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The authors investigated the effects of formulation and processing parameters on floating matrix-controlled drug-delivery systems.
Famotidine is a histamine H2-receptor antagonist. It is widely prescribed in the treatment of gastric ulcers, duodenal ulcers, Zollinger-Ellison syndrome, and gastroesophageal reflux disease in doses ranging from 10 to 80 mg (1). The low bioavailability (40–45%) and short biological half-life (2.5–4.0 h) of famotidine following oral administration favors the development of a sustained-release formulation. Gastroretentive drug delivery systems can be retained in the stomach, and thus can help improve the oral sustained delivery of drugs that have an absorption window in a particular region of the gastrointestinal tract. These systems facilitate continuous release of a drug before it reaches the absorption window, thus ensuring optimal bioavailability (2).
The oral treatment of gastric disorders with an H2 receptor antagonist such as famotidine or ranitidine in combination with antacids promotes local delivery of these drugs to the receptor of parietal cell wall. Local delivery also increases the bioavailability of the stomach-wall receptor site and increases the efficacy of drugs to reduce acid secretion. Hence, this principle may improve systemic as well as local delivery of famotidine, which would efficiently reduce gastric-acid secretion (3).
Several approaches can be used to prolong gastric retention time, including floating drug delivery systems (i.e., hydrodynamically balanced systems), swelling and expanding systems, polymeric bioadhesive systems, modified-shape systems, high-density systems, and other delayed gastric-emptying devices (4–10).
A dosage form that delivers famotidine in the stomach as a floating drug delivery system is one approach. A floating drug delivery system can be designed by incorporating at least one porous structural element that is less dense than gastric juice (11). Research also has been done in making floating (effervescent-type) drug delivery system for gastroretention using famotidine (12). A new type of multiparticulate floating drug delivery system consists of a highly porous carrier material (foam powder), drug, and polymer as low density microparticles (13–14). The material has a low density, large cavities interconnected by smaller pores (which give it a highly permeable structure), good compressibility, and good flowability. This article describes the development of gastroretentive matrix tablets of famotidine to increase therapeutic efficacy, reduce frequency of administration, and improve patient compliance. The study includes the use of low-density polymers for their high porosity and floating efficiency.
The following materials were used: famotidine (lot 1160573, Torrent Pharmaceuticals, Chhatral, Kalol, India); low-density powder poly(styrene-divinyl benzene) copolymer [PSDVB] (lot 061117, Polygenetics, Los Gatos, CA); xanthan 150 (lot 8E0087K) and Klucel HXF (lot 4653, Cadila Pharma, Dholka, India); chitosan (lot 6843, Central Institute of Fisheries Technology, Cochin, Kochi, India); psyllium (lot 818, Atlas Industries, Shiddhpur, Gujarat, India); hydroxypropyl methyl cellulose K15M (lot 1240150) and hydroxypropyl methyl cellulose K100M (lot 1240225) (Torrent Pharmaceuticals); and sodium alginate, hydrochloric acid, dicalcium phosphate, talc, and magnesium stearate (SD Fine Chemicals, Mumbai, India). All ingredients were of analytical grade.
Table I: Compositions of the investigated tablets (all quantities are given in mg) .
Tablets preparation. Different tablet formulations of 100 tablets each were prepared using direct compression. All powders were passed though an 80-mesh sieve. The required quantity of drug, matrix polymer (natural and synthetic), and low-density powder were mixed thoroughly. Talc and magnesium stearate were added as a glidant and a lubricant, respectively. Blending was carried out using a laboratory-scale V-blender with a 100-g capacity (modelAP-01, Orchid Scientifics, Nashik, Maharashtra, India) for 30 min. The blend was compressed with a multipunch tablet compressor (lab press, Cadmach Csi 670, India) at dwell times of 20 s and under a pressure of 25 kg/cm2 . Each tablet contained 40 mg of famotidine and other pharmaceutical ingredients (see Table I). The tablets were round and flat with an average diameter of 8.0 ± 0.1 mm, a hardness of 4–6 kg/cm2 , and a thickness of 4.0 ± 0.2 mm. The tablets were evaluated for weight variation, drug content, and floating lag time (see Table II).
Table II: Evaluation parameter of tablets of all batches.
Floating behavior.In vitro buoyancy was determined by determining the floating lag time (i.e., the time period between placing the tablet in the medium and the tablet floating) (15). The tablets were placed in a 100-mL beaker containing 0.1 N HCl. The time required for the tablets to rise to the surface and float was defined as the floating lag time.
In vitrodissolution studies. The release rate of famotidine from the floating tablets (n = 3) was determined using United State Pharmacopoeia (USP) XXIV dissolution testing apparatus II (paddle method). The dissolution test was performed using 900 mL of 0.1 N HCl at 37 ± 0.5°C and 50 rpm. A 10-mL sample of the solution was withdrawn from the dissolution apparatus hourly for 8 h, and the samples were replaced with fresh dissolution medium. The samples were filtered through a 45-µm membrane filter and diluted to a suitable concentration with 0.1N HCl. Absorbance of these solutions was measured at 265 nm using a Shimadzu (Kyoto, Japan) UV-1601 UV–vis double-beam spectrophotometer. Cumulative percentage of drug release was calculated using an equation obtained from a standard curve.
Comparison of dissolution profiles. The similarity factor (f2) given by scale-up and postapproval changes (SUPAC) guidelines for modified-release dosage forms was used as a basis to compare dissolution profiles. The dissolution profiles are considered similar when f2 is between 50 and 100 (16).
Results and discussion
Floating behavior. Incorporating the highly porous powder in the matrix tablets results in densities that are lower than the density of the release medium (compared with 1.00 g/cm for the release the medium). Approximately 12% w/w of low-density copolymer powder (based on the mass of the tablet) was sufficient to achieve proper in vitro floating behavior for at least 8 h. In contrast to most conventional floating systems (including gas-generating systems), these tablets floated immediately upon contact with the release medium and thus showed no lag times in floating (time = 0). Extended floating times were achieved as a result of the air entrapped within the low-density powder particles, which is only slowly removed from the system upon contact with the release medium. As expected, tablets without poly(styrene–divinyl benzene) copolymer powder (e.g., consisting of 40 mg of polymer and 40 mg of famotidine) sank to the bottom of the vessel showing no floating behavior.Adding 15% w/w (based on the mass of the tablet) of low-density powder reduced the lag times to 0 s.
In vitrodrug release. To evaluate the hydrophilic matrixing polymers used to prepare floating matrix tablets; seven polymers (sodium alginate, Xanthan 150, Klucel HXF, chitosan, psyllium, HPMC K15 M, and HPMC K100 M) were selected and dosage forms were prepared and evaluated for individual drug-release profiles. Approximately 12.6 % of low-density powder was added to these formulations initially. Results showed that the type of polymer influenced the drug-release pattern (see Figure 1).
Figure 1: Effect of various matrix-forming polymers on drug release using USP paddle method.
A significantly lower rate and extent of drug release was observed from the batches B2, B3, and B6 compared with batches B1 and B7. Formulations made with chitosan (batch B4) and psyllium (batch B5) eroded at the end of 6 h, releasing 98.96 % and 99.98 % of drug, respectively. These polymers were therefore unsuitable for the desired floating matrix tablets of famotidine. The integrity of tablets made with chitosan was much better than that of tablets prepared with psyllium. The initial burst effects for the formulations B2, B3, and B6 were much lower than the required theoretical value, while those for formulations B1 and B7 (containing sodium alginate and HPMC K15 M) were near to the required theoretical profile value (which was calculated using the equations of immediate-release dose and maintenance dose). The floating lag time for most of the batches was within 5 s. Thus the low density powder poly(styrene-divinyl benzene) copolymer (PSDVB) showed its role in the buoyancy of the formulations.
Effect on drug release of mixed matrixing polymers (sodium alginate and HPMC K15M with chitosan). Various ratios of sodium alginate and chitosan (2:1, 1:1, and 2:3) were taken and the dissolution profiles were obtained. Care was taken to prevent loss of integrity of the tablets. The increase in the drug profiles of all the three batches shows the significance of the incorporation of chitosan. This increase was directly proportional to the drug release from the hydrophilic matrices. Although the initial burst effect for batches SC1, SC2, and SC3 were 19.98%, 20.61%, and 22.58%, respectively (which were close to the required theoretical value), the in vitro drug release was slowed down by the end of 8 h, that is, 78.91%, 87.88% and 89.82%. The similarity factor f2 for batch SC3 was the only one above 50 (i.e., 51.17).
Figure 2: Effect of drug release of mixed matrixing polymers (sodium alginate and HPMC K15M with chitosan).
Other ratios of HPMC K15M and chitosan (4:1, 8:3, 2:1) were tried. The ratios were selected to reduce the possibility of a loss of tablet integrity. The release profile was proportional to the content of the mixed polymers in the matrix. The initial burst effect for batches HC1, HC2, and HC3 was 21.65, 22.02, and 24.59%. respectively (see Figure 2). After 8 h, these values were 89.84, 91.58, and 94.55%, respectively. Results obtained showed all similarity factors above 50 (i.e. 55.25, 60.42, and 76.50 for batches HC1, HC2, and HC3, respectively).
Based on the release profiles, results of tablets containing HPMC K15M and chitosan were better than those of tablets made with sodium alginate and chitosan. One could conclude that the formation of a rubbery type matrix by the sodium alginate in the acidic medium was the hindrance in complete or sufficient drug release by 8 h.
Effect of low-density copolymer PSDVB on the release profile of floating matrix tablets containing HPMC K5M and chitosan. To study the effect of drug release and buoyancy of a low-density copolymer (PSDVB) on the in vitro buoyancy and drug dissolution profile of various matrix-forming agents, formulation batches HC3–HC6 containing 40 mg each of HPMC K15 M, and 15 mg of chitosan as matrixing agent with 0, 20, 30, and 40 mg of PSDVB copolymer (i.e., 0 8.2, 11.6, and 15.21%) were prepared. Results obtained from the in vitro dissolution study of floating matrix formulations of mixed polymers with PSDVB copolymer revealed that there was not a major difference observed in drug dissolution profile with the variation in the percentage (see Figure 3). The drastic change in the floating lag times occurred with the inclusion of varyious percentages of PSDVB low-density copolymer.
Figure 3: Effect of poly(styrene divinyl benzene) polymer on drug release from HPMC K15M and chitosan mixed matrix tablets.
Drug release in the first hour for HC3, HC4, HC5, and HC6 was between 21 and 25%. Drug release after 8 h was > 90%. The similarity factor f2 for batches HC3–HC6 was 76.50, 56.52, 81.66, and 56.46, respectively. During the in vitro buoyancy test, a significant change was observed in the floating lag time of the formulation with an increased amount of PSDVB. Desired floating of the tablets was not achieved in lower concentrations of PSDVB copolymer (i.e., up to 8%). The floating lag time for batch HC5, which contained approximately15% concentration of the low density copolymer, was 0 s.
Selection of the best batch. The comparative results of various formulation batches were compared with theoretical dissolution profile using the similarity factor f2 test and the floating lag time of each batch. Results of similarity tests depicted that among all the batches, batch HC3, which contained 40 mg HPMC K15M, 20 mg chitosan, and 30 mg PSDVB copolymer, showed an f2 value >> 50, indicating good fit with theoretical dissolution profile. Other criteria for the selection of best batch were that the formulation should release drug in predictable and controlled manner and have a floating lag time less than 15 s. Further to evaluate complete similarity two check points (t30 and t80) were considered in the dissolution profiles of all the batches. Results in Table II indicate that the t30 of 1.9 h and t80 of 6.3 h of batch HC3 show that the drug release is in a sustained manner for that formulation.
Swelling index. The swelling index of tablets was determined in 0.1 N HCl (pH 1.2) at room temperature. The swollen weight of the tablets was determined at predefined time intervals. The swelling index was calculated using the following equation:
Swelling index = (Wt – W0) ÷ W0
in which W0 is the initial weight of tablet, and Wt is the weight of the tablet at time t.
Tablets composed of polymeric matrices build a gel layer around the tablet core when they come in contact with water. This gel layer governs the drug release. Kinetics of swelling is important because the gel barrier is formed with water penetration. Swelling is also vital factor to ensure floating. To obtain floating, the balance between swelling and water acceptance must be restored (17, 18). The swelling index of the best batch after 8 h was 1.686, which may be attributed to the high viscosity and high water-retention property of HPMC K15 M.
Accelerated stability study of the optimized batch. Gastroretentive tablets of famotidine formulated in the present study were subjected to accelerated stability studies in aluminum–aluminum pouch pack also known as an aluminum blister (using Alu-Alu blister packing machine, Pam Pac Machines, Mumbai, India). As the dosage form is formulated for site-specific drug delivery to the stomach, no change should occur in its floating lag time and drug dissolution profile. Dose dumping and failure of buoyancy are probable effects anticipated during the stability study of such dosage forms. The tablets of batch HC3 were packed in an aluminum pouch and charged for accelerated stability studies at 40 °C and 75% relateive humidity for 3 months in a humidity jar. Floating lag time test and a drug dissolution profile of exposed samples were carried out. Results of the accelerated stability studies are shown in Figure 4.
Figure 4: Comparison of dissolution profile before and after stability studies of batch HC3.
The similarity factor f2 was calculated for comparison of the dissolution profile before and after stability studies. The f2 value was >50 (approximately 76.42), which indicates a good similarity between both dissolution profiles. Similarly, no significant difference was observed in the floating lag time after stability studies. Therefore, the results of those stability studies revealed that the developed formulation had good stability.
HPMC K15M and chitosan mixed matrices can be used to modify release rates in hydrophilic matrix tablets prepared by direct compression. Incorporating the highly porous low-density copolymer (approximately 12%) in the matrix tablets provides densities that were lower than that of the release medium. These tablets floated almost immediately upon contact with the release medium, showing no lag times (unlike conventional floating systems) in floating behavior because low density is provided from the beginning (t = 3 s). Extended floating times are achieved because of the air entrapped within the low-density copolymer particles, which is only slowly removed from the system upon contact with the release medium. As expected, tablets without low density copolymer (e.g., consisting of 40 mg polymer and 40 mg famotidine) sank to the bottom of the vessel showing no floating behavior. Faster release of the drug from the hydrophilic matrix was probably a result of faster dissolution of the highly water-soluble drug from the core and its diffusion out of the matrix forming the pores for entry of solvent molecules. Therefore, one can formulate floating dosage forms that can show excellent floating lag times using low-density copolymer and achieve desired release profile.
James R. Benson (chairman, CEO, president), Nai-Hong Li (research director), and Finny Bhathena (representative in India) of Polygenetics are acknowledged for their kind support of the research work.
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J.A. Raval, PhD,* is an assistant professor in the department of pharmaceutics and pharmaceutical technology at Shree S.K. Patel College of Pharmaceutical Education and Research, Ganpat Universiy, Kherva-382711, Gujarat, India, tel. and fax 91 2762 286082, firstname.lastname@example.org. M.M. Patel is a principal at Kalol Institute of Pharmacy (Kalol, Gujarat, India). Nai-Hong Li is a research director at Polygenetics (Los Gatos, CA). J.K. Patel is a principal at Nootan Pharmacy College (Visnagar, Gujarat, India).
*To whom all correspondence should be addressed.
Submitted: Dec. 15, 2008. Accepted: Feb. 19, 2009.