Design and evaluation of polymeric coated minitablets as multiple unit gastroretentive floating drug delivery systems for furosemide

Design and Evaluation of Polymeric Coated Minitablets as Multiple Unit Gastroretentive Floating Drug Delivery Systems for Furosemide LINGAM MEKA, BHASKAR KESAVAN, VENKATASIMHADRI NAIDU KALAMATA, CHANDRA MOHAN EAGA, SURESH BANDARI, VENKATESWARLU VOBALABOINA, MADHUSUDAN RAO YAMSANI Centre for Biopharmaceutics and Pharmacokinetics, University College of Pharmaceutical Sciences, Kakatiya University, Warangal 506 009, Andhra Pradesh, India

Received 7 May 2008; revised 24 July 2008; accepted 3 August 2008 Published online 13 November 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21562

ABSTRACT: A gastro retentive floating drug delivery system with multiple-unit minitablets based on gas formation technique was developed for furosemide. The system consists of core units (solid dispersion of furosemide:povidone and other excipients), prepared by direct compression process, which are coated with two successive layers, one of which is an effervescent (sodium bicarbonate) layer and other one an outer polymeric layer of polymethacrylates. The formulations were evaluated for pharmacopoeial quality control tests and all the physical parameters evaluated were within the acceptable limits. Only the system using Eudragit RL30D and combination of them as polymeric layer could float within acceptable time. The time to float decreased as amount of the effervescent agent increased and, when the coating level of polymeric layer decreased. The drug release was controlled and linear with the square root of time. By increasing coating level of polymeric layer decreased the drug release. The rapid floating and the controlled release properties were achieved in this present study. The stability samples showed no significant change in dissolution profiles ( f2 ¼ 81). The in vivo gastric residence time was examined by radiograms and it was observed that the units remained in the stomach for about 6 h. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2122–2132, 2009

Keywords:

bioavailability; coating; controlled release; absorption; dissolution

INTRODUCTION Oral controlled release drug delivery systems can be classified into two broad groups: single unit dosage forms (SUDFs), such as tablets or capsules, and multiple unit dosage forms (MUDFs) such as granules, pellets or minitablets. The production of MUDFs is a common strategy to control the release of a drug, as shown by the reproducibility of the release profiles when

Correspondence to: Lingam Meka (Telephone: þ91-8702446259; Fax: þ91-870-2453508; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 98, 2122–2132 (2009) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association

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compared to the ones obtained with SUDFs.1 Floating drug delivery system (FDDS) is desirable for drugs with an absorption window in the stomach or in the upper small intestine.2,3 It is also useful for drugs that act locally in the proximal part of gastrointestinal (GI) tract such as antibiotic administration for Helicobacter pylori eradication in the treatment of peptic ulcer,4–7 and for drugs that are poorly soluble or unstable in the intestinal fluid.8,9 Most of the floating systems previously reported are single unit systems. A drawback of these systems is the high variability of the GI transit time due to their all-or-nothing emptying processes.6,10–14 On the other hand, the multiple-unit dosage forms may be an attractive alternative

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since they have been shown to reduce the interand intrasubject variabilities in drug absorption as well as to lower the possibility of dose dumping.15,16 Various multiple-unit floating systems have been developed in different forms and principles such as air compartment multipleunit system,17 hollow microspheres (microballoons) prepared by the emulsion solvent diffusion method14,18 microparticles based on low-density foam powder,19 beads prepared by emulsion– gelation method,20,21 hollow/porous calcium pectinate beads for floating-pulsatile drug delivery.22 Use of swellable polymers and effervescent compounds is another approach for preparing multiple-unit FDDS. Ichigawa et al.10 developed FDDS by coating the sustained release pills or granules with tartaric acid layer, sodium bicarbonate layer and polymeric film consisting of polyvinyl acetate and shellac. The floating system using ion exchange resin loaded with bicarbonate and then coated by a semipermeable membrane was also proposed.23 The development of mini-matrices is a promising area in pharmaceutical research concerned with a high control over the release rate of the drug combined with a high flexibility on the adjustment of both the dose and the release of a drug or drugs24 and has attracted some attention in the 1990s.25–28 The concept of MUDFs is characterized by the fact that the dose is administered as a number of subunits, each one containing the drug. The dose is then the sum of the quantity of the drug in each subunit and the functionality of the entire dose is directly correlated to the functionality of the individual subunits.29–31 The production of mini-matrices using a tabletting technique is an attractive alternative to the production of pellets, as the presence of solvents (e.g., water) is avoided and high production yields like the ones observed in extrusion and spheronization are obtained. Furthermore, due to the manufacturing process, defined size and strengths can easily be produced, with small variability within and between batches.32 Furosemide (FR), a potent loop diuretic drug, widely used in patients with oedema of various origins and also for forced diuresis in case of poisoining or over dosage. FR is absorbed mostly in the stomach and upper small intestine possibly due to its weak acidic properties (pKa 3.9) and is characterized by a short half life of 1.3  0.8 h.33 The bioavailability of FR after oral administration is about 60% and is quite variable (20–60%) owing DOI 10.1002/jps

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to the presence of an absorption window in the upper intestinal tract.34,35 Diuresis and natriuresis of FR depends upon its active tubular secretion36,37 because FR acts directly on renal tubule. Rapid exposure of FR to its site of action elicits high peak natriuretic and diuretic effects. As a consequence, there is a rapid and massive activation of compensatory responses, including activation of the sympathetic nervous system and the renin angiotensin–aldosterone system.38 This results in development of resistance to the effect of FR due to sodium and water retention in nephron.39 The desirable therapy is to maintain a continuous diuresis to improve therapeutic benefit, which requires slow release of FR from the formulation close to the absorption window. In this study furosemide was selected as a model drug, whose absorption is limited to the upper part of the GIT. Therefore, prolongation of residence time of a dosage form in the stomach or the upper small intestine, close to the absorption window, would be effective in enhancing the absorption compared with that of a nonfloating dosage form and at the same time decrease the side effects. In this study, a new approach with minitablets filled into capsules based on gas formation technique was developed. The drug-containing (FR solid dispersions) core minitablets was prepared by direct compression method followed by coating of the units with effervescent layer and polymeric layer (Eudragit RS30D, RL30D and combination of them). The effect of the preparative parameters like, amount of the effervescent agent layered onto the core units, type and coating level of the polymeric layer, on the floating ability and drug release properties of the multiple-unit FDDS were evaluated.

MATERIALS AND METHODS Materials Furosemide (FR) was obtained from Zydus Cadila Healthcare Ltd. (Ahmedabad, India). Povidone (PVPK30 from ISP, Hyderabad, India), microcrystalline cellulose (MCC) (Avicel PH102), hydroxy propyl methyl cellulose (HPMC K100), ethyl cellulose 7 cps were procured from Dr. Reddy’s Labs (Hyderabad, India). Sodium bicarbonate (Merk, Mumbai, India) was used as an effervescent agent with HPMC (Methocel E15LV), plasticized with polyethylene glycol 6000 (PEG 6000 SD fines, Mumbai, India) as a JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009

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binder. The polymeric layer used was polymethacrylates (Eudragit RL30D and RS30D, Rohm Pharma, Kirchenallee, Darmstadt, Germany) plasticized with triethyl citrate (Himedia, Mumbai, India). All other reagents and solvents used were of analytical grade procured from Merck (Mumbai, India). Preparation of Furosemide Solid Dispersions Solid dispersions (SD) of FR were prepared by solvent method.40–42 Furosemide and povidone in weight ratios (1:5, w/w) were dissolved in a minimum amount of common solvent (methanol). The solvent was removed under reduced pressure in a rotary evaporator at 708C. The dispersions were vacuum dried for 48 h in a desiccator at room temperature. The residue was ground and the particle size (75–150 mm) fraction was obtained by sieving. X-Ray Diffraction Studies Powder X-ray diffraction studies were carried out by using X-ray diffractometer, over a range of 2u angles from 48 to 358, by exposing the solid to ˚ wavelength) radiation. Cu Ka (1.5406 A Determination of Equilibrium Solubility of Furosemide An excess amount of FR, PM (physical mixture), and SD were added slowly with stirring to different medium. The solution was shaken at room temperature for 24 h to achieve the equilibrium solubility. Samples were filtered and diluted with respective medium. The diluted samples were assayed for furosemide by UV–vis spectroscopy at 274 nm. Preparation of Core MUDF Core minitablets were prepared by blending solid dispersion (SD) equivalent to 40 mg of FR with HPMC K100, ethyl cellulose, MCC, by geometric mixing then passed through #40 mesh (ASTM). Magnesium stearate and talc were weighed and passed through #60 mesh (each 1%, w/w) then mixed with above blend and final blend was compressed into minitablets using 2.8 mm round concave punches and corresponding dies on rotary tablet compression machine (Riddhi, Ahmedabad, India). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009

Physical Properties of the Final Blend and Core Units Physical properties such as bulk density, tapped density, compressibility index, Hausner ratio and the angle of repose of final blend were determined, tapped density was determined by using a tapped density tester (Campbell, Mumbai, India).Percent compressibility and Hausner ratio were calculated using Eqs. (1) and (2):
 Dt  Db Percent compressibility ¼  100 (1) Dt Hausner ratio ¼

Dt Db

(2)

where Dt and Db are tapped and bulk densities. Compressed minitablets were characterized for weight variation and thickness (n ¼ 20) using analytical balance and digital micrometer (Mitutoyo, Kawasaki, Japan). Crushing strength (n ¼ 6) was measured with Monsanto tester, friability (n ¼ 6), with (Roche type friabilator, at 25 rpm for 100 revolutions) and drug content.

Coating of the Core MUDF The core units were coated with two successive layers; first with effervescent layer (sodium bicarbonate) and then with polymethacrylate (Eudragit RS30D, RL30D, and RS30D:RL30D) as an outer polymeric coating layer. An effervescent agent was incorporated into HPMC solution (water as solvent) plasticized with PEG 6000 (10% (w/w) based on the solids content) and then layered onto the core units. On a dry solid basis, the ratio of HPMC to sodium bicarbonate was 2:6 (w/w). The coating level of effervescent layer was 12% (optimized) weight gain and the solids content of coating solution was kept constant at 8% (w/w). The coating solution was sprayed onto the core units in a coating pan (Allegro, Mumbai, India). The conditions for coating were shown as follows: tablets charge 100 g; preheating temperature 40  58C; preheating time 20 min; inlet air temperature 50  58C; spray rate 8–10 mL/min. effervescent-layered units were dried in the coating chamber for 60 min at 40  58C. The prepared units were then removed from the coating pan and stored in a closed container for further processing. The effervescent-layered units were subsequently coated with polymethacrylates dispersions (Eudragit RS30D, RL30D, or RS30D:RL30D) to achieve a weight gain of 5–10% (w/w) to obtain the DOI 10.1002/jps

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complete multiple-unit FDDS. A plasticizer (triethylcitrate 10% (w/w) based on polymer solids content) was added into the polymer dispersion then the whole dispersion was stirred throughout the coating process. The solids content of the coating dispersions was 10% (w/w). The coating conditions were as follows: tablets charge 100 g; preheating temperature, 40  58C; preheating time 20 min; inlet air temperature 45  58C; spray rate 3–5 mL/min. The units were further dried in the coating chamber for 60 min after the coating was finished to evaporate the residual moisture. The prepared units were then removed from the coating chamber and stored in a closed container for further experiments.

Floating Behavior The floating abilities of the effervescent-layered units and the final coated effervescent-layered units (complete multiple-unit FDDS) were determined using USP II apparatus (50 rpm, 37  0.58C, 900 mL, pH 1.2 (enzyme free)). Units were placed in the medium; the time required to float was measured by visual observation.

In Vitro Dissolution The release rate of drug from minitablets filled into capsules (‘‘0el’’size) was determined (n ¼ 3) using USP Apparatus 2 (paddle method). The dissolution test was performed using 900 mL of 0.1 N HCl at 37  0.58C and 50 rpm. A sample (5 mL) of the solution was withdrawn from the dissolution apparatus hourly for 10 h, and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45-mm membrane filter and diluted to a suitable concentration with 0.1 N HCl. Absorbance of these solutions was measured at 274 nm using a UV/Vis double-beam spectrophotometer (Elico, Hyderabad, India). Cumulative percentage drug release was calculated using an equation obtained from a standard curve.

Kinetics of Drug Release The suitability of several equations, which are reported in the literature to identify the mechanism for the release of drug, was tested with respect to the release data. The data for analysis was taken to Q8 (drug released up to 8 h) excluding DOI 10.1002/jps

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the lag time for all models except (Korsmeyer– Peppas) model. This Peppas diffusion model expected to be valid only up to approximately 60% cumulative drug released43 thus formulations with up to 60% cumulative drug release was considered. The data were evaluated according to the following equations44  First order model ln Mt ¼ ln M0 þ K1 t  Zero-order model

(3Þ

Mt ¼ M0 þ K0 t  Higuchi model

(4Þ

Mt ¼ M0 þ KH t0:5  Korsmeyer–Peppas model

(5Þ

Mt ¼ M0 þ KK tn

(6Þ

where Mt is the amount of drug released in time t, M0 the initial amount of drug, K is the respective release constant, and n is the release exponent, which characterizes the mechanism of drug release. The magnitude of the exponent n indicates the release mechanism as Fickian diffusion, as case II transport, or as anomalous transport. In the present study (cylindrical shape) the limits considered were n ¼ 0.45 (indicates a classical Fickian diffusion-controlled drug release) and n ¼ 0.89 (indicates a case II relaxational release transport: polymer relaxation controls drug delivery). Values of n between 0.45 and 0.89 can be regarded as indicators of both phenomena (transport corresponding to coupled drug diffusion in the hydrated matrix and polymer relaxation) commonly called anomalous non-Fickian transport. Values of n greater than 0.89 indicates a super case II transport, in which a pronounced acceleration in solute release by a film occurs toward the latter stages of release experiments, resulting in a more rapid relaxation-controlled transport.45

Stability Studies The formulation kept in the humidity chamber (LabTop, Vasai, Maharashtra, India) maintained at 25 and 60% relative humidity for 3 months. At the end of studies, samples were analyzed for physicochemical parameters. For the comparison of release profiles of initial and stability samples, ‘‘difference factor’’ f1 and ‘‘similarity factor’’ f2, were calculated.46 The difference factor ( f1) JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009

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measures the percent error between the two curves over all time points and was calculated as follows:  Pn   j¼1 Rj  Tj Pn f1 ¼  100 (7) j¼1 Rj where n is the number of sampling points, Rj and Tj are the percent dissolved of the reference and test products at each time point j. The two release profiles are considered to be similar, if f1 value is lower than 15 (between 0 and 15). The similarity factor ( f2) is a logarithmic transformation of the sum of squared error of differences between the test Tj and the reference products Rj over all time points. It was calculated using the following equation (" #)0:5  X  2 1 n f2 ¼ 50 log 1 þ w j  Rj  T j  100 n j¼1 (8) where wj is an optional weight factor and other terms are as defined earlier. The two dissolution profiles are considered to be similar, if f2 value is more than 50 (between 50 and 100).

Determination of Gastric Residence Time of Floating MUDF (In Vivo X-Ray Studies) The in vivo tests discussed below were performed on six healthy male volunteers whose ages were between 25 and 32 years, weighed between 60 and 71 kg (Approval for the study was taken from University ethical committee, UCPSc, Kakatiya University, Warangal, AP, India). Eighteen percent of BaSO4 was added to the part of the final

formulation (the amount of BaSO4 that allows visibility by X-ray, but does not preclude the floating of tablets was experimentally determined). Labeled Floating MUDF (Placebo) were given to subjects with 250 mL of water after a light, 308 kcal breakfast. Following ingestion, gastric radiography was undertaken at 0.5, 1, 3, 4, and 6 h, and the duration of the minitablets stayed in the stomach was observed.

RESULTS AND DISCUSSION X-ray pattern of FR solid dispersion with povidone (1:5 weight ratio) was compared to the pure drug and polymer. The furosemide diffraction peaks at 24.8, 21.3, and 22.18 at 2u values suggests that it is crystalline in nature. In the powder XRD pattern of solid dispersion of FR:PVP no diffraction peaks were detected, suggesting that furosemide was in the amorphous state. From the results it was clear that the solubility of FR from the solid dispersions increased enormously (Tab. 1). This could be attributed to the hydrophilic character of the carrier and to the amorphous state of the drug in solid dispersions as evidenced from the X-ray diffraction studies.47 Therefore, SD providing highest solubility was selected to achieve the suitable release profiles from floating MUDFs. The floating minitablets of FR was prepared by gas entrapped technique using release rate controlling polymers (Fig. 1). The final blend of the batches showed good flowability (angle of repose <308) and compressibility. The core minitabs were prepared by direct compression using release rate controlling

Table 1. Solubility of FR, Physical Mixture, and Solid Dispersion in Different Media

Medium

Solubility (mg/mL), Mean  SD

Distilled water 0.1 N HCl (pH 1.2) Water–HCl (pH 5) Phosphate buffer (pH 5.8) Phosphate buffer (pH 6.8) 0.1 N HCl (pH 1.2) Water–HCl (pH 5) 0.1 N HCl (pH 1.2) Water–HCl (pH 5) 0.1 N HCl (pH 1.2) Water–HCl (pH 5)

39  0.3 23  1 24  1 773  8 4844  279 58  2 80  3 43  3 74  1 216  17 391  17

Sample Furosemide (pure)

Furosemide from methanol Furosemide:PVP (1:5) physical mixture Furosemide:PVP (1:5) solid dispersion

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Figure 1. Design of floating MUDF.

polymers. The formulations were evaluated for pharmacopoeial quality control tests and all the physical parameters evaluated for quality control were within the acceptable limits of Pharmacopoeia (Tab. 2). Friability of the formulation was 0.35%. This indicated that the core units were quite hard and able to withstand the mechanical stresses of the subsequent coating process. The system consisted of drug-containing core minitablets coated with effervescent layer and then polymeric layer, respectively. Since sodium bicarbonate itself could not adhere to the units, HPMC was used as a binder in the effervescent layer. An ideal coating material for a floating system should be highly water permeable in order to initiate the effervescent reaction (upon contact with acidic medium, sodium bicarbonate present in the first layer will react with acid and liberate CO2 by neutralization reaction) and the floating process rapidly. However, the wet or

Table 2. Physical Properties of Final Blend and Core Minitablets Parameter Angle of repose (8) Bulk density (g/cm3) Tapped density (g/cm3) % Compressibility Hausner ratio Hardness (kg/cm2) Friability (%) Thickness (mm) DOI 10.1002/jps

Values 27 0.5 0.6 16 1.2 1–3 0.35 2.26–2.34

hydrated coatings should also be impermeable to the generated CO2 so as to promote and maintain floatation.48 Regarding their mechanical properties, the polymeric coatings should be sufficiently flexible in wet state to be able to withstand the pressure of the generated gas and to avoid rupturing. Krogel and Bodmeier reported that the cellulosic polymers were not suitable candidates for FDDS. Cellulose acetate was too rigid and did not expand sufficiently when in contact with dissolution media, while ethyl cellulose was not flexible and ruptured easily upon CO2 formation. Gas bubbles were released rapidly after the burst of coating. According to these reasons, the higher flexibility polymer, polymethacrylates (Eudragit RS30D, RL30D, and RS30D:RL30D) were chosen and investigated as a polymeric layer in this study. Upon contact with the gastric fluid, the fluid permeated into the effervescent layer through the outer polymeric coating layer. Carbon dioxide was liberated via neutralization reaction and was entrapped in the polymeric layer. After that, the swollen minitabs with a density less than 1.0 g/mL floated and maintained the buoyancy; therefore, the drug was released from the system for a long time. To develop the multiunit FDDS based on gas formation technique, several studies were necessary to identify the formulation variables providing the desired system properties, rapid expansion and formation of low-density system within minutes after contact with gastric fluids and maintaining the buoyancy in stomach with controlled release. The effect of the preparative parameters such as amount of the effervescent agent layered onto the core minitabs, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009

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type and coating level of the polymeric layer, on the floating ability and drug release of the multiple-unit FDDS were evaluated. The floating ability of the effervescent-layered units and the effervescent-layered units coated with polymeric membrane (complete multipleunit FDDS) were investigated respected to amount of the effervescent agent coated, and type and level of the polymeric coating. The system should float within a few minutes after contact with gastric fluid to prevent the dosage form from transiting into the small intestine together with food.17 The percent coating level of effervescent layer was evaluated and found that about 12% of effervescent layer is required for floating the units within minutes. The effervescent layered units floated within 10 s after placed in acidic media. The floating time of the effervescent-layered units was quite short (less than 3 h) because HPMC dissolved and there was no polymeric layer which could entrap the generated CO2 gas. Therefore, the complete multiple-unit FDDS (effervescent-layered units coated with polymeric membrane) was prepared and evaluated for floating ability. Eudragit RL30D, RS30D and in combination were used as polymeric layer. The multiple-unit FDDS using Eudragit RL30D and Eudragit RS:RL30D as polymeric layer floated completely within 4 min. The floating lag time was found to be in the order of: effervescent layered < RL–5% < RS:RL(1:3)–5% < RS:RL(1:3)– 7.5% < RS:RL(1:3)–10%. The time to float of the systems decreased with increasing amount of effervescent agent and increased with increasing level of polymeric coating layer. The higher amount of effervescent agent caused faster and higher CO2 generation.48 With increasing level of Eudragit RL30D, the floating started later due to the delayed water penetration through the thicker coating. The duration of floating was longer than 12 h. It was indicated that Eudragit RL30D and RS:RL combination of polymeric layer was impermeable to the generated CO2 and could maintain the floatation. The multiple-unit FDDS systems coated with Eudragit RS30D as polymeric layer did not floated within 20 min even used high effervescent coating level (15% (w/w) weight gain). Eudragit RS30D might not be permeable enough for dissolution medium to induce the effervescent reaction and generate sufficient amount of CO2 to make the units floated. Eudragit RL30D is a highly water permeable polymer according to its hydrophilic content, quaternary ammonium groups in the structure.49,50 It has twice as JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009

many quaternary ammonium groups and is more hydrophilic than Eudragit RS. A faster and higher CO2 generation caused by increasing the level of effervescent resulted in higher swelling of polymeric layer and subsequent floating. It is therefore hydrated faster and resulted in a shorter time to float.48 Based on these results, Eudragit RL30D and combination of RS:RL30D were the polymers of choice as outer polymeric coating layer in this multiple-unit FDDS. The release of FR from the core units, the effervescent-layered units and the effervescentlayered units coated with Eudragit RL30D and RS:RL30D as polymeric layer was shown in Figure 2. There is no significant difference in drug release between the core units and the effervescent layered units. The drug release of the effervescent-layered units coated with Eudragit RL30D and combinations was slower than that of the uncoated effervescent layered units because the polymeric layer retarded the water penetration through the effervescent-layered cores. Besides the effect of effervescent level, the effects of polymer type and coating level on drug release were also investigated. Since only the multipleunit FDDS using Eudragit RL30D and combination of RS:RL as an outer polymeric layer coated minitablets could float, the drug release of this system was investigated for further study. The drug release decreased with increasing level of polymeric coating from 5% to 10%. The higher membrane thickness retarded water penetration, resulting in decreasing drug release.10,48 The drug release from the system using Eudragit RL30D and RS:RL combinations as an outer polymeric coating layer was found to be linear with time. The correlation coefficient (r2) was used as indicator of the best fitting, for the models

Figure 2. Cumulative percentage of furosemide released from formulations versus time (n ¼ 3). DOI 10.1002/jps

Table 3. The Correlation Coefficient (r2) Values for Different Formulations r2 Release Models Core Units Effervescent Layered RL 5% RS:RL (1:3) 5% RS:RL (1:3) 7.5% RS:RL (1:3) 10% First order Zero order Higuchi

0.892 0.949 0.974

0.872 0.940 0.973

0.852 0.943 0.979

0.887 0.948 0.965

0.886 0.955 0.972

0.891 0.966 0.974

Figure 3. In vivo gastric residence time of floating MUDF by X-ray Studies. DOI 10.1002/jps

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considered. Some release mechanisms can be better elucidated indirectly, on basis of exponent n, in Eq. (6) or comparing the fitting of the models of pure diffusion equation (5) and of relaxational polymer and matrix erosion Eq. (4). The results (Tab. 3) reveal that all formulations were best fitted in the Higuchi model. The mechanism of drug release from these minitablets was found to be diffusion controlled as seen from r2 values of Higuchi model. The n values for these systems were in the range of 0.58–0.87 which can be regarded as indicators of both phenomena (transport corresponding to coupled drug diffusion in the hydrated matrix and polymer relaxation) commonly called anomalous non-Fickian transport. The analysis of the parameter dissolution data, after storage at 258C and 60% RH for 3 months showed, no significant change indicating the two dissolution profiles are considered to be similar ( f2 value is 81 and f1 value is 4). Following ingestion of the final formulation prepared by the addition of BaSO4 to the release layer, the gastric residence time of minitablets were examined by radiogram, and it was observed that the units remained in the stomach for about 6 h (Fig. 3).

CONCLUSION The system using Eudragit RL30D and combination of them as an outer polymeric coating layer could float. The time to float decreased as amount of the effervescent agent increased and coating level of polymeric layer decreased. The optimum system could float completely within 4 min and maintained the buoyancy over a period of 12 h. The floating lag time was found to be in the order of: effervescent layered < RL–5% < RS:RL(1:3)– 5% < RS:RL(1:3)–7.5% < RS:RL(1:3)–10%. The drug release was controlled and linear with the square root of time. Increasing coating level of outer polymeric layer decreased the drug release. Both the rapid floating and the controlled release properties were achieved in the multiple-unit floating drug delivery system developed in this present study, and it was observed that the units remained in the stomach for about 6 h. A further in vivo study has to be carried out to access the bioavailability of drug.

ACKNOWLEDGMENTS The author (Meka Lingam) would like to thank Cadila Healthcare Ltd. (Ahmedabad, India) for JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009

providing gift sample of furosemide and also thankful to UGC India for providing Junior Research Fellowship.

REFERENCES 1. Borgquist P, Nevsten P, Nilsson B, Wallenberg LR, Axelsson A. 2004. Simulation of the release from a multiparticulate system validated by single pellet and dose release experiments. J Contr Release 97:453–465. 2. Rouge N, Buri P, Doelker E. 1996. Drug absorption sites in the gastrointestinal tractand dosage forms for site-specific delivery. Int J Pharm 136:117–139. 16. 3. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H. 2004. In vitro and in vivo evaluationof riboflavincontaining microballoons for a floating controlled drug deliverysystem in healthy humans. Int J Pharm 275:97–107. 4. Cooreman MP, Krausgrill P, Hengels KJ. 1993. Local gastric and serum amoxicillin concentrations after different oral application forms. Antimicrob Agents Chemother 37:1506–1509. 5. Yang L, Eshraghi J, Fassihi R. 1999. A new intragastric delivery system for the treatment of Helicobacter pylori associated gastric ulcer: In vitro evaluation. J Contr Release 57:215–222. 6. Umamaheshwari RB, Jain S, Bhadra D, Jain NK. 2003. Floating microspheres bearing acetohydroxamic acid for the treatment of Helicobacter pylori. J Pharm Pharmacol 55:1607–1613. 7. Bardonnet PL, Faivre V, Pugh WJ, Piffaretti JC, Falson F. 2006. Gastroretentive dosageforms: Overview and special case of Helicobacter pylori. J Contr Release 111:1–18. 8. Singh BN, Kim KH. 2000. Floating drug delivery systems: An approach to oral controlled drug delivery via gastric retention. J Contr Release 63:235– 259. 9. Jain SK, Awasthi AM, Jain NK, Agrawal GP. 2005. Calcium silicate based microspheres of repaglinide for gastroretentive floating drug delivery: Preparation and in vitro characterization. J Contr Release 107:300–309. 10. Ichigawa M, Watanabe S, Miyake Y. 1991. A new multiple-unit oral floating dosage system. I. Preparation and in vitro evaluation of floating and sustained-release characteristics. J Pharm Sci 80: 1062–1066. 11. Kawashima Y, Niwa T, Takeuchi H, Hino T, Ito Y. 1991. Preparation of multiple unit hollow microspheres (microballoons) with acrylic resin containing tranilast and their drug release characteristics (in vitro) and floating behavior (in vivo). J Contr Release 16:279–290. DOI 10.1002/jps

POLYMERIC COATED MINITABLETS AS GASTRORETENTIVE DRUG DELIVERY

12. Streubel A, Siepmann J, Bodmeier R. 2003. Multiple unit gastroretentive drug delivery systems: A new preparation method for low density microparticles. J Microencapsul 20:329–347. 13. Talukder R, Fassihi R. 2004. Gastroretentive delivery systems: Hollow beads. Drug Dev Ind Pharm 30:405–412. 14. Jain SK, Awasthi AM, Jain NK, Agrawal GP. 2005. Calcium silicate based microspheres of repaglinide for gastroretentive floating drug delivery: Preparation and in vitro characterization. J Contr Release 107:300–309. 15. Bechgaard H, Nielson GH. 1978. Controlled release multiple units and single unit doses. Drug Dev Ind Pharm 4:53–67. 16. Vervaet C, Baert L, Remon JP. 1995. Extrusion– spheronization: A literature review. Int J Pharm 116:131–146. 17. Iannuccelli V, Coppi G, Bernabei MT, Cameroni R. 1998. Air compartment multiple unit system for prolonged gastric residence. Part I. Formulation study. Int J Pharm 174:47–54. 18. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H. 2003. Physicochemical properties to determine the buoyancy of hollow microspheres (microballoons) prepared by the emulsion solvent diffusion method. Eur J Pharm Biopharm 55:297– 304. 19. Streubel A, Siepmann J, Bodmeier R. 2002. Floating microparticles based on low density foam powder. Int J Pharm 241:279–292. 20. Talukder R, Fassihi R. 2004. Gastroretentive delivery systems: Hollow beads. Drug Dev Ind Pharm 30:405–412. 21. Sriamornsak P, Thirawong N, Puttipipatkhachorn S. 2005. Emulsion gel beads of calcium pectinate capable of floating on the gastric fluid: Effect of some additives, hardening agent or coating on release behavior of metronidazole. Eur J Pharm Sci 24:363–373. 22. Badve SS, Sher P, Korde A, Pawar AP. 2007. Development of hollow/porous calcium pectinate beads for floating-pulsatile drug delivery. Eur J Pharm Biopharm 65:85–93. 23. Atyabi F, Sharma HL, Mohammad HAH, Fell JT. 1996. Controlled drug release from coated floating ion exchange resin beads. J Contr Release 42:25– 28. 24. Gandhi R, Kaul CL, Panchagnula R. 1999. Extrusion and spheronization in the development of oral controlled release dosage forms. Pharm Sci Technol Today 2:160–170. 25. Colombo P, Conte U, Caramella C, Gazzaniga A, La Manna A. 1985. Compressed polymeric minimatrices for drug release control. J Contr Release 1:283–289. 26. Sujja-Areevath J, Munday DL, Cox PJ, Khan KA. 1998. Relationship between swelling, erosion and

DOI 10.1002/jps

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

2131

drug release in hydrophilic natural gum minimatrix formulation. Eur J Pharm Sci 6:207–217. Cox PJ, Khan KA, Munday DL, Sujja-areevath J. 1999. Development and evaluation of a multiple unit oral sustained release dosage form for S(þ)ibuprofen: Preparation and release kinetics. Int J Pharm 193:73–84. De Brabander C, Vervaet C, Fiermans L, Remon JP. 2000. Matrix minitablets based on starch/ microcrystalline wax mixtures. Int J Pharm 199: 195–203. Gross ST, Hoffman A, Donbrow M, Benita S. 1986. Fundamentals of the release mechanism interpretation in multiparticulate systems: The prediction of the commonly observed release equations from statistical population models for particle ensembles. Int J Pharm 29:213–222. Hoffman A, Donbrow M, Gross ST, Benita S, Bahat R. 1986. Fundamentals of release mechanism interpretation in multiparticulate systems: Determination of substrate release from single microcapsules and relation between individual and ensemble release kinetics. Int J Pharm 29: 195–211. Mathiowitz E, Brannon-Peppas L. 1999. In: Microencapsulation. Mathiowitz E, editor. Encyclopedia of controlled drug delivery. New York: Wiley. pp 493–546. Rouge N, Cole ET, Doelker E, Buri P. 1997. Screening of potentially floating excipients for minitablets. STP Pharm Sci 7:386–392. Martin BK, Uihlein M, Ings RM, Stevens LA, Mc Ewen J. 1984. Comparative bioavailability of two furosemide formulations in humans. J Pharm Sci 73:437–441. Benet LZ. 1997. Pharmacokinetics/pharmacodynamics of furosemide in man: A review. J Pharmacokinet Biopharm 7:1–27. Ponto LL, Schoenwald RD. 1990. Furosemide:Apharmacokinetic/pharma-codynamic review (part I). Clin Pharmacokinet 18:381–408. Branch RA, Roberts CJC, Homeida M, Levine D. 1977. Determination and response to furosemide in normal subjects. Br J Clin Pharmacol 4:121–127. Odlind B, Beerman B. 1980. Renal tubular secretion and effects of furosemide. Clin Pharmacol Ther 27:784–790. Sjostrom PA, Odling BG, Beermann BA, Hammarlund-Udenaes M. 1988. On the Mechanism of acute tolerance to furosemide diuresis. Scand J Urol Nephrol 22:133–140. Hammarlund MM, Odlind B, Paalzow LK. 1985. Acute tolerance to furosemide diuresis in humans: Pharmacokinetic-pharmacodynamic modeling. J Pharm Exp Ther 233:447–453. Shin SC. 1979. Dissolution characteristics of furosemide–polymer coprecipitates. Arch Pharm Res 2: 35–48.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009

2132

MEKA ET AL.

41. Shin SC. 1979. Physicochemical characteristics of furosemide-/PVP coprecipitates. Arch Pharm Res 2:49–64. 42. Doherty C, York P. 1987. Mechanisms of dissolution of furosemide/PVP solid dispersions. Int J Pharm 34:197–205. 43. Ritger PL, Peppas NA. 1987. A simple equation for description of solute release. I. Fickian and nonFickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Contr Release 5:23–36. 44. Costa P, SousaLobo JM. 2001. Modelling and comparison of dissolution profiles. Eur J Pharm Sci 13: 123–133. 45. Jacques CHM, Hopfenberg HB, Stannett V. 1974. Super case II transport of organic vapors in glassy polymers. In: Hopfenberger HB, editor. Permeability of plastic films and coatings to gases, vapors, and liquids. New York: Plenum Press. pp 73–86.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009

46. Moore JW, Flanner HH. 1996. Mathematical comparison of curves with an emphasis on in-vitro dissolution profiles. Pharm Technol 20:64–74. 47. Valentina L, Gilberto C, Eliana L, Francesca F, Maria TB. 2000. PVP solid dispersions for the controlled release of furosemide from floating multiple unit system. Drug Dev Ind Pharm 26:595–603. 48. Kro¨gel I, Bodmeier R. 1999. Floating or pulsatile drug delivery systems based on coated effervescent cores. Int J Pharm 187:175–184. 49. Ghebre-Sellassie I, Nesbitt RU, Wang J. Eudragit aqueous dispersions as pharmaceutical controlled release coatings. In: McGinity JW, editor. Aqueous polymeric coatings for pharmaceutical dosage forms. 2nd edition. New York: Marcel Dekker. pp 267–286. 50. Bauer KH, Lehmann K, Osterwald HP, Rothgang G. 1998. Coated pharmaceutical dosage forms. Stuttgart: Medpharm Scientific Publishers. pp 63–119.

DOI 10.1002/jps