INTRODUCTION:

Floating drug delivery systems were used to prolong the gastric residence time of drug delivery systems. They remain buoyant in the stomach for prolonged period of time without affecting the gastric emptying rate of other contents. A floating dosage form is useful for those drugs that act locally in the proximal gastrointestinal tract (GIT), are unstable in lower parts of GIT, or are poorly absorbed in the intestine^[1]. The gastro\ retentive drug delivery systems can remain in the stomach and assist in improving the oral sustained delivery of drugs that have an absorption window in a particular region of the gastrointestinal tract. These systems help in continuously releasing the drug before it reaches the absorption window, thus ensuring optimal bioavailability ^[2].

Received on 03.02.2015 Modified on 21.02.2015

Research J. Pharm. and Tech. 8(4): April, 2015; Page 395-403

DOI: 10.5958/0974-360X.2015.00067.0

Hydrophilic polymer matrices are commonly used as oral drug delivery systems because of their good compatibility. Drug release from hydrophilic matrix tablets is controlled by formation of a hydrated viscous layer around the tablet which acts as a barrier to drug release by opposing penetration of water into tablet and also movement of dissolved solutes out of the matrix tablets. The overall drug release process is influenced not only by drug solubility but also by the physical and mechanical properties of the gel barrier that forms around the tablet. The extent of matrix swelling, erosion, and diffusion of drug determines the kinetics as well as the mechanism of drug release ^[3]. Methocel matrices hydrate rapidly only at the surface, retaining their original air bubbles and extending floatation beyond 8 h. Further addition of sodium bicarbonate (8–24%) maintains also their floatability longer than 8 h. The addition of sodium bicarbonate to Methocel matrices expands their volume due to gas bubbles formed after reaction with an acidic dissolution medium, increasing their hydration volume ^[4].

Levofloxacin, a synthetic fluorinated quinolone derivative, is effective for bacterial infection treatment, especially for H. pylori ^{[5, 6]}. It is used in life-threatening bacterial infections or bacterial infections and failure of therapy can be avoided by providing the effective concentration of antibiotics at the site of action ^[7]. Levofloxacin (fig. 1) is a fluoroquinolone antibacterial agent with a broad spectrum of activity against Gram-positive and Gram-negative aerobic bacteria and atypical bacteria, and limited activity against most anaerobic bacteria. It exerts its antibacterial effects by inhibiting bacterial DNA gyrase and topoisomerasep ^[8].

Fig.1: Chemical Structure of Levofloxacin (LVFX)

Levofloxacin is well absorbed following oral administration and the absolute bioavailability is approximately 99%. Its volume of distribution is about 1.1 L/kg and protein binding 24-38%. It is excreted through the kidneys with 64-102%of the dose as unchanged drug. The half-life of LVFX is between6-9 hours. According to Biopharmaceutics Classification System (BCS), LVFX is in Class 1 (high solubility/high permeability).Following 500 and 750 mg oral LVFX dose, it is absorbed quickly, attaining maximum plasma concentration (C_max) within approximately 1-2 h of oral administration daily for multiple-dose administration ^{[9, 10]}.

The aim of present work is to produce safe & effective floating drug delivery system which remains in vicinity of the absorption site for longer period of time and to improve bioavailability of drug. The objective of the research work is to formulate and evaluate the floating drug delivery system containing levofloxacin as a model drug by using polymer (HPMC K100M and HPMC K15M), gas generating agent (sodium bicarbonate), and other excipient. This can be done to achieve better therapeutic success compared to conventional dosage form of the same drug. It imparts advantages like, reduced dosing frequency, better patient compliance and convenience and less fluctuating plasma drug level.

MATERIALS AND METHODS:

Levofloxacin was supplied from Wockhardt limited Aurangabad, INDIA. Hydroxy propyl Methyl Cellulose k-100 and Hydroxypropyl Methyl Cellulose k-15 was a kind gift from Molychem limited, Mumbai. Sodium Bicarbonate, PVP-K30 and MCC were purchased from Molychem limited, Mumbai, INDIA. All other Excipients used in our work were of analytical grade.

Direct compression technique:

Floating tablets were prepared by direct compression method. HPMC K100M, HPMC K15 M, sodium bicarbonate, and the active ingredient were sieved through sieve no. 60 and mixed homogeneously (Table 1). Magnesium stearate and talc were added as a lubricant and the powder was compressed into tablets using CADMACH multi punch tablet machine using 12mm flat-faced punches ^[11].

Drug-Polymer Compatibility study:

The proper design and formulation of a dosage form requires consideration of the physical, chemical and biological characteristics of all drug substances and excipients to be used in the fabricating the product. The drug and excipients must be compatible with one another to produce a product that is stable, efficacious, attractive, and easy to administer and safe. If the excipients are new and not been used in formulations containing the active substance, the compatibility studies are of paramount importance. Compatibility of drug with excipient is done by FTIR. Infrared spectra were recorded on a Shimadzu FTIR-8700 spectrophotometer. Pellets were prepared from a finely ground mixture of test sample (1-2 mg) and dried KBr (200-300 mg) using a Quick Press and a 7 mm die set (Perkin-Elmer, USA). The various samples analyzed were: (a) Levofloxacin (b) crushed and powdered tablets. The samples were scanned between 4000 cm^-1 to 450 cm^-1 at an interval of 1.0 cm^-1.

Table 1: Formulation of floating tablet of levofloxacin (*all the qty in mg)

Ingredient *	D1	D2	D3	D4	D5	D6	D7	D8	D9
Levofloxacin	250	250	250	250	250	250	250	250	250
HPMC K-100	81	99	90	108	72	126	54	144	36
HPMC K-15	99	81	90	72	108	54	126	36	144
Sod. Bicarbonate	85	85	85	85	85	85	85	85	85
Mg .sterate	10	10	10	10	10	10	10	10	10
Talc	05	05	05	05	05	05	05	05	05
MCC	60	60	60	60	60	60	60	60	60
PVP	10	10	10	10	10	10	10	10	10
TOTAL	600	600	600	600	600	600	600	600	600

Flow properties:

The flow properties of powder blend (before compression) were characterized in terms of angle of repose and Carr index. For determination of angle of repose (θ), the powder blend were poured through the walls of a funnel, which was fixed at a position such that its lower tip was at a height of exactly 2.0 cm above hard surface. The powder blend was poured till the time when upper tip of the pile surface touched the lower tip of the funnel. The tan^-1 of (height of the pile / radius of its base) gave the angle of repose ^[12]. Powder blend were poured gently through a glass funnel into a graduated cylinder cut exactly to 10 ml mark. Excess powders were removed using a spatula and the weight of the cylinder with pellets required for filling the cylinder volume was calculated. The cylinder was then tapped from a height of 2.0cm until the time when there was no more decrease in the volume. Bulk density (ρb) and tapped density (ρt) were calculated¹³Carr index (IC) ¹⁴was calculated according to the two equations given below:

IC = (ρt– ρb)/ρt

Characterization of FDDS:

Uniformity of weight, hardness and friability test:

Uniformity of weight was determined with the help electronic balance. The crushing strength (Kg/cm²) of tablets was determined by using Monsanto type hardness tester. Friability was determined by weighing 10 tablets after dusting, placing them in the friabilator (Roche Friabilator) and rotating the plastic cylinder vertically at 25 rpm for 4 min. After dusting, the total remaining weight of the tablets was recorded and the percent friability (PF) was calculated using formula ^{[15, 16]}

PF = (Weight original – Weight final) / Weight original X 100.

Drug content:

Uniformity of drug content was determined by taking 5 tablets in a glass mortar and powdered; 100 mg of this powder was placed in a 100 mL stoppard conical flask. The drug was extracted in double distilled water with vigorous shaking on a mechanical shaker (100 rpm) for 5 hours and filtered into 50 Ml volumetric flask through cotton wool and filtrate was made up to the mark by double distilled water through filter, further appropriate dilution were made and absorbance was measured at 298 nm using double distilled water as blank solution by UV Visible double beam spectrophotometer (EI, India) ^{[17, 18]}.

Calibration Curve Preparation:

A stock solution of Levofloxacin (100 mg/mL) was prepared in 0.1 N HCl. It was further diluted to obtain the known standard solutions in the range of 1-10 μg/mL. Hydrochloric acid (0.1 N HCl, pH 1.2) was prepared by adding 8.5 mL concentrated acid to 991.5 mL of double-distilled water with cooling. The absorbance was measured spectrophotometrically (Shimadzu UV/Vis spectrophotometer 2100, Tokyo, Japan) at 298 nm with the mean data (n = 6) used for the calibration curve. The concentrations of dissolved drug in the formulations were calculated from the regression equation obtained from the calibration curve ^[19].

In Vitro Studies:

The release rate of Levofloxacin from floating tablets was determined using United States Pharmacopoeia (USP) Dissolution Testing Apparatus II (paddle method). The dissolution test was performed using 900 ml of 0.1N hydrochloric acid, at 37 ± 0.5°C and 50 rpm. A sample (10 ml) of the solution was withdrawn from the dissolution apparatus hourly and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45μ membrane filter and diluted to a suitable concentration with 0.1N hydrochloric acid. Absorbance of these solutions was measured at 298 nm using a Thermospectronic-1 UV/V is double-beam spectrophotometer. Percentage drug release was calculated using an equation obtained from a standard curve ^{[20, 21]}.

Floating lag time:

A tablet was placed in a dissolution flask with 400 ml of 0.1N Hydrochloric acid. Then the time in minutes taken by tablet to move from bottom to top of the flask was measured ^[22].

Duration of Buoyancy:

Duration of buoyancy was observed simultaneously when the dissolution studies were carried out. The time taken by the tablet to rise to the surface of the dissolution media and time taken for it to sink was noted, the difference of which gives the duration of buoyancy ^[23].

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 24 h ^[24]. The swelling index (SI), expressed as a percentage, and was calculated from the following equation

Weight of Swollen tablet - Initial weight of the tablet

SI = ------------------------------------------------------- × 100

Initial weight of the tablet

Data analysis:

To analyze the mechanism of drug release and release rate kinetics from the dosage form, the data obtained were fitted into zero order, first order, Higuchi release and Korsmeyer and Peppas release model using PCP Disso-software, which is specially meant for curve fitting and statistical data analysis ^[25].

Zero-Order release kinetics:

To study the zero-order release kinetics the release rate data are fitted to the following equation ^[26].

F = K.t

Where, ‘F’ is the fraction of drug release, ‘K’ is the release rate constant and‘t’ is the release time.

First -order release kinetics:

To study the first-order release kinetics the release rate data are fitted to the following equation²⁷.

F = 100 x (1 – e^-Kt)

Where, ‘F’ is the fraction of drug release, ‘K’ is the release rate constant, ‘e’ is exponent coefficient and ‘t’ is the release time.

Higuchi release model:

To study the Higuchi release model the release rate data are fitted to the following equation ^[28].

F = K.t^1/2

Where, ‘F’ is the fraction of drug release, ‘K’ is the release rate constant and ‘t’ is the release time.

Korsmeyer and Peppas release model:

To study the Korsmeyer and Peppas release model the release rate data are fitted to the following equation ^[29].

M_t/ M_∞= K.tⁿ

Where, M_t/ M_∞is the fraction of drug release, ‘K’ is the release rate constant, ‘t’ is the release time and ‘n’ is the diffusion exponent for the drug release that is dependent on the shape of the matrix dosage form (Table 2).

Table 2: Interpretation of Drug Release Mechanism

Sr. No.	Release exponent (n)	Drug transport mechanism
1	0.5	Fickian diffusion
2	0.5 < n >1.0	Anomalous transport
3	1.0	Case-II transport
4	Higher than 1.0	Super case –II transport

Stability study:

To assess the drug and formulation stability, stability studies were done according to ICH and WHO guidelines ^[30]. Optimized Batch F3, sealed in aluminum packaging coated inside with polyethylene, and various replicates were kept in the humidity chamber maintained at 45⁰C and 75% RH for 3 months. At the end of studies, samples were analyzed for the drug content, in vitro dissolution, floating behavior and other physicochemical parameters.

RESULT AND DISCUSSION:

The API is a light yellowish-white colored powder and in UV spectrophotometric analysis, the maximum wavelength (λmax) of levofloxacin in acidic buffer (pH-1.2) was found to be 298 nm (Fig. 2). The reported λmax of levofloxacin in acidic buffer (pH-1.2) is 298 nm.

Fig.2: UV spectrum of Levofloxacin

Compatibility studies:

The interaction of levofloxacin with the polymer used was studied using FTIR spectroscopy method. The IR spectrum (Fig. 3) of pure drug levofloxacin having characteristic bands in FTIR spectrum at 2935cm^–1 indicates -CH3 stretching, 1620 cm^–1indicates aromatic -CC stretching, 1724 cm^–1indicates carbonyl group of quinolone moiety, 1452 cm^–1 indicates -CH₃ bending frequency, 1396 cm^–1indicates plane bending of carboxyl moiety and 1049 cm^–1 indicates cyclic ether functionality of the molecule (Table 3).

Table 4:Pre-Compression Parameters of Designed Formulations

Batch Code	Bulk Density (g/cc)	Tapped density (g/cc)	Angle of Repose (θ)	Carr’s Index (%)
D1	0.503 ± 0.30	0.685 ± 0.54	29.2 ± 0.25	17.83
D2	0.484 ± 0.21	0.698 ± 0.36	30.3 ± 0.30	18.71
D3	0.449 ± 0.01	0.654 ± 0.22	30.5 ± 0.21	17.44
D4	0.477 ± 0.31	0.660 ± 0.02	29.6 ± 0.38	23.52
D5	0.543 ± 0.40	0.711 ± 0.04	25.4 ± 0.12	17.13
D6	0.567 ± 0.03	0.705 ± 0.54	27.3 ± 0.34	18.33
D7	0.588 ± 0.26	0.720 ± 0.64	29.9 ± 0.39	22.24
D8	0.461 ± 0.34	0.661 ± 0.08	29.7 ± 0.11	24.75
D9	0.488 ± 0.35	0.685 ± 0.06	29.5 ± 0.60	24.84

Table 5: Post compression parameters for designed formulations

Batch code	Hardness (Kg / cm2)	Friability (%)	Thickness (mm)	Weight Variation (mg)	Floating Lag time (sec)	Total floating time (hr)
D1	5.5 ± 0.03	0.543 ± 0.64	4.5 ± 0.01	600 ± 0.85	65	14
D2	6.0 ± 0.06	0.520 ± 0.27	4.3 ± 0.03	595 ± 0.64	55	15
D3	5.0 ± 0.01	0.658 ± 0.20	4.4 ± 0.01	600 ± 0.05	49	12
D4	5.5 ± 0.08	0.456 ± 0.19	4.3 ± 0.01	597 ± 0.26	60	10
D5	6.0 ± 0.31	0.445 ± 0.07	4.5± 0.01	600 ± 0.26	81	12
D6	5.5 ± 0.24	0.488 ± 0.09	4.5 ± 0.02	605 ± 0.35	94	14
D7	5.0 ± 0.16	0.532 ± 0.13	4.4 ± 0.01	602 ± 0.33	39	14
D8	5.0 ± 0.64	0.689 ± 0.61	4.5 ± 0.01	600 ± 0.25	75	15
D9	5.5 ± 0.40	0.444 ± 0.21	4.3 ± 0.02	598 ± 0.55	42	16

Fig. 6: FTIR. Spectra of levofloxacin +HPMC Physical mixture

Table 7: Dissolution Data of Formulations

Time (hr)

% Drug release

21.13

±0.03

21.56

±0.35

21.63

±0.10

14.82

±0.34

19.60

±0.01

28.00

±1.03

17.20

±0.35

21.51

±0.84

23.59

±1.32

29.49

±0.10

31.90

±0.37

35.11

±0.05

22.31

±0.49

26.41

±0.12

36.27

±0.31

23.87

±1.65

29.37

±1.32

37.04

±1.45

35.23

±0.21

41.05

±0.46

46.96

±0.04

27.99

±0.61

33.65

±0.31

45.79

±1.23

29.64

±1.32

35.60

±1.12

48.35

±1.36

44.61

±0.05

47.81

±0.10

56.17

±0.11

32.90

±0.34

39.19

±0.25

55.56

±0.97

35.84

±1.21

43.58

±0.32

56.08

±0.65

47.62

±0.03

5312

±0.70

65.80

±0.09

38.15

±0.25

44.94

±0.51

64.80

±0.65

43.41

±0.56

50.08

±0.25

63.66

±0.92

51.24

±0.61

59.95

±0.39

72.00

±0.16

41.53

±0.61

51.41

±0.61

70.21

±1.62

49.29

±0.95

55.28

±1.51

70.89

±0.64

56.75

±0.34

64.58

±0.41

79.19

±0.04

46.99

±0.18

56.36

±0.42

77.39

±1.32

52.27

±0.35

61.66

±0.20

75.30

±0.51

62.28

±0.50

74.65

±0.49

87.40

±0.25

52.48

±0.17

63.58

±0.25

86.74

±1.65

61.12

±0.64

71.48

±1.23

82.21

±0.35

66.22

±0.42

79.72

±0.50

89.81

±0.09

57.20

±0.34

71.88

±0.34

90.32

±0.59

63.58

±1.65

73.20

±1.54

86.29

±0.25

71.25

±0.34

83.70

±0.64

92.24

±0.04

60.53

±0.46

73.13

±0.26

93.14

±0.98

69.37

±1.35

77.01

±0.54

88.29

±0.46

73.26

±0.62

84.71

±0.13

95.46

±0.07

63.86

±0.57

75.25

±0.53

95.19

±1.21

73.87

±0.84

81.78

±0.65

90.10

±0.75

76.35

±0.19

91.52

±0.30

98.96

±0.8

71.18

±0.43

80.15

±0.19

96.47

±0.96

78.79

±0.49

86.40

±1.32

96.70

±0.67

Table 8: % Swelling Study of Optimized Formulation

Formulation	% swelling index after time (hr)
Formulation	2hr	4hr	6hr	8hr	10hr	12hr
D1	50	65	72	85	90	100
D2	55	67	74	90	100	103
D3	65	80	95	110	115	122
D4	55	65	73	93	102	107
D5	50	68	79	88	95	105
D6	55	63	70	95	100	108
D7	40	51	77	88	95	103
D8	58	75	88	90	100	110
D9	62	78	90	110	110	120

Data analysis:

Data of release profile for designed formulations:

In case of most of the formulations the R² values were higher for First order model than for Zero order model indicating that the drug release from the formulation followed First order kinetics (Table 9).

Fig.7: % Swelling index of optimize formulation

Table 9: Zero order release kinetics, first order release Kinetics and Higuchi model

Batch Code	Zero-order release kinetics			First order release kinetics			Higuchi model
Batch Code	K (h^-1)	SEM	R²	K (h^-1)	SEM	R²	K (h^-1)	SEM	R²
D1	7.442	0.4136	0.6563	0.1279	0.0048	0.9466	0.1279	0.0048	0.9466
D2	8.707	0.419	0.774	0.1686	0.0053	0.9765	0.1689	0.0053	0.9765
D3	9.904	0.550	0.692	0.2273	0.0068	0.9857	0.2273	0.0068	0.9857
D4	6.371	0.245	0.873	0.0962	0.0025	0.9745	0.0962	0.0025	0.9745
D5	7.592	0.329	0.830	0.1292	0.0037	0.9761	0.1292	0.0037	0.9761
D6	9.831	0.567	0.636	0.2251	0.0083	0.9728	0.2251	0.0083	0.9728
D7	7.215	0.265	0.887	0.1172	0.0029	0.982	0.1172	0.0029	0.982
D8	8.173	0.373	0.804	0.1483	0.0044	0.9766	0.1483	0.0044	0.9766
D9	9.549	0.575	0.591	0.2145	0.0048	0.0989	0.2145	0.0048	0.0989

Table 10: Korsmeyer and Peppas Model

Batch Code	Korsmeyer and Peppas model
Batch Code	K (h^-n)	N	SEM (K)	SEM (n)	T_50%(hr)	R²
D1	20.28	0.5365	0.533	0.01252	5.378	0.9964
D2	21.11	0.5912	0.7371	0.0165	4.3	0.9951
D3	25.89	0.5563	1.476	0.02707	3.264	0.9854
D4	13.31	0.6605	0.5323	0.01871	7.418	0.995
D5	16.99	0.6285	0.8222	0.02274	5.571	0.9918
D6	26.98	0.5334	1.37	0.02421	3.179	0.9867
D7	14.61	0.6752	0.5455	0.01744	6.188	0.9959
D8	19.06	0.6093	0.7258	0.01794	4.869	0.9945
D9	19.34	0.6195	0.6797	0.01654	4.634	0.9955

The Korsmeyer and Peppas model showed higher correlation coefficient values (R²) for all batches. Obtained values of n lies between 0.5365 - 0.6195, indicating non-Fickian release kinetics, which is indicative of drug release mechanisms involving, diffusion mechanisms. Therefore, the release of drug from the prepared tablets is controlled by swelling of the polymers, followed by drug diffusion through the swelled polymer (Table 10).

Stability study:

The optimized floating tablet batch D3 was selected for stability study on basis of in vitro buoyancy and in vitro drug dissolution studies. The batch D3 was kept at 45⁰C/75% RH for 3 month. From the data, the formulation is found to be stable under the condition mentioned since there was no significant change in the percentage amount of drug content (Table 11). Thus it was found that the floating tablet of levofloxacin batch D3 were stable under this storage condition for at least 3 month.

Table 11: Stability Data of Optimized Formulations at 45°C/75% Rh

Evaluation parameter	Initially	After 3 month
Weight variation	600±0.2	600±.02
Hardness	5.0	4.9
% friability	0.658	0.655
Floating lag time (sec)	49	50
Total floating time (hr)	12	12
In vitro % drug release	98.69	98.20

ACKNOWLEDGEMENTS:

Authors are thankful to Wockhardt Ltd., Aurangabad for providing the levofloxacin as a gift sample for this work and they also thank Dr. V. N. Shrikhande (Principal) IBSS College of Pharmacy, Malkapur (Buldana) for providing the required facilities to carry out this work.

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Functional Group	Carbonyl C=O	Aromatic C-H	OH group of Carboxyl (-COOH) moiety
Levofloxacin	1724.81 cm^-1	2935.62 cm^-1	3265.81 cm^-1
Levofloxacin +HPMC (Physical mixture)	1725.81 cm^-1	2936.25 cm^-1	3263.34 cm^-1

Concentration (mcg/ml)	Absorption
Concentration (mcg/ml)	I	II	III	Mean ±SD
Blank	0	0	0	0±0
2	0.1689	0.1688	0.169	0.1689±0.0001
4	0.3412	0.3409	0.3413	0.3411±0.000208
6	0.5222	0.5219	0.5224	0.5221± 0.000252
8	0.7053	0.7017	0.7085	0.7051±0.003402
10	0.9011	0.9125	0.9005	0.9047±0.006762