In the last decades, considerable efforts have been made to develop new pharmaceutically viable and therapeutically effective controlled drug delivery systems [1, 2]. But bioavailability of an oral pharmaceutical composition is always less than 100% due to for four reasons:

1 Drug is not absorbed out of the gut lumen into the cells of the intestine and is eliminated in the feces;

2 Drug is absorbed into the cells of the intestine but back-transported into the gut lumen;

3 Drug is biotransformed by the cells of the intestine (to an inactive metabolite);

4 Drug is eliminated by the cells of the liver, either by biotransformation and/or by transport into the bile

Gastro retentive dosage forms significantly extend the period of time over which drugs may be released, prolong dosing intervals and increase patient compliance. Such retention systems are much important for drugs that are degraded in intestine or for drugs like antacids or certain antibiotics, enzymes that act locally in the stomach such systems are more advantageous in improving GI absorption of drugs with narrow absorption windows as well as for controlling release of the drugs having site-specific absorption limitation.

Retention of drug delivery systems in the stomach prolongs overall GIT transit time, thereby resulting in improved bioavailability for some drugs. The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion, floatation, sedimentation, expansion, modified shape systems, or by the simultaneous administration of pharmacological agents that delay gastric emptying. Floating drug delivery offers several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract [12]. It retains the dosage form at the site of absorption and thus enhances the bioavailability as shown in the fig 1.

1 Gastroretentive Approaches:

The main approaches used to increase the gastric residence time of Pharmaceutical dosage forms include:

a) Floating Systems [13]

b) Bio/Mucoadhesive System [14,15]

 Hydration- mediate adhesion

 Bonding mediated adhesion

c) Swelling system [16,17]

 Expanding systems [18-19]

 High density system [20-21]

d) Raft system

e) Modified shaped system [22]

Figure 1: Comparison between conventional oral dosage forms and FDDS Based dosage forms

1.2 Floating System:

It is low-density system, which is having a sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period. While the system floats over the gastric content, the drug is released slowly at the desired rate as shown in Fig 2. It results in increased gastro retentive time and reduces fluctuation in the plasma drug concentration [23].

Fig 2: Schematic Localization of intragastric Floating System

1.3 Classification of Floating Drug Delivery Systems (FDDS):

Floating drug delivery systems are classified depending upon the use of two formulation variables viz. effervescent and non-effervescent systems

1.3.1 Effervescent System:

Floatation of a drug delivery system in the stomach can be achieved by incorporating a floating chamber filled with vacuum, air or an inert gas. The air trapped by the swollen polymer lowers the density and confers the buoyancy to the dosage form. Although this type of sophisticated dosage form might be used to administer a drug at a controlled rate for a prolonged period of time, it could not be recommended for smokers because of safety reasons [24].

Ozdemir et al. prepared controlled release floating bilayer tablets of furosemide with β-cyclodextrin as one layer of the tablet contained the drug, polymers - HPMC 4000, HPMC 100 and CMC and the second layer contained the effervescent mixture of sodium bicarbonate and citric acid. Evaluation of the tablets showed that floating tablets were retained in stomach for 6 hrs and bioavailability of these tablets was 1.8 times that of conventional tablets [25].

Choi et al [26] prepared floating alginate beads using gas forming agents (calcium carbonate and sodium bicarbonate) and studied the effect of carbon dioxide generation on the physical properties, morphology and release rates. In vitro floating studies revealed that the beads free of gas generating agents in proportions ranging from 5:1 to 1:1 demonstrated excellent floating [27].

Talwar et al [28] 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 % xanthan gum, 13.7% sodium bicarbonate and 12.1% cross-linked polyvinyl pyrollidine. The hydrated gel matrix created a tortuous diffusion path for the drug, resulting in sustained release of the drug.

Baumgartner [29] prepared a matrix floating tablet containing 54.7% of the drug, HPMC K4M, avicel PH101, and a gas-generating agent. In vitro experiments with fasted state beagle dogs revealed prolonged gastric residence time. The comparison of gastric motility and stomach emptying between human 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 the known literature for human.

Moursy et al [30] developed sustained release floating capsules of nicardipin hydrochloride. For floating, hydrocolloids of high viscosity grade were used and to aid in buoyancy sodium bicarbonate was added to allow the release of carbon dioxide. In vitro analysis of a commercially available 20 mg capsule of Nicardipine HCl (MISCARD) was performed for comparison. Results showed an increase in floating with increase in proportion of hydrocolloid.

A gastro retentive drug delivery system of ranitidine hydrochloride was designed using guargum, xanthan gum and hydroxy methyl propyl cellulose and sodium bicarbonate as a gas-generating agent. The effect of citric acid and stearic acid on drug release profile and floating properties was investigated using 3² full factorial designs. Result showed that a low amount of citric acid and a high amount of stearic acid favor sustained release of ranitidine hydrochloride from a gastro retentive formulation. [31]

1.3.2 Non effervescent floating dosage forms: When such dosage forms come in contact with an aqueous medium, the hydrocolloid starts to hydrate by first forming a gel at the surface of the dosage form. The resultant gel structure then controls the rate of diffusion of solvent in and drug out of the dosage form. As the exterior surface of the dosage form goes into solution, the gel layer becomes hydrated. As a result of this, the drug dissolves in and diffuses out with the diffusing solvent, creating a receding boundary within the gel structure as shown in Fig 4. [32]

Fig 4:Schematic Diagram showing Non-Effervescent Floating Drug Delivery System

Sheth and Tossounian [33] developed a Hydrodynamically balanced system capsule containing a mixture of a drug and hydrocolloids. Upon contact with gastric fluid, the capsule shell dissolves; the mixture swells and forms a gelatinous barrier thereby remaining buoyant in the gastric juice for an extended period of time.

Mitra [34] described a multilayered, flexible sheet-like medicament device that was buoyant in the gastric juice of the stomach and had SR characteristics. The device consisted of at least one dry, self-supporting carrier film made up of water-insoluble polymer matrix having a drug dispersed or dissolved therein, and a barrier film overlaying the carrier film. The barrier film consisted of one water- insoluble and a water- and drug- permeable polymer or copolymer. Both barrier and carrier films were sealed together along their periphery, in such a way as to entrap a plurality of small air pockets, which brought about the buoyancy of laminated films. A patent assigned to Eisai Co. Ltd. [35-36] of Japan described a floatable-coated shell, which consisted essentially of a hollow globular shell made from polystyrene. The external surface of the shell was coated with cellulose acetate phthalate followed by a final coating containing ethyl cellulose and HPMC in combination with an effective.

Iannuccelli and co-workers [37] described a multiple-unit system that contained an air compartment. The units forming the system were composed of a calcium alginate core separated by an air compartment from a membrane of calcium alginate or calcium alginate, PVA. The porous structure generated by leaching of the PVA, which was employed as a water- soluble additive in the coating composition, was found to increase the membrane permeability, preventing the collapse of the air compartment. The in vitro results suggested that the floating ability increased with an increase in PVA concentration and molecular weight.

Streubel et al [38] prepared single unit floating tablets based on polypropylene foam powder, matrix forming polymer(s), drug and an optional filler. It was concluded that varying the ratios of matrix forming polymers and the foam powder could alter the drug release pattern effectively.

Floating alginate beads of amoxycillin were developed by drop wise 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 hrs and high drug loading levels were achieved. [39]

Bulgarelli et al [40] studied the effect of matrix composition and process conditions on casein by virtue of its emulsifying properties causes incorporation of air bubbles and formulation 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 efficiencies of high porous matrices is lower than that of low porous matrices.

1.4 Properties of Drugs having therapeutic interest to prolong the gastric residence time of pharmaceutical dosage form:

 are locally active in the stomach (e.g., misoprostol [41], antacids [42] and antibiotics against Helicobacter pylori [43-45]);

 have an absorption window in the stomach or in the upper small intestine (e.g., L-DOPA [46,47], p-aminobenzoic acid [48], furosemide [49,] and riboflavin [50,51];

 are unstable in the intestinal or colonic environment (e.g., captopril [52]);

 Exhibit low solubility at high pH values (e.g., diazepam, chlordiazepoxide [53] and verapamil HCl [54-56]).

1. 5 Suitable Drug Candidates for FDDS:

Acyclovir [57-58], Alendronate [59], Atenolol [60], Captopril [61], Ciprofloxacin [62], Cisapride[63], Furosemide [64,67], Verapamil [65], Ketoprofen [66], ,Levodopa [67], Melatonin [68], Misoprostol [69], Minocyclin [70], Metformin [71], Riboflavin[72] , Sotalol [73], Tetracyclin [74], Verapamil [75].

1. 6 Evaluation of Floating Multiparticulate:

Floating Multiparticulate is characterized by their micromeritics properties such as particle size, tapped density, compressibility index, true density and flow properties including angle of repose. The particle size is determined by optical microscopy; true density is determined by liquid displacement method; tapped density and compressibility index are calculated by measuring the change in volume using a bulk density apparatus; angle of repose is determined by fixed funnel method [76, 77, and 78]. The surface morphology of the multiple unit systems can be studied by scanning electron microscopy. The determination of physical state of the drug in the multiple unit systems is important. There may be chances of change in crystallinity of the drug during the process, and such changes may influence the drug release properties. The crystallinity of drug can be studied by X-ray powder diffraction technique (XRD) and differential scanning colorimetry (DSC) [79]. Floating properties of the dosage form such as buoyancy, lag time and floating time are to be evaluated, as they influence the dosage form behavior. The buoyancy lag time is determined in order to assess the time taken by the dosage form to float on the top of the dissolution medium, after placing the dosage form in the medium. This parameter can be measured as a part of dissolution test [80]. The floating ability of the system i.e. the time for which the system continuously floats on the dissolution media can also be evaluated as a part of dissolution test. In vivo gastric residence time of a floating dosage form can be determined by X-ray diffraction studies and gamma scintigraphy.

1.7 Applications of Floating Drug Delivery Systems:

Floating drug delivery offers a number of applications for drugs having poor bioavailability because of narrow absorption window in the upper part of gastrointestinal tract. It retains the dosage form at the site of absorption and thus enhances the bioavailability. These are summarized as follows:

Sustained drug delivery:

Hydrodynamic Balanced Systems (HBS) can remain in stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral CR formulation hence can be overcome with these systems. These systems have a bulk density of < 1 as a result of which these can float on the gastric contents. These systems are relatively larger in size and passing from the pyloric opening is prohibited.

Site-specific drug delivery:

These systems are particularly advantageous for drugs that are specifically absorbed from stomach or proximal part of small intestines e.g. riboflavin, furosemide etc.

Absorption Enhancement:

Drugs that have poor bioavailability because of site-specific absorption from upper part of gastrointestinal tract are potential candidates to be formulated as Floating Drug Delivery System thereby maximizing their absorption.

Drug Absorption Barriers

For a drug to be transported from the lumen of the gut into the systemic circulation and exert its biological actions, it needs to cross the epithelial barrier of the mucosa. But oral drug delivery system has many hurdles to penetrate the epithilia membrane due to anatomical and biological barriers. Drug needs to cross the lipid membrane by mainly passive diffusion or carrier mediated transport involving the spending of energy. It is recently identified that drug efflux pump like p-glycoprotein possess very important role in inhibiting efficient drug entry into the systemic circulation.

Future Potential

FDDS approach may be used for various potential active pharmaceutical agents with narrow absorption window, e.g. antiviral,antibiotic agents and antifungal agents (sulphonamides, quinolones, penicillins, cephalosporins and tetracyclines) which are absorbed from very specific regions of Gastrointestinal tract and whose development has been halted due to the lack of appropriate pharmaceutical technologies. In addition, by continual supplying the drug to its most efficient site of absorption, the dosage form may allow for more effective oral use of peptide and protein drugs such as calcitonin, erythropoetin, vasopressin, insulin and LHRH. Some of the critical issues related to the rational development of FDDS include, the quantitative efficiency of floating delivery systems in the fasted and fed states and the correlation between prolonged Gastroretentive Tract and Slow Release/Pharmacokinetic characteristics.

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Received on 22.05.2014 Accepted on 10.06.2014

Asian J. Pharm. Res. 4(2): April-June 2014; Page 65-69

Emerging Trends in Floating Drug Delivery Systems

Smriti Khatri*, Babita Sarangi