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Doodipala et al: Development and Clinical PK Evaluation of Gastroretentive Floating Matrix Tablets of Levofloxacin

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International Journal of Pharmaceutical Sciences and Nanotechnology Volume 4 • Issue 3 • October –December 2011 MS ID: IJPSN-07-12-11-NARENDER

Research Paper

Pharmaceutical Development and Clinical Pharmacokinetic Evaluation of Gastroretentive Floating Matrix Tablets of Levofloxacin N. Doodipala, C.R. Palem, S. Reddy and Y. M. Rao* National Facilities in Engineering and Technology with Industrial Collaboration Centre, University College of Pharmaceutical Sciences, Kakatiya University, Warangal–506 009, Andhra Pradesh, India. Received July 12, 2011; accepted October 31, 2011

ABSTRACT The most common approach for achieving sustained drug release is by the use of hydrophilic polymeric excipients directly compressed with active ingredients into tablets. Hydrophilic polymers swell in the presence of water to form hydrogel structures from which drugs are released by slow diffusion. The purpose of this study was to prepare a floating drug delivery system of levofloxacin, a fluoroquinolone antibiotic. Levofloxacin is highly soluble in acidic media and precipitates in alkaline media, thereby losing its solubility. We designed a gastroretentive system of levofloxacin to enhance bioavailability by retaining them in the acidic environment of the stomach. Tablets were prepared by the direct compression technique using polymers such as hydroxypropylmethylcellulose (HPMC K4M, HPMC K15M, and HPMC K100M). Sodium bicarbonate was utilized as a gas-generating

agent. Tables were evaluated for their physical characteristics such as hardness, thickness, friability, weight variation, drug content, swelling studies, and floating properties. Tablet formulations were evaluated by in vitro dissolution studies. Formulations showed a floating lag time of 30 seconds and a floating time above 12 hours. Among these formulations F3, F7 and F11 exhibited controlled and prolonged drug release profiles while floating over the dissolution medium. The best formulation (F3) was selected based on in vitro characteristics and further tested in healthy volunteers by radiographic studies of tablets by incorporating BaSO4. These clinical studies revealed that the tablets remained in the stomach for 240 ± 30 minutes in fasting human volunteers, indicating gastric retention of the system.

KEYWORDS: Levofloxacin; floating matrix tablets; gastric retention; radiographic studies.

Introduction Helicobacter pylorus (H. pylori) has been recognized as a major gastric pathogen with worldwide distribution. H. pylori is a causative organism in chronic active gastritis, duodenal ulcers, and gastric adenocarcinoma (Forman et al., 1994; Negrayd and Kaniykuattem 1992). The pathogen is susceptible to many antibiotics in vitro, but it is difficult to eradicate from the human body. Extended resident time of the antimicrobial agents is desirable for effective eradication of H. pylori. In order to extend the gastric residence period, a number of approaches have been developed such as floating drug delivery systems, swelling and expanding systems, polymeric bioadhesive systems, modified shape systems, high-density systems and other delayed gastric emptying devices (Brazel and Peppas, 2000; Bardonn et al., 2006; Bomma et al., 2009; Bandari et al., 2010). The gastroretentive floating drug delivery system (GRFDDS) has a bulk density lower than gastric fluids and thus remains buoyant in the stomach without affecting the gastric emptying rate for a prolonged period

of time (Park and Park, 1998; Singh and Kim, 2000; Klaussner et al., 2003; Patel and Patel, 2006). While the system is floating on the gastric content, the drug is released slowly at a desired rate from the system. Floating drug delivery systems offer important advantages: they are less prone to gastric emptying resulting in reduced intra- and inter-subject variability in plasma drug levels, effective for delivery of drugs with narrow absorption windows, require reduced dosing and increased patient compliance, reduced Cmax and prolonged drug levels above the minimum effective concentration, and they provide an improved safety profile for drugs with side-effects associated with high Cmax. The various buoyant preparations include microballoons, granules, powders, capsules, tablets, and laminated films. Based on the mechanism of buoyancy, two distinctly different technologies, non-effervescent and effervescent systems, have been utilized in the development of floating systems (David et al., 1986; Chavanpatil et al., 2005; Hamid et al., 2006; Janardhan et al., 2009; Meka et al., 2009). Non-effervescent systems commonly use gel-forming or highly swellable cellulose 1463

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Int J Pharm Sci Nanotech

type hydrocolloids, polysaccharides and matrix forming polymers such as polycarbonate, polyacrylate, polymethacrylate, and polystyrene (Rosa et al., 1994; Lapidus and Lordi, 1966). Effervescent systems utilize matrices prepared with swellable polymers such as methocel or chitosan and effervescent compounds such as sodium bicarbonate and citric or tartaric acid or matrices containing chambers of liquid that gasify at body temperature (Korsmeyer et al., 1983; Hoffman et al., 1986; Park and Park, 1998; Singh and Kim, 2000). Levofloxacin is a widely used synthetic fluorinated quinolone antibiotic. Chemically, levofloxacin is (-)-(S)-9fluro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperzinyl)-7oxo-7H-pyrido-[1,2,3-de]-1,4-benzoxazine-6-caboxylic acid. Levofloxacin acts by inhibiting bacterial DNA gyrase enzyme that is required for DNA replication and thus causes bacterial lyses. It is effective for the treatment of H. pylori (Warren and Marshal, 1983; Okeri and Arhewoh, 2008). The failure of the antibiotic therapy can be avoided by providing the effective concentration of the drug at the site of action. Levofloxacin has a half-life of 5-7 hours and 85% oral bioavailability. In this study, we sought to develop a site-specific sustained dosage form of levofloxacin using three grades of hydrophilic matrix agents. The formulation was characterized by in vitro and in vivo release studies including clinical kinetic testing of drug product in healthy human volunteers to assess the gastric residence time.

Materials and Methods Drugs and Chemicals Levofloxacin was generous gift from Euro Drugs (Hyderabad, India). HPMC K4M, HPMC K15M and HPMC K100M were obtained from ISP, India. Sodium bicarbonate, citric acid, talc and magnesium stearate were purchased from S.D. Fine Chemicals Ltd (Mumbai, India). All chemicals and drugs were of analytical grade.

Formulation and Evaluation Methodology

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drug- to-polymer ratio and effervescent composition. The formulations were prepared with varying proportions of 4:1, 3:1 and 1:1 (12.5% from the total weight of the tablet) of a gas-generating agent composition (sodium bicarbonate: citric acid) in order to determine the effect of gas-generating agent concentration on the buoyancy behavior of the formulations. Drug-excipients compatibility study.

Differential scanning calorimetry (DSC): The DSC thermograms were recorded on a DSC (model Dsc-60, Shimadzu). Samples were heated in hermetically sealed aluminum pans over a temperature range of 10oC-300oC at a constant rate of 10oC/minutes under nitrogen purge. Fourier Transform Infra Red Spectroscopy (FTIR):

FTIR spectra were obtained on FTIR-8400S (Shimadzu). Samples were prepared in KBr disks. Data were collected over a spectral region from 4000 to 400 cm-1.

Preparation of LFH floating tablets. Preliminary formulations were studied to optimize the effervescent composition. Then, the floating tablets were prepared with an optimized concentration of gas-generating agent. The powder mixture containing drug, polymers and other excipients were weighed as per required quantity and thoroughly blended in mortar and pestle and then passed through sieve no. 40 and directly compressed using 8 mm flat punches on a rotary compression machine (Riddhi, India). The compression force was adjusted to obtain tablets with crushing strength in the range of 6 to 7 kg/cm2. Twelve batches of tablets were prepared by direct compression technique according to the formula depicted in Table 1. Evaluation of final blend. The flow properties of granules (before compression) were characterized in terms of angle of repose, tapped density, bulk density and the Carr’s index and Hausner ratio. Evaluation of physicochemical properties. The formulated tablets were evaluated for weight variation, thickness, crushing strength, friability, content uniformity, in vitro buoyancy properties, in vitro release studies and in vivo residence time.

Optimization of gas-generating agent concentration. Preliminary formulations were studied to optimize the TABLE 1 Composition of levofloxacin floating tablets. Formulation

HPMCK4M

HPMCK15M

HPMCK100M

Sodium bicarbonate

Citric acid

MCC

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

--------50 75 100 125

50 62.5 75 87.5 ---------

----25 50 62.5 75 -----

50 50 50 50 50 50 50 50 50 50 50 50

12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5

127.5 115 102.5 90 152.5 127.5 115 102.5 127.5 85.5 60.5 45.5

All the tablets contain 250 mg levofloxacin, 5 mg magnesium stearate and 5 mg talc. The average weight of each formulation was 500mg.


Weight variation: 20 tablets were selected at random and the average weight of the tablets was determined. The weight of individual tablets was compared with the average weight. Thickness: The thickness in millimeters (mm) was measured individually for 10 pre weighed tablets by using Vernier Calipers. The average thickness and standard deviation were reported. Crushing strength and friability: Crushing strength of tablet was determined by the Monsanto tester (Campbell Electronics, India) hardness tester. Friability tests were carried out using a Roche friabilator (Erection Instrument & Engineering, Ahmedabad, India). 10 tablets were weighed and subjected to the combined effect of attrition and shock by utilizing a plastic chamber. The friabilator was operated for 100 revolutions (4 minutes, 25 rpm). The tablets were dedusted and re-weighed to calculate the percentage of friability. Drug content uniformity: Prepared tablets were accurately weighed and finely powdered by pestle in a mortar. A weighed portion of each powder equivalent to dose (mg) of the prepared tablet was transferred in to a volumetric flask and the drug was extracted with methanol as the solvent. The contents of the flask were sonicated for 10 min and diluted with 0.1 N HCl as the solvent. The samples were analyzed spectrophotometrically at 293 nm. In vitro buoyancy studies: The in vitro buoyancy was determined by the method described by Rosa et al. 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 was determined as floating lag time and duration of the tablet remaining buoyant was observed visually. In vitro release studies: The release of LFH from floating matrix tablets was studied using the USP (11) dissolution apparatus II (Tab Machines, India). The dissolution medium was 900 ml of 0.1 N HCl maintained at 37°C ± 0.5°C with a rotation speed of 50 rpm. Aliquots of 5 ml were collected at predetermined time intervals, filtered through a 0.45 mm membrane filter and replenished with an equivalent volume of fresh medium. Drug contents in the samples were determined by a UVvisible double beam spectrophotometer (Elico, India) at 293 nm.

Intra-gastric Behavior of the Floating Tablets in Human Subjects The intra-gastric behavior of the floating tablets was carried out by administering the LFH floating matrix tablets to healthy human male volunteers and monitoring them through a radiological method. To make the tablets X-ray opaque, the incorporation of BaSO4 was necessary. The amount of the X-ray opaque material in these tablets was sufficient to ensure visibility by X-ray, but at the same time this amount of BaSO4 was low enough to enable tablets to float. Four healthy male subjects (mean age, 27 years; mean body weight, 60 kg) participate after giving informed consent. The study was

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approved by the Ethical Committee (UCPSc, Kakatiya University, Warangal). The study was conducted by administering to each subject one floating tablet on during a fasted state; the subjects fasted overnight then swallowed the floating tablets with 150 ml of water. Afterwards, the subjects were not allowed to eat or drink. In each subject, the position of the floating tablet was monitored by X-ray photographs (Konica Minolta, Siemens, Karlsruhe, Germany) of the gastric region at determined time intervals. All X-ray films were taken in anterior positions.

Results and Discussion IR Spectroscopic Studies IR spectroscopic studies were conducted to determine possible drug-polymer interactions. IR spectra of pure drug levofloxacin hemihydrate, HPMC K4M, K15M, K100M and physical mixtures of levofloxacin hemihydrate with these polymers were obtained which show all the characteristic peaks of levofloxacin hemihydrate and polymers present in the physical mixture. The major peaks C=O peak at 1724.81 cm-1, aromatic C-H peak at 2935.62 cm-1 (Figure 1) and OH group of carbonyl moiety at 3265.81 cm-1 which were present in pure drug levofloxacin hemihydrate was also present in the physical mixture, which indicates that there is no interaction between drug and the polymers, which confirms the stability of drug. The pure drug showed a sharp endothermic peak at 227 oC corresponding to its melting point. The polymers showed endothermic peaks of 252.5 oC and 255 oC (Figure 2) respectively. The appearance of two or more endothermic peaks in the heating DSC curves of levofloxacin hemihydrate-polymers may be an indication of the stability of drug. The tablets of LFH were prepared by direct compression using HPMC K4M, HPMC K15M and HPMC K100M, sodium bicarbonate and citric acid. Magnesium stearate and talc were used as lubricant and glidant, respectively. The data of physical parameters like thickness, weight variation, content uniformity, friability of all the formulations is enclosed in Table 2. All parameters fall within the limits. The average weight of the tablets was 500 mg and the weight variation for every batch was less than ±5%. The hardness was maintained as 6.5-7 kg/cm2 in all the formulations. The friability of all the formulations falls in the acceptable limit. The content uniformity was found to be in range of 96.33−98.56%.

In vitro Buoyancy Studies The prepared floating matrix tablets were buoyant for 12 hours with a floating lag time of less than 70 seconds. The optimized concentration of the effervescent mixture (sodium bicarbonate and citric acid) contributed to the buoyancy of all tablets. Buoyancy results of floating matrix tablets are shown in Table 3.

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Fig. 1. FTIR spectra of A) LFH, B) LFH & HPMCK4 C) LFH and HPMC K15M D) LFH and HPMC K100M E) Optimized formulation (F3).

Fig. 2. DSC thermograms of A) LFH, B) LFH & HPMC K15 C) LFH and K4M and D) Optimized formulation (F3).

TABLE 2 Physical evaluation parameters. Formulation code

Weight variation (mg)a

Hardness (kg/cm2)b

Thickness (mm)

Friability (%)

F1

503 ± 1.2

6.8±0.5

6.76±0.06

0.23

98.56± 1.2

F2

502 ± 1.1

7±0.3

6.86±0.03

0.48

98.21± 1.6

F3

503± 1.2

6.5±0.5

6.76±0.04

0.51

97.91± 1.5

F4

501± 1.3

6.8±0.2

6.63±0.06

0.22

97.75± 1.6

F5

502± 1.2

6.8±0.5

6.68±0.05

0.35

97.48± 1.4

F6

501± 1.1

7±0.2

6.55±0.25

0.38

97.69± 1.3

F7

503± 1.2

6.8±0.5

6.5±0.04

0.41

97.35± 1.6

F8

505± 1.4

6.5±0.3

6.62±0.07

0.29

96.55± 1.4

F9

501± 1.3

7±0.3

6.56±0.07

0.25

97.41± 1.2

F10

500± 1.4

7.2±0.1

6.48±0.04

0.28

97.97± 1.2

F11

505± 1.4

6.8±0.2

6.61±0.06

0.39

96.54± 1.3

F12

504± 1.7

7.2±0.5

6.94±0.08

0.48

96.33± 1.4

Mean ± SD: a n = 20, b n = 6, c n = 3.

Drug Content (%)c

Doodipala et al: Development and Clinical PK Evaluation of Gastroretentive Floating Matrix Tablets of Levofloxacin TABLE 3 Floating properties of prepared tablets. Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

Floating lag time (sec) 55 58 61 60 68 66 65 66 58 55 51 48

Floating time (h) >12 >12 >12 >12 >12 >12 >12 >12 >12 >12 >12 >12

In vitro Release Studies The in vitro drug release studies revealed that formulations F1 and F2 showed a release of 91.9% and 97.04%, respectively, in 8 and 10 hours (Figure 3A). Formulation F3 showed the maximum drug release of 98.7% in 12 hours. The variation in drug release was due to different polymer concentrations in all four formulations. Formulations F1 and F2 were unable to sustain the drug release desired period of time but in the case of formulation F3, 98.7% and 73.31% of drug was released in 12 hours. This could be due to different polymer concentrations in all the four formulations. All four formulations floated for 12 hours. Formulations F4 failed to release the required drug profile. Formulation F3 obtained the desired drug release profile and floated with a lag time of 65 seconds and for these reasons, it was considered as best formulation among the four. Formulations F5-F8, composed of HPMC K100M, showed a release of 93.4, 95.7, 96.8 and 80.9% in 4, 8, and 12 hours, respectively. These variations in drug release were due to changes in polymer concentrations of the tablets. However, formulations F5, F6 and F9 failed to meet the desired drug release profile in 12 hours. Formulation F8 met the desired drug release profile in

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12 hours and floated with a lag time of 55 seconds. It was, therefore, considered the best formulation among all the four formulations in this series. The results are shown in Figure 3B. The drug release from the floating matrix tablets was sustained for a prolonged period of time due to the viscous nature of the HPMC matrix through which the drug diffuses. HPMC K4M helped to increase the drug release within 12 hours and maintained the integrity and buoyancy of the tablets but floating lag time decreased with increased concentration. The results are shown in Figure 3C. The increased drug release from the floating matrix tablets with high concentration of HPMC K4M compared to the floating matrix tablets containing a smaller amount may be due to matrix erosion in the former and swelling diffusion and a slight erosion mechanism in the latter. However, the matrix containing a high viscosity grade of polymer with a large molecular mass mainly results in swelling properties with little erosion and vice versa. Integrity and floating properties of floating matrix tablets were thus maintained. The drug released was found to be 97.2% 12 hours from formulation F11. Data of the in vitro release was fit into kinetic models to explain the release kinetics of LFH from the floating tablets (Higuchi, 1963; Hoffman et al., 1986; Gohel et al., 2000). The kinetic models used were zero-order equation, first-order equation, and Higuchi and KorsemeyerPeppas models. The cumulative amount of the drug released from the tablets, when plotted against squareroot of time, the release profiles of the drug seem to follow the Higuchi model, as it was evidenced by correlation coefficients (r2 = 0.98 to 0.99) better than zero order (r2 = 0.93 to 0.98) and first order (r2 = 0.52 to 0.57). The data was further treated as per the following equation: Mt/M∞ = K.t.n

Fig. 3A. Drug release profiles of LFH floating matrix tablets composed of HPMC K15M (F1, F2, F3 and F4).

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Fig. 3B. Drug release profiles of LFH floating matrix tablets composed of HPMC K100M (F5, F6, F7 and F8).

Fig. 3C. Drug release profiles of LFH floating matrix tablets composed of HPMC K4M (F9, F10, F11 and F12).

Where, Mt/M∞ is the fractional release of the drug, Mt is the amount released at time t, M∞ is the total amount of drug contained in the formulation, t is the release time, K is a kinetic constant, and n is the diffusional release exponent indicative of the operating release mechanism. The n values obtained (0.487 to 0.5) by this equation indicated that the drug release was by a non-Fickian model. The results are shown in Table 4.

In Vivo Radiographic Studies in Human Subjects The optimized formulation was selected based on the correlation factor (r2) values of all formulations and dissolution parameters and physical characteristics of formulation. Formulation (F3) selected as optimized and in vivo X-ray studies revealed that tablets float in the

stomach for 240 ± 30 minutes in healthy human volunteers in fasting conditions and the results are shown in Figure 4. TABLE 4 Correlation coefficient (R2) and release exponent (n) values for different kinetic models. Formulation

zero-order

First-order

Higuchi

F1 F2 F3 F4 F5 F6 F7 F8 F9

0.896 0.944 0.972 0.961 0.982 0.89 0.928 0.934 0.954

0.491 0.451 0.469 0.533 0.497 0.449 0.454 0.483 0.455

0.991 0.979 0.995 0.991 0.913 0.992 0.995 0.997 0.994

Korsmeyer Peppas 0.487 0.69 0.251 0.534 0.49 0.371 0.435 0.504 0.464


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Fig. 4. Radiographic images showing the presence of a BaSO4-loaded floating tablet in the stomach at different time periods (the tablet is indicated with an arrow). The tablet altered its position in the stomach. Images were taken after: a) 0.5 h , b) 1.5 h, c) 3 h and d) 4 h after tablet administration (n=4 subjects).

Conclusions Overall, the results of the present study suggest that effervescent-based floating drug delivery is a promising approach to achieve excellent in vitro buoyancy. The addition of gel-forming polymer (HPMC K4M, HPMC K15M and HPMC K100M) and a gas-generating agent such as sodium bicarbonate is essential to achieve optimum in vitro buoyancy. Our results suggest that formulation F3 showed controlled drug release and has adequate floating properties. The kinetics of drug release can be best explained by the Higuchi model. Our clinical pharmacokinetic studies indicate that the tablets floated in the stomach for over 4 hours in healthy volunteers, indicating that gastric retention time can be successfully achieved by the floating principle. References Bandari S, Eaga CM, Thadishetty A and Rao YM (2010). Formulation and evaluation of multiple tablets as a biphasic gastro retentive floating drug delivery system for fenoverine. Acta Pharm 60: 89–97. Bardonn PL, Faivre V, Pugh WJ, Piffaretti JC and Falson F (2006). Gastroretentive dosage forms: Overview and special case of Helicobacter pylori. J Control Rel 111:1-18. Bomma R, Naidu RAS, Rao YM and Veerabrahma K (2009). Development and evaluation of gastro retentive norfloxacin floating tablets. Acta Pharm 59:211–221. Brazel CS and Peppas NA (2000). Modeling of drug release from swellable polymers. Eur J Pharm Biopharm 49:47-58. Chavanpatil M, Jain P, Chaudhari S, Shear R and Vavia P (2005). Development of sustained release gastro retentive drug delivery system for ofloxacin: In vitro and in vivo evaluation. Int J Pharmaceutics 304: 178-184. David G, Friedmann JC, Marmo E and Pierre R (1986). Pharmacodynamic profile of fenoverine, a novel modulator of smooth muscle motility. Acta Ther 12: 309–335. Forman D, Webb P and Parsonnet J (1994). Helicobacter pylori and gastric cancer. Lancet 343:243-244. Gandhi R, Kaul CL and Panchagnula R (1999). Extrusion and spheronization in the development of oral controlled release dosage forms. Pharm Sci Tech Today 2: 160–170. Gohel MC, Panchal MK and Jogani VV (2000). Novel mathematical method for quantitative expression of deviation from the Higuchi model. AAPS Pharm Sci Tech 1:45-50. Hamid AM, Harris MS, Jaweria Tand Rabia IY (2006). Once-daily tablet formulation and in vitro release evaluation of cefpodoxime using hydroxypropyl methylcellulose: A technical note. AAPS PharmSciTech 7: Article 78.

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