations of chitosan and stirred ceaselessly until a consistent dispersion was achieved. For the preparation of microspheres, The bubble-free dispersion was dropped through a syringe (with a 0.5 mm inner diameter nozzle) into 20ml of a gently agitated solution of the cross-linking agent, i.e. (TPP). The rate of bead drop was 30 per minute. The drop was 5 centimetres. Unless otherwise stated, the processed gelled microspheres were separated after a 2-hour reaction period, rinsed with deionized water, and air-dried for 48hours. Each batch was duplicated three times. In batches F1 to F8, the influence of formulation factors such as chitosan and cross-linking agent concentrations, as well as stirring rate, varied (Table 1).

Table 1: Microsphere Formulations

Formulation code	Factor combinations	Crosslinking agent		Stirring Rate (rpm)
Formulation code	Chitosan concentration(mg) (polymer: drug)	TPP (%)	SLS (%)	Stirring Rate (rpm)
F1	200 (1:1)	1	-	200
F2	400 (2:1)	2	-	400
F3	400 (2:1)	2	-	400
F4	600 (3:1)	3	-	600
F5	200 (1:1)	-	1	200
F6	400 (2:1)	-	2	400
F7	400 (2:1)	-	2	400
F8	600 (3:1)	-	3	600

2.2 Preformulation Studies:

It refers to the physical and chemical characteristics of drug substances on their own and in combination with excipients. The ultimate goal of preformulation testing is to gather the information useful for the formulator for developing safe, effective, stable and bioavailable dosage forms, which can be mass-produced⁶.

3.0 EVALUATION OF MICROSPHERES:

3.1Micromeritic properties:

The micromeritic properties⁷of microspheres were measured viz. particle size, shape, bulk density⁸, angle of repose⁹, Hausner's ratio¹⁰, tapped density, and compressibility index.. The particle size was determined with the use of an optical microscope with the help of a calibrated ocular and stage micrometer, and the particle size range was examined by measuring the size of about 100 particles.

3.2 Percent yield of microspheres:

For the determination of this parameter microspheres dried at room temperature and then weighed and afterthat percent yield of microsphereswas calculated using the following formula.

Mean Particle size = (Mean particle size of the fraction × weight fraction)/Weight fraction

3.3 Drug Content:

The drug content was determined by taking the microspheres equivalent to 50mg of the drug. Microspheres were crushed very well and were dissolved in 0.1 N HCl and diluted to 100ml. Then it was stirred continuously on a magnetic stirrer for 24hours and filtered. At the end of 24hours sample was withdrawn, diluted suitably, and measured for the drug content by spectrophotometer at 330nm.

3.4 Drug Entrapment Efficiency:

By using 100mg of microspheres in 50ml ethanol, the drug content of drug-filled microspheres was determined or the solvent choose according to its solubility observed by agitation with a magnetic stirrer for about 30 minutes to dissolve the polymer and to extract the drug. After filtration through a 5μm membrane filter, the drug concentration in the ethanol phase was examined by taking the absorbance of this solution spectrophotometrically at 330nm. As a result, the total amount of drug encapsulated in the total number of yielded microspheres was determined.

3.5 Floating Behavior of Microspheres (percentage buoyancy):

The buoyancy study of the microspheres was examined with a shaking speed of 100rpm at 37±0.5° by using a water bath shaker. The calculated amount (50 microspheres) was used in 100ml of enzyme-free SGF (HCl/NaCl solution containing 0.02% Tween 80; pH 1.2). The floating duration (FT) (which is the time during which the microspheres remain buoyant on the test solution) and the quantity of microspheres (F) (seen visually) were then determined at set time intervals during a 24-hour period. All of the information was based on the sum of at least three different determinations.

3.6 Equilibrium swelling studies:

The prepared blank chitosan microspheres were weighed (100mg) and placed in 500ml of different solutions of distilled water and enzyme-free SGF (HCl/NaCl solution; pH 1.2) and permitted to swell for the necessary time at 37±0.5° via the USP dissolution apparatus with the assembly of dissolution basket at 50 rpm. The microspheres were sporadically removed, blotted with filter paper, and their mass changes werenoted throughout the swelling until equilibrium was achieved. Finally, after a time of 4 hours, the weight of the swollen microspheres was noted and the swelling ratio (SR) was calculated.

3.7 Scanning Electron Microscopy:

The shape and surface characteristics of the microspheres were studied using a scanning electron microscope (Hitachi S- 4800). The microparticles were coated uniformly by using a sputter coater (Polaron SC-76430) with gold-palladium after fixing the sample in individual stubs. An acceleration voltage of 20kV was used as the operating parameter and chamber pressure of 0.6 mm Hg (n = 3). Size distribution based on the mean diameter of the microspheres was determined by the optical microscopy method. Approximately, 100 microspheres were counted using a calibrated optical microscope (Magnus MLX-DX), and then mean particle size was calculated and recorded.

3.8 In-vitro Drug Release Studies:

The drug release rate pattern of microspheres was determined using the USP XXIV basket-type dissolution apparatus. A capsule (size 0) was filled with a weighed volume of microspheres equal to 5mg of drug and put in the basket. The dissolution medium used was 900ml of 0.1N HCl and maintained at 37±0.5°C at a rotation speed of 100rpm. Perfect sink conditions persisted for the drug release trials,.

4.0 RESULT AND DISCUSSION:

4.1 Determination of λmax:

The absorption spectrum of pure drug was scanned between 300-700nm with 10μg concentration. The λmax of pure drug Gentamicin was found to be 330nm. The calibration curve in acidic buffer wasshown in Figure 1.

Figure 1: Calibration curve

4.2 Identification of Pure Drug by FT-IR Spectroscopy:

The FT-IR spectrum of the pure drug was found to be similar to the standard spectrum of Gentamicin.The characteristic broad band of adsorption O–H shows in plane bending from 1392cm^-1to 1287cm^-1. The characteristic adsorption band at 2077cm^-1 was ascribed to the methylene group (–CH₂) symmetrical and asymmetrical stretching. The Peak observed from 1626cm^-1to 1522cm^-1 is due to amide group (-NH₂). Another characteristic adsorption band at 1465cm^-1 was ascribed to C–O stretching. The bands at 876cm^-1 in the sample correspond to the angular deformation hydroxycyclohexyl (-OH)^11-13.

4.3 Compatibility Studies:

Below spectra shows the peaks of pure drug sample and polymer as compared to standard drug sample is that is no chemical reaction occurs between polymer and drug sample. The IR spectra showed all the principal IR absorption peak of Gentamicin 1627cm^-1, 1392cm^-1, 2084cm^-1. FTIR of drug and all polymers shows that all the peaks of drug and carrier as it is and drug is present in free form. This indicates that there is no interaction in between drug and the entire polymer employed in formulation¹⁴.

4.4 Effect of various formulation parameters on gentamicin floating microspheres:

4.4.1. Percentage yield and Drug content:

Percent recovery yield (n=3) and Drug content (n=3) observed increased from batches F1 to F3 ranges from 77.82% to 86.35%, (75.60% to 96.44%) with highest recovery yield with batch F3 and further it decrease respectively and as drug polymer ratio increase, decrease in percentage yield and drug content of the formulation. Table 2represents the percentage yield of all the formulations.

4.4.2. Encapsulation Efficiency of Microsphere:

The encapsulation efficiency (n=3) was found to be suddenly increasing with increase polymer drug ratio. Encapsulation efficiencies of batches F1-F8 ranged from 65.20% to 95.40%. Maximum encapsulation efficiency was observed of the batch F3, where ratio of 2:1 of the chitosan and gentamicin was used. The highest entrapment efficiency (93%) was observed by varying polymer-drug ratio from 1:1 to 3:1.

TPP concentration had a negative effect on the entrapment efficiency and positive effect on MD of microspheres. By increasing TPP concentration the entrapment could be decreases due to the increased binding of the 32 main groups of the drug to the added TPP. TPP shows positive effect (MD increased with the increase in TPPconcentration) on MD of microspheres as in the presence of sufficient amount of TPP, The fusion of smaller microspheres results in chitosan microspheres of a considerable larger scale. The multifunctional TPP aids inter-microparticles binding of the chitosan.^15-17

Changing in the stirring speed of the method also influenced the entrapment efficiency. With the stirring speed of 300rpm the highest entrapment efficiency (95%) was observed, the alter of stirring rate from 200 rpm to 300rpm considerably decrease due to the formation of larger and smaller emulsion droplets it shows entrapment efficiency, appropriately, ensuring drug diffusion out of the microspheres before they solidify. The concentration of counter ions utilised had an effect on drug integration efficiency; increasing counterion concentration from 1% to 3% resulted in a significant drop in drug loading efficiency from 95.40 to 78.03 percent. and drug entrapment with SLS (65.20%) shows least loading as compared to TPP (78.03)^18-19.

4.4.3. Floating Behavior of Microsphere (Percentage Buoyancy):

Buoyancy tests (n=3) were observed in pH 1.2 buffers with tween 80(0.02% w/v) in order to simulate the surface tension of human gastric juice (35–50mN/m²)²⁰.

The % buoyancy of the prepared floating microspheres was found 65 to 96. The % buoyancy of prepared floating microspheres in Table 3shows the floating behavior of different batches.

By doing complete research work the outcome showed a propensity that the higher the SLS and TPP concentration, the poor the elaborate on F (floating %) properties of microspheres (Table 3). On the other hand, the F capacity was not affected by the stirring rate and chitosan added as nearly all of the hollow microcapsules remained buoyant after the buoyancy test period (18 hours). The lack of a floatation lag time means that the microcapsules' original density was less than one prior to matrix swelling in simulated biofluids. In reality, the F process dependents on the equilibrium between the weight and the volume differences of the dosage forms. The increase in volume leads to an increase in weight and then the dosage form floatation²¹.

4.4.4. Swelling Study of Microspheres:

The pH of the atmosphere influences microparticle swelling, which is usually greater at lower pH than in water. The SR (equilibrium water uptake) of the cross-linked microspheres shown in Figure 3 and Table 4, be a sign of, as the amount of SLS and TPP in the matrices increased from 1 to 3%, the equilibrium water uptake decreased drastically from 12% to 1.4%. The increase in the amount of SLS and TPP has resulted in a decrease in water uptake capability and will increase the polymer density, resulting in reduction of the macromolecular chain mobility, and the development of more stable and rigid spheres in case of microsphere prepared from SLS (form water insoluble complex) that show a lower tendency to swell as compared to TPP (formed water soluble complex). As a result, the crosslinking of microspheres has a major impact on the equilibrium water uptake and release rates. It's worth noting that formulations with higher chitosan content swelled faster than those with lower chitosan content.

As a result, formulation F3 (3% w/w, chitosan) swelled 20% more than formulation F1, which swelled just 2% (1% percent, w/w, chitosan); likewise, formulation F7 (2%, w/w, chitosan) express a greater swelling than formulation F5. There will be an surplus of NH2 groups in the network if chitosan is present in excess under these conditions. The effect favouring the hydration and unfolding of the cross-linked polymeric structure, and hence its swelling, is due to protonation of any excess amino group of the polysaccharide in stomach pH conditions^22-26.

4.4.5. Micromeretic Properties:

Microspheres were observed as spherical and discrete. Microspheres, on the other hand, came in a wide variety of particle sizes. The particle size increased with increase in SLS and TPP concentration. Tapped density, bulk density, and flow properties of microspheres of batches F1 - F8 are shown in table 5.

Angle of repose and compressibility index indicates good flowability of microspheres and also indicating that glidants are not needed to improve flowability. The non-aggregated microspheres created have a better flow property than aggregated microspheres.

Angle of repose was found to be in the range of 25° to 34° in all formulations. Carr's index, or compressibility, was between 11.0 and 15.5% and Hausner’s ratio < 1.2, all the parameters indicating good flow property.

4.4.6 Morphology and particle size:

Scanning electron microphotographs showed that the microspheres were spherical with a smooth to rough surface (fig. 2). Pores were observed on the microsphere surface prepared from SLS.

4.5 In vitro Drug Release Studies:

· To investigate the extent of crosslinking on the in vitro release profiles the results of % cumulative release versus time for drug loaded microspheres for formulations F3, F7 were compared in Fig. 5. F3 has a higher rate of release than F7. This is endorsed to an increase in the extent of cross-linking, leading to the formation of a denser network structure and water soluble matrix¹⁷. Gentamicin release was higher in the case of microspheres prepared at a higher agitation speed but the difference in drug release was not statistically significant (fig.4). The results of the in-vitro dissolution studies of formulations F1 to F8are shown in table 6.

· Among all the formulations F3 showed good dissolution profile with 94.2% of drug release in 12 hours. The chitosan matrices, thus, demonstrated to serve as barriers to the liberation of Gentamicin¹⁸.

· The in-vitro drug release showed the highest regression coefficient values for the Higuchi's model and representing diffusion to be the predominant mechanism of drug release (r2=0.98). Drug release kinetic datafor microspheres was shown in table 6. All the formulations exhibited anomalous (Non-Fickian) diffusion mechanism (n value is in between 0.5 to 1.0). The drug release mechanismwas diffusion controlled as the plot of Higuichi model is linear.F3 showed a higher release rate than F7. This is attributed to an increase in the extent of cross-linking, leading to the formation of a denser network structure and water soluble matrix. The effect of stirring rate on drug release were shown in figure 6.

Figure: 2 SEM images of gentamicin microspheres

Figure: 3 swellingstudy of microspheres

Table: 2 Evaluation of %Yield, Drug content and Encapsulation efficiency of Microspheres

Formulation Code	% Yield	Drug Content	Encapsulation Efficiency (%)
F1	77.82	75.60	78.03
F2	83.35	92.21	93.10
F3	86.70	96.44	95.40
F4	81.41	65.93	83.72
F5	68.22	70.40	65.20
F6	77.10	84.50	71.63
F7	84.31	86.0	85.90
F8	80.04	62.43	75.82

Table: 3 Evaluation % Buoyancy of Microspheres

Formulation Code	% Buoyancy	Duration of Buoyancy (hr)
F1	65.13	16
F2	95.41	18
F3	96.50	18
F4	71.06	15
F5	60.23	16
F6	96.00	18
F7	96.32	18
F8	80.04	17

Table: 5 Characterization of Gentamicin Microspheres

Formulation Code	Bulk Density (g/ml)	Tapped Density (g/ml)	Carr’s Index (%)	Hausner’s Ratio	Angle of Repose (0)	Average Particle Size (μm)
F1	0.224	0.324	10.91	0. 901	22018´	312.10
F2	0.222	0.316	10.31	0.906	210 49´	339.08
F3	0.241	0.322	8.25	0.923	210 18´	329.42
F4	0.239	0.282	9.62	0.912	220 51´	354.20
F5	0.252	0.371	10.65	0.903	240 75´	401.05
F6	0.255	0.376	9.31	0.914	230 47 ´	423.40
F7	0.257	0.377	9.24	0.915	230 66´	416.31
F8	0.268	0.411	10.33	0.906	230 21´	434.50

Table: 6 Dissolution data of all formulations of gentamicin microspheres

Time (Hours)	Formulations
Time (Hours)	F1	F2	F3	F4	F5	F6	F7	F8
1	0.24	4.89	5.63	0.56	0.26	0.95	1.74	0.48
2	1.34	10.6	11.4	1.89	0.68	2.64	6.12	0.73
3	4.35	22.4	25.4	4.12	0.94	5.42	10.7	4.12
4	6.90	27.8	29.9	6.89	2.95	7.12	18.6	6.89
5	1.05	33.45	38.9	8.53	5.63	9.53	23.3	8.32
6	12.5	39.6	42.6	10.6	8.65	11.6	29.5	10.2
7	15.7	49.5	50.5	12.1	11.2	19.5	35.6	11.5
8	22.4	57.5	62.43	19.8	15.7	25.5	41.8	13.3
9	39.1	68.9	75.04	28.5	20.4	37.8	54.0	19.5
10	57.5	78.7	82.3	46.7	35.87	52.6	83.6	28.5
11	69.4	87.8	89.8	57.4	48.9	66.4	79.6	46.7
12	72.6	89.9	95.71	61.6	65.7	80.12	82.4	59.4

Figure: 4 Percentages drug releases plot for different formulations

Figure: 5 Effect of chitosan on drug release

Figure: 6 Effect of crosslinking agent on drug release

Figure: 7 Effect of stirring rate on drug release

Figure: 8 Higuchi release kinetics for different formulations

Figure: 9 Korsmeyer peppas release kinetics for different formulations

Figure: 10 First order release kinetics for different formulations

5. CONCLUSION:

The present study has been satisfactorily attempted to formulate a floating drug delivery system of an aminoglycoside antibiotic drug like Gentamicin for oral administration with a view of enhancing the release of the drug orally. From the experimental results, it can be concluded that, - during the optimization of formulation, the dissolution study was observed that the cumulative release of Gentamicin considerably decreased with an increase in chitosan concentration. At higher concentrations, the density of the polymer matrix increased, resulting in an increased diffusion path. As a result of this may decrease the complete drug release from the polymer matrix. Furthermore, smaller microspheres with a larger surface area exposed to the dissolution medium were formed at a lower polymer concentration, resulting in faster drug release.

Several kinetic models are described for drug release from floating microspheres and the model that best fits the release data was evaluated by correlation coefficient (r = 0.994). Higuchi release kinetics, Korsmeyer peppas release kinetics, First order release kinetics for different formulations were shown in figure 7, 8, 9, 10 respectively. The r value was found to be higher in higuchi model as compared to zero order, which indicates the formulations, follows higuchi kinetic mechanisms, therefore drug release from floating microspheres was found to be diffusion controlled and followed higuchi kinetics. The n value of korsmeyer peppas is less than 0.5 i.e. 0.192, that indicates formulations followed anomalous transport (non fickian) drug release.

CONFLICT OF INTEREST:

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS:

We are thankful to the School of Pharmacy, Bharat Institute of Technology, the Chairpersons and the whole management for offering us such an educational and research platform.

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Received on 21.07.2023 Modified on 13.01.2024

Asian J. Pharm. Res. 2024; 14(2):133-140.

DOI: 10.52711/2231-5691.2024.00023

Formulations Code	Swelling Ratio % hr
Formulations Code	H₂O	pH (1.2)
F1	0.5	8.08
F2	1.62	12.53
F3	2.30	13.70
F4	3.63	16.03
F5	0.12	2.04
F6	0.7	6.41
F7	1.1	8.07
F8	0.6	11.5