Floating tablets are classified depending on the use of 2 formulation variables: effervescent and non-effervescent systems.
Floating tablets are classified depending on the use of 2 formulation variables: effervescent and non-effervescent systems.A) Effervescent Floating tablets
These are matrix types of systems prepared with the help of swellable polymers such as methylcellulose and chitosan and various effervescent compounds, eg, sodium bicarbonate, tartaric acid, and citric acid. They are formulated in such a way that when in contact with the acidic gastric contents, CO2 is liberated and gets entrapped in swollen hydrocolloids, which provides buoyancy to the dosage forms.
Ichikawa et al28 developed a new multiple type of floating dosage system composed of effervescent layers and swellable membrane layers coated on sustained release pills. The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid was divided into 2 sublayers to avoid direct contact between the 2 agents. These sublayers were surrounded by a swellable polymer membrane containing polyvinyl acetate and purified shellac. When this system was immersed in the buffer at 37ºC, it settled down and the solution permeated into the effervescent layer through the outer swellable membrane. CO2 was generated by the neutralization reaction between the 2 effervescent agents, producing swollen pills (like balloons) with a density less than 1.0 g/mL. It was found that the system had good floating ability independent of pH and viscosity and the drug (para-amino benzoic acid) released in a sustained manner28 (Figure 2, A and B).
Yang et al30 developed a swellable asymmetric triple-layer tablet with floating ability to prolong the gastric residence time of triple drug regimen (tetracycline, metronidazole, and clarithromycin) in Helicobacter pylori–associated peptic ulcers using hydroxy propyl methyl cellulose (HPMC) and poly (ethylene oxide) (PEO) as the rate-controlling polymeric membrane excipients. The design of the delivery system was based on the swellable asymmetric triple-layer tablet approach. Hydroxypropylmethylcellulose and poly(ethylene oxide) were the major rate-controlling polymeric excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple-layer matrix for controlled delivery, while bismuth salt was included in one of the outer layers for instant release. The floatation was accomplished by incorporatinga gas-generating layer consisting of sodium bicarbonate: calcium carbonate (1:2 ratios) along with the polymers. The in vitro results revealed that the sustained delivery of tetracycline and metronidazole over 6 to 8 hours could be achieved while the tablet remained afloat. The floating feature aided in prolonging the gastric residence time of this system to maintain high-localized concentration of tetracycline and metronidazole (Figure 3).
Ozdemir et al31 developed floating bilayer tablets with controlled release for furosemide. The low solubility of the drug could be enhanced by using the kneading method, preparing a solid dispersion with β cyclodextrin mixed in a 1:1 ratio. One layer contained the polymers HPMC 4000, HPMC 100, and CMC (for the control of the drug delivery) and the drug. The second layer contained the effervescent mixture of sodium bicarbonate and citric acid. The in vitro floating studies revealed that the lesser the compression force the shorter is the time of onset of floating, ie, when the tablets were compressed at 15 MPa, these could begin to float at 20 minutes whereas at a force of 32 MPa the time was prolonged to 45 minutes. Radiographic studies on 6 healthy male volunteers revealed that floating tablets were retained in stomach for 6 hours and further blood analysis studies showed that bioavailability of these tablets was 1.8 times that of the conventional tablets. On measuring the volume of urine the peak diuretic effect seen in the conventional tablets was decreased and prolonged in the case of floating dosage form.
Choi et al32 prepared floating alginate beads using gas-forming agents (calcium carbonate and sodium bicarbonate) and studied the effect of CO2 generation on the physical properties, morphology, and release rates. The study revealed that the kind and amount of gas-forming agent had a profound effect on the size, floating ability, pore structure, morphology, release rate, and mechanical strength of the floating beads. It was concluded that calcium carbonate formed smaller but stronger beads than sodium bicarbonate. Calcium carbonate was shown to be a less-effective gas-forming agent than sodium bicarbonate but it produced superior floating beads with enhanced control of drug release rates. In vitro floating studies revealed that the beads free of gas-forming agents sank uniformly in the media while the beads containing gas-forming agents in proportions ranging from 5:1 to 1:1 demonstrated excellent floating (100%).
Li et al33, 34 evaluated the contribution of formulation variables on the floating properties of a gastro floating tablets using a continuous floating monitoring device and statistical experimental design. The formulation was conceived using taguchi design. HPMC was used as a low-density polymer and citric acid was incorporated for gas generation. Analysis of variance (ANOVA) test on the results from these experimental designs demonstrated that the hydrophobic agent magnesium stearate could significantly improve the floating capacity of the delivery system. High-viscosity polymers had good effect on floating properties. The residual floating force values of the different grades of HPMC were in the order K4 M~ E4 M~K100 LV> E5 LV but different polymers with same viscosity, ie, HPMC K4M, HPMC E4M did not show any significant effect on floating property. Better floating was achieved at a higher HPMC/carbopol ratio and this result demonstrated that carbopol has a negative effect on the floating behavior.
Penners et al35 developed an expandable tablet containing mixture of polyvinyl lactams and polyacrylates that swell rapidly in an aqueous environment and thus reside in stomach over an extended period of time. In addition to this, gas-forming agents were incorporated. As the gas formed, the density of the system was reduced and thus the system tended to float on the gastric contents.
Fassihi and Yang36 developed a zero-order controlled release multilayer tablet composed of at least 2 barrier layers and 1 drug layer. All the layers were made of swellable, erodible polymers and the tablet was found to swell on contact with aqueous medium. As the tablet dissolved, the barrier layers eroded away to expose more of the drug. Gas-evolving agent was added in either of the barrier layers, which caused the tablet to float and increased the retention of tablet in a patient’s stomach.
Talwar et al37 developed a once-daily formulation for oral administration of ciprofloxacin. The formulation was composed of 69.9% ciprofloxacin base, 0.34% sodium alginate, 1.03% xanthum gum, 13.7% sodium bicarbonate, and 12.1% cross-linked poly vinyl pyrrolidine. The viscolysing agent initially and the gel-forming polymer later formed a hydrated gel matrix that entrapped the gas, causing the tablet to float and be retained in the stomach or upper part of the small intestine (spatial control). The hydrated gel matrix created a tortuous diffusion path for the drug, resulting in sustained release of the drug (temporal delivery).
Two patents granted to Alza Corporation revealed a device having a hollow deformable unit that was convertible from a collapsed to expandable form and vice versa. The deformable unit was supported by a housing that was internally divided into 2 chambers separated by a pressure-sensitive movable bladder. The first chamber contained the therapeutic agent and the second contained a volatile liquid (cyclopentane, ether) that vaporized at body temperature and imparted buoyancy to the system. The system contained a bioerodible plug to aid in exit of the unit from the body.
Baumgartner et al40 developed a matrix-floating tablet incorporating a high dose of freely soluble drug. The formulation containing 54.7% of drug, HPMC K4 M, Avicel PH 101, and a gas-generating agent gave the best results. It took 30 seconds to become buoyant. In vivo experiments with fasted state beagle dogs revealed prolonged gastric residence time. On radiographic images made after 30 minutes of administration, the tablet was observed in animal’s stomach and the next image taken at 1 hour showed that the tablet had altered its position and turned around. This was the evidence that the tablet did not adhere to the gastric mucosa. The MMC (phase during which large nondisintegrating particles or dosage forms are emptied from stomach to small intestine) of the gastric emptying cycle occurs approximately every 2 hours in humans and every 1 hour in dogs but the results showed that the mean gastric residence time of the tablets was 240 ± 60 minutes (n = 4) in dogs. The comparison of gastric motility and stomach emptying between humans and dogs showed no big difference and therefore it was speculated that the experimentally proven increased gastric residence time in beagle dogs could be compared with known literature for humans, where this time is less than 2 hours.
Atyabi and coworkers42 developed a floating system using ion exchange resin that was loaded with bicarbonate by mixing the beads with 1 M sodium bicarbonate solution. The loaded beads were then surrounded by a semipermeable membrane to avoid sudden loss of CO2. Upon coming in contact with gastric contents an exchange of chloride and bicarbonate ions took place that resulted in CO2 generation thereby carrying beads toward the top of gastric contents and producing a floating layer of resin beads (Figure 4) .The in vivo behavior of the coated and uncoated beads was monitored using a single channel analyzing study in 12 healthy human volunteers by gamma radio scintigraphy. Studies showed that the gastric residence time was prolonged considerably (24 hours) compared with uncoated beads (1 to 3 hours). B) Non-Effervescent Floating tablets
Non-effervescent floating tablets use a gel forming or swellable cellulose type of hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, polymethacrylate, and polystyrene. The formulation method includes a simple approach of thoroughly mixing the drug and the gel-forming hydrocolloid. After oral administration this dosage form swells in contact with gastric fluids and attains a bulk density of < 1. The air entrapped within the swollen matrix imparts buoyancy to the dosage form. The so formed swollen gel-like structure acts as a reservoir and allows sustained release of drug through the gelatinous mass.
Thanoo et al43 developed polycarbonate microspheres by solvent evaporation technique. Polycarbonate in dichloromethane was found to give hollow microspheres that floated on water and simulated biofluids as evidenced by scanning electron microscopy (SEM). High drug loading was achieved and drug-loaded microspheres were able to float on gastric and intestinal fluids. It was found that increasing the drug-to-polymer ratio increased both their mean particle size and release rate of drug.
Nur and Zhang44 developed floating tablets of captopril using HPMC (4000 and 15 000 cps) and carbopol 934P. In vitro buoyancy studies revealed that tablets of 2 kg/cm2 hardness after immersion into the floating media floated immediately and tablets with hardness 4 kg/cm2 sank for 3 to 4 minutes and then came to the surface. Tablets in both cases remained floating for 24 hours. The tablet with 8 kg/cm2 hardness showed no floating capability. It was concluded that the buoyancy of the tablet is governed by both the swelling of the hydrocolloid particles on the tablet surface when it contacts the gastric fluids and the presence of internal voids in the center of the tablet (porosity). A prolonged release from these floating tablets was observed as compared with the conventional tablets and a 24-hour controlled release from the dosage form of captopril was achieved.
Bulgarelli et al45 studied the effect of matrix composition and process conditions on casein gelatin beads prepared by emulsification extraction method. Casein by virtue of its emulsifying properties causes incorporation of air bubbles and formation of large holes in the beads that act as air reservoirs in floating systems and serve as a simple and inexpensive material used in controlled oral drug delivery systems. It was observed that the percentage of casein in matrix increases the drug loading of both low and high porous matrices, although the loading efficiency of high porous matrices is lower than that of low porous matrices.
Fell et al46 prepared floating alginate beads incorporating amoxycillin. The beads were produced by dropwise addition of alginate into calcium chloride solution, followed by removal of gel beads and freeze-drying. The beads containing the dissolved drug remained buoyant for 20 hours and high drug-loading levels were achieved.
Streubel et al47 prepared single-unit floating tablets based on polypropylene foam powder and matrix-forming polymer. Incorporation of highly porous foam powder in matrix tablets provided density much lower than the density of the release medium. A 17% wt/wt foam powder (based on mass of tablet) was achieved in vitro for at least 8 hours. It was concluded that varying the ratios of matrix-forming polymers and the foam powder could alter the drug release patterns effectively.
Asmussen et al48 invented a device for the controlled release of active compounds in the gastrointestinal tract with delayed pyloric passage, which expanded in contact with gastric fluids and the active agent was released from a multiparticulate preparation. It was claimed that the release of the active compound was better controlled when compared with conventional dosage forms with delayed pyloric passage.
El-Kamel et al49 prepared floating microparticles of ketoprofen, by emulsion solvent diffusion technique. Four different ratios of Eudragit S 100 with Eudragit RL were used. The formulation containing 1:1 ratio of the 2 above-mentioned polymers exhibited high percentage of floating particles in all the examined media as evidenced by the percentage of particles floated at different time intervals. This can be attributed to the low bulk density, high packing velocity, and high packing factor.
Illum and Ping50 developed microspheres that released the active agent in the stomach environment over a prolonged period of time. The active agent was encased in the inner core of microspheres along with the rate-controlling membrane of a water-insoluble polymer. The outer layer was composed of bioadhesive (chitosan). The microspheres were prepared by spray drying an oil/water or water/oil emulsion of the active agent, the water-insoluble polymer, and the cationic polymer.
Streubel et al51 developed floating microparticles composed of polypropylene foam, Eudragit S, ethyl cellulose (EC), and polymethyl metha acrylate (PMMA) and were prepared by solvent evaporation technique. High encapsulation efficiencies were observed and were independent of the theoretical drug loading. Good floating behavior was observed as more than 83% of microparticles were floating for at least 8 hours. The in vitro drug release was dependent upon the type of polymer used. At similar drug loading the release rates increased in the following order PMMA < EC < Eudragit S. This could be attributed to the different permeabilities of the drug in these polymers and the drug distribution within the system.
Sheth and Tossounian52 developed hydrodynamically balanced sustained release tablets containing drug and hydrophilic hydrocolloids, which on contact with gastric fluids at body temperature formed a soft gelatinous mass on the surface of the tablet and provided a water-impermeable colloid gel barrier on the surface of the tablets. The drug slowly released from the surface of the gelatinous mass that remained buoyant on gastric fluids (Figure 6, A and B).
Bolton and Desai54 developed a noncompressed sustained release tablet that remained afloat on gastric fluids. The tablet formulation comprised 75% of drug and 2% to 6.5% of gelling agent and water. The noncompressed tablet had a density of less than 1 and sufficient mechanical stability for production and handling.
Kawashima et al prepared multiple-unit hollow microspheres by emulsion solvent diffusion technique. Drug and acrylic polymer were dissolved in an ethanol-dichloromethane mixture, and poured into an aqueous solution of PVA with stirring to form emulsion droplets. The rate of drug release in micro balloons was controlled by changing the polymer-to-drug ratio. Microballoons were floatable in vitro for 12 hours when immersed in aqueous media. Radiographical studies proved that microballoons orally administered to humans were dispersed in the upper part of stomach and retained there for 3 hours against peristaltic movements.55
Spickett et al57 invented an antacid preparation having a prolonged gastric residence time. It comprised 2 phases. The internal phase consisted of a solid antacid and the external phase consisted of hydrophobic organic compounds (mono-, di-, and triglycerides) for floating and a non-ionic emulsifier.
Franz and Oth58 described a sustained release dosage form adapted to release of the drug over an extended period of time. It comprised a bilayer formulation in which one layer consisted of drug misoprostal and the other had a floating layer. The uncompressed bilayer formulation was kept in a capsule and was shown to be buoyant in the stomach for 13 hours. The dosage form was designed in such a way that all the drug was released in the stomach itself.
Wu et al59 developed floating sustained release tablets of nimodipine by using HPMC and PEG 6000. Prior to formulation of floating tablets, nimodipine was incorporated into poloxamer-188 solid dispersion after which it was directly compressed into floating tablets. It was observed that by increasing the HPMC and decreasing the PEG 6000 content a decline in in vitro release of nimodipine occurred.
Wong et al60 developed a prolonged release dosage form adapted for gastric retention using swellable polymers. It consisted of a band of insoluble material that prevented the covered portion of the polymer matrix from swelling and provided a segment of a dosage form that was of sufficient rigidity to withstand the contractions of the stomach and delayed the expulsion of the dosage form from the stomach.
Mitra61 developed a sustained release multilayered sheet-like medicament device. It was buoyant on the gastric contents and consisted of at least 1 dry, self-supporting carrier film of water-insoluble polymer. The drug was dispersed or dissolved in this layer and a barrier film overlaid the carrier film. The barrier film was compsosed of 1 water-insoluble layer and another water-soluble and drug-permeable polymer or copolymer layer. The 2 layers were sealed together in such a way that pluralities of small air pockets were entrapped that gave buoyancy to the formulation.
Harrigan62 developed an intragastric floating tablet that was composed of a drug reservoir encapsulated in a microporous compartment having pores on top and bottom surfaces. However, the peripheral walls were sealed to prevent any physical contact of the drug in the reservoir with the stomach walls.
Joseph et al25 developed a floating dosage form of piroxicam based on hollow polycarbonate microspheres. The microspheres were prepared by the solvent evaporation technique. Encapsulation efficiency of ~95% was achieved. In vivo studies were performed in healthy male albino rabbits. Pharmacokinetic analysis was derived from plasma concentration vs time plot and revealed that the bioavailability from the piroxicam microspheres alone was 1.4 times that of the free drug and 4.8 times that of a dosage form consisting of microspheres plus the loading dose and was capable of sustained delivery of the drug over a prolonged period.
There are several commercial products available based on the research activity of floating drug delivery.