Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention

Journal of Controlled Release 63 (2000) 235–259 www.elsevier.com / locate / jconrel

Review

Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention Brahma N. Singh, Kwon H. Kim* Drug Delivery Systems Research Laboratory, College of Pharmacy and Allied Health Professions, St. John’ s University, Jamaica, NY 11439, USA Received 19 January 1999; accepted 19 August 1999

Abstract In recent years scientific and technological advancements have been made in the research and development of rate-controlled oral drug delivery systems by overcoming physiological adversities, such as short gastric residence times (GRT) and unpredictable gastric emptying times (GET). Several approaches are currently utilized in the prolongation of the GRT, including floating drug delivery systems (FDDS), also known as hydrodynamically balanced systems (HBS), swelling and expanding systems, polymeric bioadhesive systems, modified-shape systems, high-density systems, and other delayed gastric emptying devices. In this review, the current technological developments of FDDS including patented delivery systems and marketed products, and their advantages and future potential for oral controlled drug delivery are discussed.  2000 Elsevier Science B.V. All rights reserved. Keywords: Intragastric floating systems; Hydrodynamically balanced systems; Gastroretentive systems; Microballoons; Buoyant delivery systems

1. Introduction The de novo design of an oral controlled drug delivery system (DDS) should be primarily aimed at Abbreviations: CR, controlled-release; DDS, drug delivery system; F, floating; FDDS, floating drug delivery systems; FT, floating or floatation time; GET, gastric emptying time(s); GRT, gastric residence time(s); GI, gastrointestinal; HBS, hydrodynamically balanced systems; HPC, hydroxypropylcellulose; HPMC, hydroxypropylmethylcellulose; MMC, migrating myoelectric complex; NF, non-floating; PK, pharmacokinetic; PAA, polyacrylic acid; PMA, polymethacrylic acid; PVA, polyvinyl alcohol; SR, sustained-release *Corresponding author. Tel.: 11-718-990-6063; fax: 11-718990-6316.

achieving more predictable and increased bioavailability of drugs. However, the development process is precluded by several physiological difficulties, such as an inability to restrain and localize the DDS within desired regions of the gastrointestinal (GI) tract and the highly variable nature of gastric emptying process. It can be anticipated that, depending upon the physiological state of the subject and the design of pharmaceutical formulation, the emptying process can last from a few minutes to 12 h. This variability, in turn, may lead to unpredictable bioavailability and times to achieve peak plasma levels, since the majority of drugs are preferentially absorbed in the upper part of the small intestine [1]. Furthermore, the relatively brief GET in humans,

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which normally averages 2–3 h through the major absorption zone (stomach or upper part of the intestine), can result in incomplete drug release from the DDS leading to diminished efficacy of the administered dose. Thus, control of placement of a DDS in a specific region of the GI tract offers numerous advantages, especially for drugs exhibiting an absorption window in the GI tract or drugs with a stability problem. Overall, the intimate contact of the DDS with the absorbing membrane has the potential to maximize drug absorption and may also influence the rate of drug absorption [2,3]. These considerations have led to the development of oral controlledrelease (CR) dosage forms possessing gastric retention capabilities. As the first part in this series of reviews on contemporary gastroretentive systems, the current technological developments in FDDS, including patented and clinically available products, formulation development strategy, and their advantages and future potential for oral controlled drug delivery are discussed.

2. Basic physiology, problems, and approaches

2.1. Gastric emptying and problems It is well recognized that the stomach may be used as a ‘depot’ for sustained-release (SR) dosage forms, both in human and veterinary applications. The stomach is anatomically divided into three parts: fundus, body, and antrum (or pylorus). The proximal stomach, made up of the fundus and body regions, serves as a reservoir for ingested materials while the distal region (antrum) is the major site of mixing motions, acting as a pump to accomplish gastric emptying [4]. The process of gastric emptying occurs both during fasting and fed states; however, the pattern of motility differs markedly in the two states. In the fasted state, it is characterized by an interdigestive series of electrical events which cycle both through the stomach and small intestine every 2–3 h [5]. This activity is called the interdigestive myoelectric cycle or migrating myoelectric complex (MMC), which is often divided into four consecutive phases. As described by Wilson and Washington [6], phase I is a quiescent period lasting from 40 to 60 min with rare

contractions. Phase II is a period of similar duration consisting of intermittent action potentials and contractions that gradually increase in intensity and frequency as the phase progresses. Phase III is a short period of intense, large regular contractions lasting from 4 to 6 min. It is this phase, which gives the cycle the term ‘housekeeper’ wave, since it serves to sweep undigested materials out of the stomach and down the small intestine. As phase III of one cycle reaches the end of the small intestine, phase III of the next cycle begins in the duodenum. Phase IV is a brief transitional phase that occurs between phase III and phase I of two consecutive cycles. In the fed state, the gastric emptying rate is slowed since the onset of MMC is delayed [7]. In other words, feeding results in a lag time prior to the onset of gastric emptying. Scintigraphic studies involving measurements of gastric emptying rates in healthy human subjects have revealed that an orally administered CR dosage form is mainly subject to two physiological adversities: the short GRT and the variable (unpredictable) GET. Yet another major adversity encountered through the oral route is the first-pass effect, which leads to reduced systemic bioavailability of a large number of drugs. Overall, the relatively brief GI transit time of most drug products, which is approximately 8–12 h, impedes the formulation of a once daily dosage form for most drugs. These problems can be exacerbated by alterations in gastric emptying that occur due to factors such as age, race, sex, and disease states, as they may seriously affect the release of a drug from the DDS. It is, therefore, desirable to have a CR product that exhibits an extended GI residence and a drug release profile independent of patient related variables.

2.2. Approaches to gastric retention Over the last three decades, various approaches have been pursued to increase the retention of an oral dosage form in the stomach, including floating systems [8], swelling and expanding systems [9,10], bioadhesive systems [3,11–13], modified-shape systems [14–19], high-density systems [20–22], and other delayed gastric emptying devices [23,24]. FDDS or hydrodynamically balanced systems have a bulk density lower than gastric fluids and thus

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remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, the drug is released slowly at a desired rate from the system. After the release of drug, the residual system is emptied from the stomach. This results in an increase in the GRT and a better control of fluctuations in plasma drug concentrations in some cases. Swelling type dosage forms are such that after swallowing, these products swell to an extent that prevents their exit from the stomach through the pylorus. As a result, the dosage form is retained in the stomach for a long period of time. These systems may be referred to as ‘plug type systems’ since they exhibit a tendency to remain lodged at the pyloric sphincter. Bioadhesive systems are used to localize a delivery device within the lumen and cavity of the body to enhance the drug absorption process in a site-specific manner [11]. The approach involves the use of bioadhesive polymers that can adhere to the epithelial surface of the GI tract. The proposed mechanism of bioadhesion is the formation of hydrogen- and electrostatic bonding at the mucus-polymer boundary [6]. Rapid hydration in contact with the muco-epithelial surface appears to favor adhesion, particularly if water can be excluded at the reactive surfaces [6]. Modified-shape systems are nondisintegrating geometric shapes molded from silastic elastomer or extruded from polyethylene blends, which extend the GRT depending on size, shape and flexural modulus of the drug delivery device [14– 19]. High-density formulations include coated pellets, which have a density greater than that of the stomach contents (|1.004 g / cm 3 ). This is accomplished by coating the drug with a heavy inert material such as barium sulfate, zinc oxide, titanium dioxide, iron powder, etc. Other delayed gastric emptying approaches of interest include sham feeding of indigestible polymers [25–27] or fatty acid salts [23,24,28] that change the motility pattern of the stomach to a fed state, thereby decreasing the gastric emptying rate and permitting considerable prolongation of drug release.

2.3. Factors affecting gastric retention There are several factors that can affect gastric emptying (and hence GRT) of an oral dosage form.

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These factors include density, size, and shape of dosage form, concomitant intake of food and drugs such as anticholinergic agents (e.g., atropine, propantheline), opiates (e.g., codeine) and prokinetic agents (e.g., metoclopramide, cisapride), and biological factors such as gender, posture, age, body mass index, and disease states (e.g., diabetes, Crohn’s disease). Most of these factors have been described here in the context of FDDS. FDDS are retained in the stomach for a prolonged period of time by virtue of their floating properties, which can be acquired by several means. Generally speaking, in order for a HBS dosage form to float in the stomach, the density of the dosage form should be less than the gastric contents. A density of less than 1.0 g / ml has been reported in the literature. However, the floating force kinetics of such dosage forms has shown that the bulk density of a dosage form is not the most appropriate parameter for describing its buoyant capabilities. The buoyant capabilities are better represented and monitored by resultant-weight measurements and swelling experiments [29]. This is because the magnitude of floating strength may vary as a function of time and usually decreases after immersion of the dosage form into the fluid as a result of the development of its hydrodynamic equilibrium [30]. While considering the role of specific gravity in GRT, the potential of food in modifying GRT should not be overlooked (Table 1). One of the earlier in ¨ vivo evaluations of FDDS by Muller-Lissner et al. [34] demonstrated that a GRT of 4–10 h could be achieved after a fat and protein test meal. Furthermore, food affects the GRT of dosage forms depending on its nature, caloric content and the frequency of intake [35–37]. For example, Oth et al. [35] reported that the mean GRT of a bilayer floating capsule of misoprostol was 199669 min after a single light meal (breakfast). However, after a succession of meals, the data showed a remarkable prolongation of the mean GRT, to 6186208 min. In another study, Iannuccelli et al. [38] reported that in the fed state after a single meal, all the floating units had a floating time (FT) of about 5 h and a GRT prolonged by about 2 h over the control. However, after a succession of meals, most of the floating units showed a FT of about 6 h and a GRT prolonged by about 9 h over the control, though a certain vari-

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Table 1 Effects of food on GRTs of floating and non-floating (control) dosage forms a Dosage forms [References]

Non-floating

Floating

Fasted

Fed

Fasted

Fed

Isradipine caps [31] Radiolabeled tabs b [22]

1.59 (n55) 1.65 (n54)

2.15 (n54) 4.43 (n54)

Radiolabeled tabs b [32] Radiolabeled tabs [33] Theophylline [7]

1.1 (n57) 2.53 (n54) 2.32 (n53)

1.32 (n57) 6.27 (n54) 7.54 (n53)

1.0 (n55) 0.82 (n54) 3.37 (n58)c 1.1 (n57) 2.2 (n54) 1.57 (n53)

3.60 (n54) 5.25 (n54) 7.0 (n58)c 7.15 (n57) 6.77 (n54) 7.15 (n53)

a

Values are represented as mean (h); n5number of healthy human volunteers. Results are expressed as gastric emptying times (GET). c Floating capsules. b

ability of the data owing to mixing with heavy solid food ingested after the dosing was observed. Obviously, when the gastroretentive properties of a floating dosage form is independent of meal size, it can be suggested that the dosage form will be suitable for patients with a wide range of eating habits [39]. Interestingly, most of the studies related to effects of food on GRT of FDDS share a common viewpoint that food intake is the main determinant of gastric emptying, while specific gravity has only a minor effect on the emptying process [22,31,33,40]. Stated otherwise, the presence of food, rather than buoyancy, is the most important factor affecting GRT and floating does not invariably increase GRT. In fact, studies have shown that the GET for both floating (F) and non-floating (NF) single units are shorter in fasted subjects (less than 2 h), but are significantly prolonged after a meal (around 4 h) [22,40]. In a similar study, Agyilirah et al. [32] found that in the fed state, balloon (floating) tablets prolonged the GET by an average of 6 h over that of uncoated, nondisintegrating tablets; however, in the fasted state, the balloon tablets did not significantly prolong GET and both tablets had much shorter emptying times compared to the fed state. Studies of Mazer et al. [31] suggested that the release and absorption kinetics of a lipophilic drug (isradipine) from a ‘floating’ modified-release capsule might be affected by intragastric interaction with the lipid phase of a high-fat meal. Further, for the modifiedrelease capsule, GRT was regarded as the duration of intragastric release to reach 90% release, since no further intragastric release could occur after the

capsule left the stomach. Thus, in view of foregoing discussions, it may be concluded that although floating systems possess an inherent ability for gastric retention, they rely more on the presence of a meal to retard their emptying. From the results presented in Table 1, there does not appear to be large difference between the GRT of the F and NF dosage forms. This consistency can be explained based on the fact that the gastric emptying depends on the onset of the MMC. Therefore, the GRT is significantly increased under fed conditions, since the onset of MMC is delayed [7]. Nevertheless, the efficiency of intragastric buoyant dosage forms in the fed stomach is questionable because of the intensive contractile activity of the stomach and the density of the viscous chyme. Moreover, in the fasted stomach the amount of liquid is not sufficient for the drug delivery buoy and the stomach’s entire contents are emptied down the small intestine within 2–3 h because of the typical phase III activity [41]. Concern regarding the role of food in the prolongation of the GRT has also provided insights into other determinants of gastric retention. For instance, studies have shown that the GRT of a dosage form in the fed state can also be influenced by its size. Small-size tablets are emptied from the stomach during the digestive phase, while larger-size units are expelled during the housekeeping waves [35]. Timmermans et al. [42] studied the effect of size on the GRT of F and NF units using g-scintigraphy. They found that F units with a diameter equal to or less than 7.5 mm had longer GRTs compared to NF units. However, the GRTs were similar for F and NF units having a larger diameter

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of 9.9 mm. This study also demonstrated that F units, which remain buoyant on gastric contents, are protected against gastric emptying during digestive phases. On the other hand, NF units lie in the antrum region and are propelled during the digestive process by peristalsis. The prolongation of the GRT by food is expected to maximize drug absorption from a FDDS. This may be rationalized in terms of increased dissolution of drug and longer residence at the most favorable sites of absorption. However, there may be rare exceptions, where the presence or absence of food in the stomach has no effect on the absorption of a drug from HBS type dosage forms [43]. The effects of food on various aspects of drug absorption have been extensively discussed in a separate publication [44]. Apart from food and buoyancy effects, there are other biological factors that can influence the GRT. Sangekar et al. [33] concluded that the increase in retention time of HBS may also be due to effects such as adhesion to the gastric mucosa, rather than the effect of floating per se. Mojaverian et al. [45] investigated the effects of gender, posture, and age on the GRT of an indigestible solid, the Heidelberg capsule. As a result of this study, authors found that the mean ambulatory GRT in the males was significantly faster than in their age (63 years)- and race-matched female counterparts (3.460.6 vs. 4.661.2 h, P,0.01). Further, the data indicated that women emptied their stomach slower than men, regardless of weight, height, body surface area and even when the hormonal changes due to the menstrual cycle were normalized. The mean GRT for volunteers in the supine state was not statistically significant from that in the upright, ambulatory state (3.460.8 vs. 3.560.7 h, P.0.05). In the case of elderly, the GRT was prolonged, especially in subjects .70 years old (mean GRT55.8 h; n53). Another confounding factor is the variability of GI transit within and between individuals. Studies by Coupe et al. [46] revealed that variability in gastric emptying of single- and multiple-unit systems was large compared to that in small intestinal transit times; however, the intrasubject variation was less than intersubject for both gastric and small intestinal transit times. A comparative evaluation of the gastric transit of F and NF matrix dosage forms indicated that

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buoyancy and non-buoyancy of the forms lead to distinct intragastric behaviors [47]. It was also concluded that depending on the subject posture, either standing or supine, the gastric residence period of a dosage form is function of either its buoyancy or the diametric size of the matrix. Recently, a triple radionuclide scintigraphic technique has been described for intragastric monitoring that allowed the measurement of the effects on GRT of galenic parameters (size, density of matrices), as well as of physiological parameters such as subject posture [48]. Studies were conducted in nonfasting human volunteers either in upright or in supine posture, who concurrently were given one optimized F and one NF hydrophilic matrix capsules of the same size, and three different sizes (small, [5; medium, [0; large, [000). In upright subjects, all the F forms stayed continuously above the gastric contents irrespective of their size, whereas the NF units sank rapidly after ingestion and never rose back to the surface thereafter. Thus, in upright subjects the F forms were protected against postprandial emptying. Consequently, the F forms showed prolonged and more reproducible GRTs compared to the NF forms. The significance and extent of this prolongation when compared with NF units were the most marked for the small size units (P,0.001) but gradually lessened as the dosage form size increased (P,0.05 for the medium size units), to become insignificant for the large size units (P.0.05). However, there was no significant difference between the mean GRTs of the small, medium, and large F units (P.0.05). These findings indirectly confirm that the intragastric buoyancy of the F forms is the main factor determining their prolonged GRTs and protecting them from random gastric emptying related to antral peristaltism [49]. Similar results were reported in a recent study [50]. The mean GRTs of the NF forms were much more variable and highly dependent on their size, which were in the order of small,medium,large units, P,0.05. Moreover, in supine subjects, a size effect influenced the GRT of both the F and NF forms (P,0.05). The F forms were more often emptied before the NF forms but size for size, the mean GRTs did not differ in the aggregate. Bennett et al. [51] have also demonstrated the role of posture in gastric emptying. They observed that an alginate raft emptied faster than food in subjects lying on

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their left side or on their backs and slower in subjects lying on their right side with the raft positioned in the greater curvature of the stomach. This is because when the subjects laid on their left side, the raft was presented to the pylorus ahead of the meal and so emptied faster [6].

3. Technological developments in FDDS The concept of FDDS was described in the literature as early as 1968 [52], when Davis disclosed a method for overcoming the difficulty experienced by some persons of gagging or choking while swallowing medicinal pills. The author suggested that such difficulty could be overcome by providing pills having a density of less than 1.0 g / ml so that pill will float on water surface. Since then several approaches have been used to develop an ideal floating delivery system. The various buoyant

preparations include hollow microspheres (‘microballoons’), granules, powders, capsules, tablets (pills), and laminated films. Most of the floating systems reported in literature are single-unit systems, such as the HBS and floating tablets. These systems are unreliable and irreproducible in prolonging residence time in the stomach when orally administered, owing to their fortuitous (‘all-or-nothing’) emptying process [53]. On the other hand, multiple-unit dosage forms appear to be better suited since they are claimed to reduce the intersubject variability in absorption and lower the probability of dose-dumping [54]. A list of drugs used in the development of FDDS thus far is given in Tables 2 and 3. Based on the mechanism of buoyancy, two distinctly different technologies, i.e., noneffervescent and effervescent systems, have been utilized in the development of FDDS. The various approaches used in and their mechanisms of buoyancy are discussed in the following subsections.

Table 2 List of drugs explored for various floating dosage forms a Microspheres Aspirin, griseofulvin and p-nitroaniline [55] Ibuprofen [56] Terfenadine [57] Tranilast [53,56] Granules Diclofenac sodium [58] Indomethacin [59] Prednisolone [60] Films Cinnarizine [61] Drug delivery device [62] Powders Several basic drugs [63] Capsules Chlordiazepoxide HCl [64] Diazepam [34,64,65] Furosemide [66] L-Dopa and benserazide [67] Misoprostol [35,68] Propranolol HCl [69] Ursodeoxycholic acid [70] a

Numbers in parentheses indicate the references.

Tablets /Pills Acetaminophen [71,72] Acetylsalicylic acid [73] Amoxycillin trihydrate [74] Ampicillin [75] Atenolol [76,77] Chlorpheniramine maleate [8] Cinnarizine [61] Diltiazem [78] Fluorouracil [79] Isosorbide mononitrate [80] Isosorbide dinitrate [81] p-Aminobenzoic acid [81,82] Piretanide [77] Prednisolone [83] Quinidine gluconate [32] Riboflavin-59-phosphate [8,84] Sotalol [85] Theophylline [4,7,86] Verapamil HCl [87–89]

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Table 3 Comparison of GRTs of floating and non-floating solid dosage forms a Drugs

Diazepam Ethmozine (Moricizine HCl) Gentamycin sulfate Isradipine Metoprolol tartrate Miocamycin Pepstatin Salbutamol sulfate Tranilast a b

Dosage forms

Capsules Tablets Tablets Capsules Tablets Tablets Minicapsules Capsules Microballoons

GRT (h)

References

NFDS

FDDS

1.0–1.5 1–1.5 1–2 0.51–2.87 b 1–1.5 3–4 NR NR NR

4.0–10.0 .6 .4 2.4–4.8 b 5–6 .7 3–5 b 8–9 .3

[34,64,65] [90] [91] [31] [92] [93] [94] [95] [53]

GRT, gastric residence time; NFDS, non-floating delivery system; FDDS, floating drug delivery system. Values obtained in fed state; NR, not reported.

3.1. Noneffervescent FDDS The most commonly used excipients in noneffervescent FDDS are gel-forming or highly swellable cellulose type hydrocolloids, polysaccharides, and matrix forming polymers such as polycarbonate, polyacrylate, polymethacrylate and polystyrene. One of the approaches to the formulation of such floating dosage forms involves intimate mixing of drug with a gel-forming hydrocolloid, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than unity within the outer gelatinous barrier [74]. The air trapped by the swollen polymer confers buoyancy to these dosage forms. In addition, the gel structure acts as a reservoir for sustained drug release since the drug is slowly released by a controlled diffusion through the gelatinous barrier. Sheth and Tossounian [64] postulated that 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 is maintained by the immediate adjacent hydrocolloid layer becoming hydrated. As a result, the drug dissolves in and diffuses out with the diffusing solvent, creating a ‘receding boundary’ within the gel structure [64]. The working principle of the HBS is more clearly illustrated in Fig. 1. Sheth and Tossounian [97] developed a HBS

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

Fig. 1. Working principle of the hydrodynamically balanced system (HBS). The hard gelatin capsule contains a special formulation of hydrocolloids, which swell into a gelatinous mass upon contact with gastric fluids. Adapted from Bogentoft [96].

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gastric juice for an extended period of time. Ushimaru et al. [98] developed SR capsules containing a mixture of a drug, a cellulose derivative or starch derivative which forms a gel in water, and a higher fatty acid glyceride or higher alcohol or a mixture thereof which is solid at room temperature. The capsules were prepared by filling capsules with the above mixture, then heating them to a temperature above the melting point of the fat / oil component and finally cooling and solidifying the mixture. A recent patent issued to G.D. Searle and Co. described a bilayer buoyant dosage form consisting of a capsule, which included a non-compressed bilayer formulation. One layer was a drug release layer containing misoprostol and other was a buoyant or floating layer. Each layer included a hydrocolloid gelling agent such as hydroxypropylmethylcellulose (HPMC), gums, polysaccharides and gelatin, which upon contact with gastric fluid formed a gelatinous mass, sufficient for cohesively binding the drug release layer and floating layer. The dosage form was shown to be buoyant in gastric fluid for a period up to about 13 h, whereby a substantial amount of drug was released in the stomach [68]. Desai and Bolton [7,99] developed CR floating tablets of theophylline using agar and light mineral oil. Tablets were made by dispersing a drug / mineral oil mixture in a warm agar gel solution and pouring the resultant mixture into tablet molds, which on cooling and air drying formed floatable CR tablets. Interestingly, the amount of agar needed to form the floating tablet was remarkably low (2% per tablet). The light mineral oil was essential for the floating property of the tablet since relatively high amounts of drug (75%) were used. Secondly, the light mineral oil in the formulation may prevent the air entrapped in the gel matrix from escaping when placed in gastric fluid owing to its inherent hydrophobicity; however, the mechanism is not yet clear [7]. The air entrapped in the tablet gel network may reduce the density and contribute towards the buoyancy of the tablet. Their study also indicated the importance of an agar gel network in providing tablet binding properties to these non-compressed tablets, which gives the desired hardness and friability, and in controlling the drug release characteristics. In another study, these authors developed a similar formulation without using an oil [100]. Gupta [75]

developed floating ampicillin tablets using a formula and procedure similar to those of Desai [4]. However, the former formula included a buffer system that was expected to improve the stability of ampicillin in the acidic medium, especially in the slow release tablets. In this study, sodium citrate was used as a buffering agent, which maintained a pH of about 6.0 in the microenvironment of the ampicillin molecules in the tablets; the drug was most stable at pH 6.5 in non-buffered solution. Moreover, the buffering agent did not affect the dissolution rate of ampicillin. The results of this study also demonstrated that calcium gluconate increased the hardness of tablets reasonably. Dennis et al. [63] described a buoyant CR powder formulation, which may be either filled into capsules or compressed into tablets. The formulation consisted of a drug of basic character, a pH-dependent polymer, which was a water-soluble salt of alginic acid (such as sodium or potassium alginate), and a pH-independent hydrocolloid gelling agent (such as HPMC, methyl cellulose, HPC, or a mixture of two or more), and binder. The formulation was considered unique in the sense that it released the drug at a controlled rate regardless of the pH of the environment, being free of calcium ion and CO 2 producing material, and had drug release properties similar to a tablet of identical composition. Other authors have also prepared tablets with alginate and HPMC that were able to float on gastric contents and provided SR characteristics [22,34,64]. Sheth and Tossounian [73,101] developed SR floating tablets that were hydrodynamically balanced in the stomach for an extended period of time until all the drug-loading dose was released. Tablets were comprised of an active ingredient, 0–80% by weight of inert materials, and 20–75% by weight of one or more hydrocolloids such as methylcellulose, HPC, HPMC, hydroxyethylcellulose, and sodium carboxymethylcellulose, which upon contact with gastric fluid provided a water impermeable colloid gel barrier on the surface of tablets (Figs. 2 and 3). Mitra [62] 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, selfsupporting carrier film made up of a water-insoluble polymer matrix having a drug dispersed or dissolved

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Fig. 2. Intragastric floating tablet (US Patent [4, 167, 558, September 11, 1979). Reproduced with permission from Chien [102].

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 and in such a way as to entrap a plurality of small air pockets, which brought about the buoyancy of laminated films. Both the desired time period for buoyancy and the

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rate of drug release can be modulated by the appropriate selection of a polymer matrix. Polymers such as polycarbonate has been used to develop hollow microspheres that were capable of floating on the gastric fluid and released their drug contents for prolonged period of time. Thanoo et al. [55] developed drug-loaded polycarbonate microspheres using a solvent evaporation technique. A high drug loading (.50%) was achieved by this process. Further, increasing the drug to polymer ratio in the microspheres increased their mean particle size and the release rate of the drugs. Kawashima and coworkers [53,56] prepared hollow microspheres (‘microballoons’) with a drug loaded in their outer shells by an emulsion-solvent diffusion method. The ethanol / dichloromethane solution of a drug and an enteric acrylic polymer was poured into an aqueous solution of polyvinyl alcohol (PVA) that was maintained at 408C. The latter solution was constantly stirred while adding the former solution to form emulsion droplets. The gas phase generated in the dispersed polymer droplet by the evaporation of dichloromethane formed an internal cavity in the microsphere of the polymer with the drug. During in vitro testing, the microballoons floated continuously over the surface of an aqueous or an acidic dissolution medium containing surfactant for more than 12

Fig. 3. Intragastric floating bilayer tablet (US Patent [4, 140, 755, February 20, 1979). Adapted from Desai [4].

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h. Further, the drug release profiles from the microballoons exhibited enteric behavior, and drug release rates were controlled by changing the ratio of polymer to drug in the balloon. A patent assigned to Eisai Co. Ltd. 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 an under-coating and a final coating. While the former was a layer of a cellulose acetate phthalate, the latter consisted of a layer of ethyl cellulose and HPMC in combination with an effective amount of a pharmaceutically active ingredient selected from the group consisting of a gastric acid secretion inhibitor, a gastric acid neutralizer and an anti-pepsin inhibitor. Although these capsules were buoyant, because of the air present in the empty capsule shell, and were able to achieve prolonged residence in the stomach, it was difficult to incorporate drugs into such a system [103]. Harrigan [104] described a floating system, known as an intragastric floating drug delivery device. The device comprised of a drug reservoir encapsulated in a microporous compartment having pores along its top and bottom surfaces. The peripheral walls of the drug reservoir compartment were completely sealed to prevent any physical contact of the undissolved drug with the stomach walls (Fig. 4). The floatation chamber caused the system to float in the gastric fluid. Yuasa et al. [58] developed intragastric floating and SR granules of diclofenac sodium using a polymer solution of hydroxypropylcellulose L grade (HPC-L) and ethylcellulose, and calcium silicate as a floating carrier, which has a characteristically porous structure with numerous pores and a large individual pore volume. The coated granules acquired floating

ability from the air trapped in the pores of calcium silicate when they were coated with a polymer. Whitehead et al. [105] developed a multiple-unit floating dosage form from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm in diameter were produced by dropping a sodium alginate solution into aqueous calcium chloride. After the internal gelation was complete, beads were separated from the solution and snap-frozen in liquid nitrogen before being freeze-dried at 2408C for 24 h. The results of resultant-weight measurements suggested that these beads maintained a positive floating force for over 12 h. In their subsequent study [39], the gastroretentive properties of F beads were investigated in fed healthy male subjects, using the technique of g-scintigraphy, and compared with that of NF beads made from identical material. A prolonged GRT of over 5.5 h was achieved in all subjects for the F formulations, whereas the NF beads displayed short GRTs, with a mean onset emptying time of 1 h. Iannuccelli and co-workers [38,106] 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. A synergism between a bioadhesive system and a floating system has also been explored. Chitnis et al.

Fig. 4. Intragastric floating drug delivery device (US Patent [ 4, 055, 178, October 25, 1977). Reproduced with permission from Chien [102].

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[80] synthesized a series of bioadhesive polymers that were cross-linked polymers of methacrylic acid (PMA) and acrylic acid (PAA). Floating tablets of isosorbide mononitrate were prepared and then dipcoated with Carbopol  suspensions or 0.5% suspension of these bioadhesive polymers in 0.5% Carbopol  gel, and finally air-dried. The results showed that tablets coated with bioadhesive polymers had better adhesive properties at pH 1.0 as compared to those coated with suspensions of Carbopol  . Further, the coated tablets had lower densities, indicating that the polymer coat might confer buoyancy to these tablets. Such studies provide a rational basis to further improve gastroretentive systems.

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3.2. Effervescent FDDS

release pills as seeds surrounded by double layers (Fig. 5a). The inner layer was an effervescent layer containing both sodium bicarbonate and tartaric acid. The outer layer was a swellable membrane layer containing mainly polyvinyl acetate and purified shellac. Moreover, the effervescent layer was divided into two sublayers to avoid direct contact between sodium bicarbonate and tartaric acid. Sodium bicarbonate was contained in the inner sublayer and tartaric acid was in the outer layer. When the system was immersed in a buffer solution at 378C, it sank at once in the solution and formed swollen pills, like balloons, with a density much lower than 1 g / ml. The reaction was due to carbon dioxide generated by neutralization in the inner effervescent layers with the diffusion of water through the outer swellable membrane layers (Fig. 5b). The system was found to

These buoyant delivery systems utilize matrices prepared with swellable polymers such as Methocel  or polysaccharides, e.g., chitosan, and effervescent components, e.g., sodium bicarbonate and citric or tartaric acid [41] or matrices containing chambers of liquid that gasify at body temperature [107–109]. The matrices are fabricated so that upon arrival in the stomach, carbon dioxide is liberated by the acidity of the gastric contents and is entrapped in the gellified hydrocolloid. This produces an upward motion of the dosage form and maintains its buoyancy. A decrease in specific gravity causes the dosage form to float on the chyme [41]. The carbon dioxide generating components may be intimately mixed within the tablet matrix, in which case a single-layered tablet is produced [110], or a bilayered tablet may be compressed which contains the gas generating mechanism in one hydrocolloid containing layer and the drug in the other layer formulated for a SR effect [84]. This concept has also been exploited for floating capsule systems. Stockwell et al. [111] prepared floating capsules by filling with a mixture of sodium alginate and sodium bicarbonate. The systems were shown to float during in vitro tests as a result of the generation of CO 2 that was trapped in the hydrating gel network on exposure to an acidic environment. Recently a multiple-unit type of floating pill, which generates carbon dioxide gas, has been developed [82]. The system consisted of sustained-

Fig. 5. (a) A multiple-unit oral floating dosage system. Reproduced with permission from Ichikawa et al. [82]. (b) Stages of floating mechanism: (A) penetration of water; (B) generation of CO 2 and floating; (C) dissolution of drug. Key: (a) conventional SR pills; (b) effervescent layer; (c) swellable layer; (d) expanded swellable membrane layer; (e) surface of water in the beaker (378C). Reproduced with permission from Ichikawa et al. [82].

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float completely within 10 min and approximately 80% remained floating over a period of 5 h irrespective of pH and viscosity of the test medium. While the system was floating, a drug ( p-aminobenzoic acid) was released. A variant of this approach utilizing citric acid (anhydrous) and sodium bicarbonate as effervescing agents and HPC-H grade as a release controlling agent has also been reported [79]. In vitro results indicated a linear decrease in the FT of the tablets with an increase in the amount of effervescing agents in the range of 10–20%. Attempts have also been made to develop SR floating tablets using a mixture of sodium bicarbonate, citric acid and chitosan. Inouye et al. [83] used two types of chitosan with different degrees of deacetylation (chitosan H and L) and prednisolone as a model drug. Although both chitosans provided SR of drug in acidic dissolution medium, and imparted quick buoyancy to the preparations, the drug release from the preparation using chitosan L was slower than that from the preparation of chitosan H. In a follow up study by the same group, the release properties were controlled by regulating the chitosan content of the granules, or the chitosan L membrane thickness of the laminated preparations [60]. Chitosan based SR floating granules for indomethacin have also been developed [59]. Umezawa [94] developed floating minicapsules having a diameter in the range of 0.1–2.0 mm. The core (center) of minicapsules was comprised of a granule of sodium bicarbonate admixed with lactose and polyvinylpyrrolidone, coated by repeated spraying with a 2% methanol solution of HPMC in a coating pan. The center was then outer coated with pepstatin. The CO 2 that was liberated on contact with gastric acid caused the minicapsules to float and permitted pepstatin to stay longer in the stomach. It was claimed that oral administration of an amount containing 50–200 mg pepstatin per dose could release enough pepstatin to suppress the pepsin activity in patients being treated for gastric and duodenal ulcers. Ichikawa et al. [112] described a similar capsule, which contained a plurality of granules having different residence times in the stomach. The granules were comprised of a core containing the drug, coated by double layers. The inner coat was a foamable layer, and the outer layer was an expansive

film layer comprising a polymer, which allowed gastric juice to pass therethrough and expand by foam produced by the reaction between the gastric juice and the foamable layer. Moreover, the foamable layer was divided into two sublayers: an inner layer containing bicarbonate and an outer layer containing an organic acid. It is worth mentioning here that carbonates, in addition to imparting buoyancy to these formulations, provide the initial alkaline microenvironment for polymers to gel [8]. Moreover, the release of CO 2 helps to accelerate the hydration of the floating tablets, which is essential for the formation of a bioadhesive hydrogel [87]. This provides an additional mechanism (‘bioadhesion’) for retaining the dosage form in the stomach, apart from floatation. Based on this approach, Asrani [87] developed a novel floating bioadhesive DDS using verapamil HCl as the model drug. In the study, tablet buoyancy was found to be affected by the amount of sodium bicarbonate added and the type of polymer used in the formulations. Further, these formulations were capable of sustaining release up to 24 h. As a matter of fact, there are several factors that influence the buoyancy of floating tablets. These include nature of excipients, viscosity grades of the polymers, tablet weight, tablet density, tablet diameter and pH of the dissolution medium [71,72,113]. Similar formulation variables are known to affect the in vitro performance of floating capsules. These variables include polymer excipients, contents of the polymer, weight of the filled powdered mixture (i.e., density of the capsules), and the amount of the effervescent added [89]. Atyabi and co-workers [114–116] developed a floating system utilizing ion exchange resins. The system consisted of resin beads, which were loaded with bicarbonate and a negatively charged drug that was bound to the resin. The resultant beads were then encapsulated in a semipermeable membrane to overcome rapid loss of CO 2 . Upon arrival in the acidic environment of stomach, an exchange of chloride and bicarbonate ions took place, as was expected. As a result of this reaction, CO 2 was released and trapped in the membrane, thereby carrying beads toward the top of gastric contents and producing a floating layer of resin beads. In contrast, the uncoated beads sank quickly. Radioactivity mea-

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surement by scintigraphy showed that gastric residence was substantially prolonged, compared with a control, when the system was given after a light, mainly liquid meal. Furthermore, the system was capable of slow release of drug, a property which widens the scope of such floating system for SR preparation of drugs possessing negative charge since they can be easily bound to the resin in combination with bicarbonate ions. Todd and Fryers [117] described a similar formulation, which contained anhydrous cholestyramine (an anionic exchange resin), low viscosity grade alginic acid / sodium alginate, citric acid, and sufficient sodium carbonate or bicarbonate mixtures thereof to neutralize the acid groups of the alginic and citric acids. Two patents on FDDS issued to the Alza Corporation disclosed drug delivery devices for the controlled and continuous administration of medicinal agents [108,109]. As an osmotically controlled floating system, the device comprised of a hollow deformable unit that was convertible from a collapsed to an expanded position and returnable to a collapsed position after an extended period of time. A housing was attached to the deformable unit and it was internally divided into a first and second chamber with the chambers separated by an impermeable, pressure responsive movable bladder. The first chamber contained an active drug, while the

247

second contained a volatile liquid, such as cyclopentane or ether that vaporizes at physiological temperature to produce a gas, enabling the drug reservoir to float. To enable the unit to exit from the stomach, the device contained a bioerodible plug that allowed the vapor to escape (Figs. 6 and 7). 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 [6]. Floating dosage forms with an in situ gas generating mechanism are expected to have greater buoyancy and improved drug release characteristics. However, the optimization of the drug release may alter the buoyancy and, therefore, it is sometimes necessary to separate the control of buoyancy from that of drug release kinetics during formulation optimization [1]. Mitchell and Phadke (Drug release modulation in a press-coated hydrophilic polymer matrix containing an effervescent core, Marion Merrell Dow Inc., Kansas City, MO, unpublished data) investigated the release of pseudoephedrine HCl from press-coated tablets where the core was composed of an effervescent mixture (anhydrous citric acid and sodium bicarbonate) and HPMC formed the outer coat. Their results demonstrated that by press coating the hydrophilic polymer and drug matrix onto an effervescent core, it was possible to modify

Fig. 6. Intragastric osmotic controlled drug delivery system (US Patent [ 3, 786, 813, January 22, 1974). Reproduced with permission from Chien [102].

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Fig. 7. Gastro-inflatable drug delivery device (US Patent [3, 901, 232, August 26, 1975). Reproduced with permission from Chien [102].

the dissolution rate of pseudoephedrine HCl from the matrix, allowing slower initial release and more complete release than could be obtained with a single layer polymer matrix tablet. It is noteworthy here that release kinetics for effervescent floating systems significantly deviate from the classical Higuchi model and approach zero-order kinetics systems [82,89,110]. This deviation in drug release behavior has been attributed to the air entrapped in the matrix [118], which is considered a barrier to diffusion, and matrix relaxation [89]. In contrast, noneffervescent floating systems obey the Higuchi model, indicating that drug release occurs via a diffusion mechanism [7,69,89,95].

3.3. Marketed products of FDDS The last three decades of intensive research work have resulted in the development of five commercial FDDS. Madopar  HBS (Prolopa  HBS) is a commercially available product used in Europe and other countries, but not available in the US. It contains 100 mg levodopa and 25 mg benserazide, a peripheral dopa decarboxylase inhibitor. This CR formulation consists of a gelatin capsule that is designed to float on the surface of the gastric fluids. After the gelatin shell dissolves, a mucus body is formed that consists of the active drugs and other substances. The drugs diffuse as successively hydrated boundary layers of the matrix dissipate [67]. Valrelease  is a second example of a floating capsule, marketed by Hoffmann-LaRoche, that contains 15 mg diazepam; the latter is more soluble at low pH. Thus, diazepam (pKa 53.4) absorption is more desirable in the stomach, not in the intestine

where it is practically insoluble and is poorly absorbed. The HBS system maximizes the dissolution of the drug by prolonging the GRT. Moreover, pharmacokinetic data have demonstrated the blood level equivalence of once per day dosing with the HBS capsule to three times daily dosing from conventional, 5-mg Valium  tablets [64]. Floating liquid alginate preparations, e.g., Liquid Gaviscon, are used to suppress gastroesophageal reflux and alleviate the symptoms of ‘heart burn’. The formulation consists of a mixture of alginate, which forms a gel of alginic acid, and a carbonate or bicarbonate component (e.g., sodium bicarbonate), which reacts with gastric acid and evolve CO 2 bubbles. The gel becomes buoyant by entrapping the gas bubbles, and floats on the gastric contents as a viscous layer, which has a higher pH than the gastric contents [119]. Topalkan  is a third-generation aluminum–magnesium antacid that involves not only its antacid properties but an even greater degree the availability of alginic acid in its formula. It has antipeptic and protective effects with respect of the mucous membrane of the stomach and esophagus, and provides, together with the magnesium salts, a floating layer of the preparation in the stomach [120]. Almagate FlotCoat  is another novel antacid formulation that confers a higher antacid potency together with a prolonged GRT and a safe as well as extended delivery of antacid drug [121]. It is obvious that these newer formulations differ from the standard antacid products, which are either rapidly neutralized to water-soluble ions or sediment to the fundus of the stomach, and are evacuated into the duodenum by normal peristalsis [121].

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4. Development and evaluation of FDDS

4.1. Formulation development For the optimum design of a CR oral dosage form, the key step is to understand the principles of GI dynamics such as gastric emptying, small intestinal transit, colonic transit, etc. [122]. Acquiring knowledge about the rate and extent of drug absorption from different sites of GI tract, and factors that can alter or limit the absorption further aid in designing the type of dosage form that is needed for a particular drug. For instance, with drugs such as sulpiride, furosemide, theophylline and albuterol which are predominantly absorbed from the upper part of the GI tract, designing a gastroretentive dosage form is a logical strategy for improving and extending their limited oral bioavailabilities [7,32,123,124]. With the advent of g-scintigraphy, it is now possible to understand the various physiological and pharmaceutical factors involved in oral drug delivery [125]. One of the most reliable and novel approaches includes the use of the InteliSiteE Capsule, which provides quick assessment of the oral absorption of drugs within specific regions of the GI tract. The method is simple, operator-controlled, non-invasive, and leads to cost-effective development of novel oral DDS [126]. Further, as the F forms show prolonged and more reproducible GRTs compared to NF [49], the former would be a preferred choice for a gastroretentive dosage form. For the formulation of a HBS dosage form, three major conditions must be met [64]: (i) it must have sufficient structure to form a cohesive gel barrier; (ii) it must maintain an overall specific gravity lower than that of gastric contents (reported as 1.004–1.01 g / cc); and (iii) it should dissolve slowly enough to serve as a ‘reservoir’ for the delivery system. The task of designing a dosage form to achieve a consistent and controlled residence in the stomach begins with selection of potential excipients that allow the formulation of matrices having sustained delivery characteristics and a bulk density of less than unity. Ideally water-soluble cellulose derivatives are best suited for such purposes. Gerogiannis and co-workers [29,113] have described the floating and swelling characteristics of commonly used excipients. From the results of resultant-weight measure-

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ments of various excipients, these authors concluded that higher molecular weight polymers and slower rates of polymer hydration are usually associated with enhanced floating behavior. Therefore, the selection of high molecular weight and less hydrophilic grades of polymers seems to improve floating characteristics [29]. However, there are certain undesirable properties associated with hydrophilic polymers. For instance, a capsule containing hydrophilic minimatrices (‘minitablets’) has a stronger tendency to quickly form a single cohesive mass in vivo, due to the imbibed gastric fluids, which would be emptied from the stomach as such [127]. In fact, such capsules exhibit a tendency to adhere to one another before being administered orally, which is due to the inherent nature of gelatin capsule shells and the hydration of the minitablets on storage. Rouge et al. [54] have described two different approaches to circumvent this problem: (1) addition of a protective filler excipient into the capsule, and (2) coating the minitablets with Eudragit  NE30D (ethyl acrylate / methylmethacrylate), which is insoluble in gastric juice but permeable and swellable. Thus, prevention of aggregation improves the dispersion of minitablets, thereby increasing the contact surface area of tablets with the medium, which may increase the drug release.

4.2. In vitro and in vivo evaluation The various parameters that need to be evaluated for their effects on GRT of buoyant formulations can mainly be categorized into following different classes. 1. Galenic parameters: diametral size (‘cut-off size’), flexibility and density of matrices. 2. Control parameters: floating time, dissolution, specific gravity, content uniformity, and hardness and friability (if tablets). 3. Geometric parameters: shape. 4. Physiological parameters: age, sex, posture, food, and bioadhesion. The test for buoyancy and in vitro drug release studies are usually carried out in simulated gastric and intestinal fluids maintained at 378C. In practice, floating time is determined by using the USP dis-

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integration apparatus containing 900 ml of 0.1 N HCl as a testing medium maintained at 378C. The time required to float the HBS dosage form is noted as floating (or floatation) time. Dissolution tests are performed using the USP dissolution apparatus. Samples are withdrawn periodically from the dissolution medium, replenished with the same volume of fresh medium each time, and then analyzed for their drug contents after an appropriate dilution. Recent methodology as described in USP XXIII states ‘‘The dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started. A small, loose piece of nonreactive material such as not more than a few turns of a wire helix may be attached to the dosage units that would otherwise float’’. However, standard dissolution methods based on the USP or British Pharmacopoeia (BP) have been shown to be poor predictors of in vitro performance for floating dosage forms [128,129]. Pillay and Fassihi [128] investigated the application of the helical wire sinker to the swellable floating system containing theophylline (a sparingly water-soluble drug). They observed that the procedure tends to inhibit the three-dimensional swelling process of the dosage form and consequently drug release from the formulation was suppressed. Based on their observations, the authors proposed an alternative method in which the floatable delivery system was fully submerged under a ring / mesh assembly. The results showed significant increase in drug release (.20%). In addition, the proposed method was found to provide reproducible hydrodynamic conditions and consistent release profiles. However, in the case of a swellable floating system, which contained diltiazem (a highly watersoluble drug), the authors did not find any difference in release between the proposed method and the USP method. These finding led to the conclusion that drug release from swellable floating systems depends on full surface exposure, unhindered swelling and the drug solubility in water. Another attempt to modify official dissolution methods was made by Burns et al. [130] who developed and validated an in vitro dissolution method for a floating dosage form which had both rapid release and SR properties. The method, although based on the standard BP (1993) / USP (1990) apparatus 2 method, was modified such that paddle

blades were positioned at the surface of the dissolution medium. The results obtained with this modified paddle method showed reproducible biphasic-release dissolution profiles when paddle speeds were increased from 70 to 100 rpm and the dissolution medium pH was varied from 6.0 to 8.0. The dissolution profile was also unaltered when the bile acid concentration in the dissolution medium was increased from 7 to 14 mM. In contrast, the standard paddle or basket methods as described in the BP (1993) were unable to provide either sufficient mixing of the dissolution medium to disperse oily rapid release material or sufficient mechanical erosion of the SR component of the formulation. In additional studies [129], the authors modified a standard dissolution vessel for more reliable assessment of the performance of floating dosage forms, particularly those which rely on an erosion mechanism for drug release. The results showed a more reproducible dissolution profile while eliminating the need for the positioning of the paddle blades at the surface of the dissolution medium, thereby simplifying sampling procedures and preventing adhesion of dosage forms to the paddle blades. Nevertheless, the method retained its ability to differentiate between acceptable and unacceptable dissolution performance. The specific gravity of FDDS can be determined by the displacement method using analytical grade benzene as a displacing medium [33]. Timmermans ¨ [30] recommended that the initial (dry and Moes state) bulk density of the dosage form and changes in the floating strength with time should be characterized prior to in vivo comparison between F and NF units. Further, the optimization of floating formulations should be realized in terms of stability and durability of the floating forces produced, thereby avoiding unforeseeable variations in floating capability that might occur during in vivo studies. These investigators have also described a method for determining the buoyant capabilities of the F forms and the sinking characteristics of the NF forms [131,132]. The method involves the use of a specially designed apparatus for measuring the total force acting vertically on an object immersed in a liquid. The technical details of the apparatus used in this method have been described elsewhere [131,133]. The in vivo gastric retentivity of a floating dosage

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form is usually determined by g-scintigraphy [42] or roentgenography [53,81,95]. Studies are done both under fasted and fed conditions using F and NF (control) dosage forms. It is also important that both dosage forms are nondisintegrating units, and human subjects are young and healthy.

5. Advantages, future potential, and limitations of FDDS

5.1. Sustained drug delivery As mentioned earlier, drug absorption from oral CR dosage forms is often limited by the short GRT available for absorption. However, HBS type dosage forms can remain in the stomach for several hours and, therefore, significantly prolong the GRT of numerous drugs (Table 3). These special dosage forms are light, relatively large in size and do not easily pass through the pylorus, which has an opening of approximately 0.9–1.9 cm [18]. It is worth noting here that a prolonged GRT is not responsible for the slow absorption of a lipophilic drug such as isradipine that has been achieved with a ‘floating’ modified-release capsule [31]. This is because the major portion of drug release from the modified-release capsule took place in the colon, rather than in the stomach. However, the assumed prolongation in the GRT is postulated to cause sustained drug-release behavior [41]. A recent study by a Chinese group indicated that the administration of diltiazem floating tablets twice a day may be more effective compared to normal tablets in controlling the blood pressure of hypertensive patients [78]. Although there was no significant difference between the two formulations in terms of maximal decreases in systolic and diastolic pressure, the duration of hypotensive effects was longer with floating tablets than that with normal ones. Further, the t 1 / 2 (6.464.4 h) and Cmax (56623 ng / ml) were longer and lower for floating tablets than those of normal tablets (2.361.1 h and 96630 ng / ml, P, 0.01), respectively; however, the two formulations were bioequivalent. In case of Madopar  HBS, the formulation has been shown to release levodopa for up to 8 h in vitro, whereas the release from the standard

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Madopar  formulation is essentially complete in less than 30 min [67]. Pharmacokinetic (PK) studies in Parkinsonian patients and healthy volunteers have also revealed that Madopar  HBS behaves as a controlled / slow-release formulation of L-dopa and benserazide [43,134]. In comparison with standard Madopar  , the rate of absorption was reduced, providing lower peak concentrations of L-dopa. Further, the drug was released and absorbed over a period of 4–5 h, thus maintaining substantial plasma concentrations for 6–8 h after dosing [43]. Desai and Bolton [7] compared the dissolution profiles of floating theophylline CR tablet (300 mg) and a commercial SR tablet (Theo-Dur  ; 300 mg). They found that floating tablets showed a more gradual release of the drug. The initial release rate was found to be comparatively faster, with a slower rate after 8 h. On the other hand, the release rate of Theo-Dur  was slower initially but increased later. However, these differences were not statistically significant, and two formulations were regarded as bioequivalent.

5.2. Site-specific drug delivery A floating dosage form is a feasible approach especially for drugs such as furosemide and riboflavin, which have limited absorption sites in the upper small intestine. In fact, the absorption of furosemide has been found to be site-specific, the stomach being the major site of absorption, followed by the duodenum [123]. This property prompted the development of a monolithic floating dosage form for furosemide, which could prolong the GRT, and thus its bioavailability was increased [66]. Recently, a bilayer floating capsule has been used to achieve local delivery of misoprostol at the gastric mucosa level [35]. It is a synthetic prostaglandin E 1 analog approved and marketed in the US (as Cytotec  ) for prevention of gastric ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDs). Basically it replenishes the GI-protective prostaglandins that are depleted by NSAIDs. Thus, the controlled, slow delivery of misoprostol to the stomach provides sufficient local therapeutic levels and limit the systemic and intestinal exposure to the drug. This reduces the side effects that are caused by the presence of the drug in the blood circulation

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(uterotonic activity), or a combination of intestinal and systemic exposure (diarrhea), while maintaining its antiulcer efficacy. In addition, the prolonged gastric availability of the misoprostol from a sitedirected delivery system may also reduce the dosing frequency [135]. Floating tablets containing 20–50 mg of 5-fluorouracil have been successfully evaluated in four patients with stomach neoplasms in which tablets remained floating in the stomach for a period of 2 h after administration [79].

5.3. Pharmacokinetic advantages and future potential As sustained release systems, floating dosage forms offer various potential advantages evident from several recent publications. Drugs that have poor bioavailability because their absorption is restricted to the upper GI tract can be delivered efficiently thereby maximizing their absorption and improving their absolute bioavailabilities. For instance, a significant increase in the absolute bioavailability of the floating dosage form of furosemide has been obtained (42.9%), compared to the commercially available tablet (Lasix  ; 33.4%) and enteric product (Lasix  long; 29.5%) (Table 4). Furthermore, among these three dosage forms, only the floating dosage form yielded satisfactory in vitro results that were significantly correlated (P,0.05) with in vivo absorption kinetics. The findings of this study were based on a previous postulation that site-specific absorption and longer GRT could possibly increase the bioavailability of furosemide [123]. Similar observations were made by Ichikawa et al. [81] who found that floating pills containing p-aminobenzoic acid, a drug with a limited absorption site in the GI tract, had 1.61 times greater AUC than the control pills (32.2966.06 vs. 20.1065.81 mg?h / ml). These authors, however, did not find any significant difference in bioavailabilty of isosorbide5-nitrate when floating and control pills were compared. This difference in results could be explained by the fact that isosorbide-5-nitrate is well absorbed from both the stomach and small intestine. Thus, prolonging the GRT of a dosage form appears to offer no advantage (in terms of bioavailability) for drugs with multiple absorption sites in the GI tract [1].

Pharmacokinetic studies by Miyazaki et al. [59] demonstrated that floating granules of indomethacin prepared with chitosan were superior to the conventional commercial capsules in terms of the decrease in the peak plasma concentration and maintenance of indomethacin concentration in plasma. The values of various bioavailability parameters are shown in Table 4. There are only few instances in which the relative bioavailability of a floating dosage form is reduced compared to the conventional dosage form. An illustrative example is that of SR floating tablets of amoxycillin trihydrate the in vivo evaluation of which in healthy fasted males indicated that the relative bioavailability was reduced to 80.5% when compared with the conventional capsules; other pharmacokinetic parameters indicated no improved efficacy even though the tablets remained buoyant for 6 h and had a satisfactory release pattern in vitro [74]. However, the lower bioavailability of drugs could be balanced in part by potential clinical advantages of FDDS, and may be compensated by taking a higher daily dose. For instance, in patients with advanced Parkinson’s disease, who experienced pronounced fluctuations in symptoms while on standard L-dopa treatment, a HBS dosage form provided a better control of motor fluctuations [136,137] (for review, see Ref. [138]), although its bioavailability had been found to be 50 to 60% of the standard formulation [134,139]. There were significant improvements with regard to both akinetic and dyskinetic phenomena. The reduced fluctuations in the plasma levels of drugs result from delayed gastric emptying. After oral dosing the bioavailability of standard Madopar  has been found to be 60–70%; the difference in bioavailabilities of standard and HBS formulations seems to be due to incomplete absorption rather than an altered disposition of the drug [43]. Cook et al. [140] demonstrated that a HBS capsule containing iron salts has an increased efficacy and reduced side effects. Floating dosage forms with SR characteristics can also be expected to reduce the variability in transit performance [50] and various pharmacokinetic parameters [134]. It might be expected that developing HBS dosage form for tacrine might provide a better delivery system and reduce its GI side effects in Alzeihmer’s patients. In addition, buoyant delivery systems might provide a beneficial

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253

Table 4 Comparative pharmacokinetic parameters for floating (F) and non-floating (NF) dosage forms a Drugs

Numbers of subjects

Oral dose (mg)

Cmax (mg/ml)

AUC u – ` (mg?h/ml)

t max (h)

t 1 / 2 (h)

F

NF

F

NF

F

NF

F

NF

Acetaminophen b [72]

6

500

2.027 (0.69–2.787)

10.399 c (7.736–14.086) 1.467 d (0.560–1.944)

27.025 (8.725–44.267)

32.348 c (11.259–45.872) 20.283 d (3.762–41.103)

3.00 (0.5–5.0)

0.67 c (0.5–1.0) 3.50 d (2.0–5.0)

NR

NR

Amoxycillin e [74]

6

500

2.933 f (0.763)

6.833 c (1.989)

15.283 f (5.043)

18.967 c (4.167)

3.667 f (1.862)

1.917 c (1.068)

NR

NR

Atenolol [76] g

6

25

0.091 (0.032)

0.167 c (0.053) 0.068 d (0.023)

1.021 (0.507)

1.228 c (0.354) 0.876 d (0.174)

5.3 (1.5)

2.6 c (0.9) 3.7 d (1.2)

11.3 (8.1)

7.1 c (1.5) 9.9 d (5.2)

Furosemide h [66]

6

30 F,f

0.323 (0.102)

0.127 f (0.026) 0.431 c (0.071)

0.982 (0.186)

0.66 f (0.121) 1.02 c (0.051)

1.05 (0.22)

2.01 f (0.43) 0.53 c (0.12)

2.05 (0.44)

3.33 f (1.19) 3.07 c (0.714)

3.62 j (1.75) 2.23 k (0.33)

5.76 c (2.11) 2.59 f (0.35)

11.63 j (3.12) 10.65 k (2.30)

9.39 c (2.51) 9.37 f (1.56)

1.5–2 j

0.5–1.5 c

NR

NR

3–6 k

1–2 f

NR

NR

40 c Indomethacin i [59]

3

25

Isradipine l [31]

5

10

0.00082 g (0.00066–0.00107) 0.64 m (0.38–24.6)

0.0132 g (0.00387–0.0182) 24.5 m (15.6–105)

0.0114 g (0.0106–0.015) 0.42 m (0.16–8.59)

0.0283 g (0.0139–0.0357) 21.7 m (7.35–66.2)

24 g (24) 0.5 m (0.25–0.75)

1.5 g (1–1.5) 1.0 m (0.5–1.25)

13.5 g (7.7–26.5)

NR

Theophylline b [7]

6

300

3.04 (0.77)

3.69 f (1.28)

105.77 (54.48)

92.19 f (46.45)

10.83 (7.86)

8.0 f (0.0)

NR

NR

Ursodeoxycholic acid n [70]

12

450

5.65 f (0.65)

5.53 c (1.16) 8.67 d,f (2.07)

29.3 f (3.4)

30.5 c (4.9) 39.5 d,f (8.5)

3.67 f (0.99)

3.0 c (0.86) 4.17 d,f (1.35)

NR

NR

a

Values represented as mean (6S.D. or range) except for isradipine in which median value is listed for each parameter; NR, not reported. Data obtained from saliva of healthy human volunteers (fasted). c Immediate release formulations. d High density formulations. e AUC 0 – 12 h f Sustained-release formulations. g Data obtained from plasma of healthy human volunteers (fasted). h Data obtained from plasma of beagle dogs. i Data obtained from plasma of rabbits and AUC represented as AUC 0 – 8 h. . j Drug–chitosan ratio51:0.5 k Drug–chitosan ratio51:2 l AUC 0 – 24 h m Data obtained from gastric juice of healthy human volunteers (fasted), Cmax as mg / g and AUC 0 – 24 h as mg?h / g). n Cmax as mmol / l and AUC 0 – 8 h as mmol?h / l. b

strategy for the treatment of gastric and duodenal cancers. The concept of FDDS has also been utilized in the

development of various anti-reflux formulations. Washington et al. [141] investigated the gastric distribution and residence time of a pectin-containing

254

B.N. Singh, K.H. Kim / Journal of Controlled Release 63 (2000) 235 – 259

formulation. They observed that the formulation was able to float and form a discrete phase on top of the stomach contents. Indeed, the product emptied from the stomach more slowly than the food (P,0.05), and more than 50% of the formulation remained in the fundal region for 3 h. Atyabi et al. [114] reported a floating system prepared from anionic exchange resins that could also be used as a protective barrier (‘floating seal’) against gastroesophageal reflux. Todd and Fryers [117] have described a similar pharmaceutical composition that could be used in the treatment of biliary gastritis, which results from duodeno-gastric reflux of bile into the stomach. Apart from aforementioned advantages, floating systems are particularly useful for acid-soluble drugs [6], drugs which are poorly soluble or unstable in intestinal fluids [142], and those which may undergo abrupt changes in their pH-dependent solubility due to factors such as food, age and pathophysiological conditions of the GI tract. Developing controlled release systems for such drugs as bromocriptine might lead to potential treatment of Parkinson’s disease. After oral administration, approximately 30% of the dose is absorbed from the GI tract [143]. However, its low absorption potential, which often results from low dose usage, might be improved by a HBS dosage form, which could significantly enhance its therapeutic efficacy. Furthermore, the co-delivery of bromocriptine and metoclopramide based on a dual delivery concept similar to that of the Madopar  HBS might further improve the therapeutic efficacy of the HBS dosage form. The use of metoclopramide, a standard antiemetic agent, is justifiable since it can prevent the side effects caused especially by high doses of bromocriptine [144]. Another therapeutic area in which FDDS can be explored is the eradication of Helicobacter pylori, which is now believed to be the causative bacterium for chronic gastritis and peptic ulcers. Although the bacterium is highly sensitive to most antibiotics, its eradication from patients requires high concentrations of drug be maintained within the gastric mucosa for a long duration [145]. Recently Katayama et al. [146] developed a SR liquid preparation of ampicillin using sodium alginate that spreads out and adheres to the gastric mucosal surface whereby the drug is continuously released. Thus, it

can be expected that topical delivery of a narrowspectrum antibiotic through a FDDS may result in complete removal of the organisms in the fundal area of the gastric mucosa due to bactericidal drug levels being reached in this area, and might lead to better treatment of peptic ulcer disease.

5.4. Limitations One of the disadvantages of floating systems is that they require a sufficiently high level of fluids in the stomach for the drug delivery buoy to float therein and to work efficiently. However, this limitation can be overcome by coating the dosage form with bioadhesive polymers, thereby enabling them to adhere to the mucous lining of the stomach wall [80]. Alternatively, the dosage form may be administered with a glass full of water (200–250 ml). Floating systems are not feasible for those drugs that have solubility or stability problems in gastric fluids. Drugs such as nifedipine, which is well absorbed along the entire GI tract and which undergoes significant first-pass metabolism, may not be desirable candidates for FDDS since the slow gastric emptying may lead to reduced systemic bioavailablity [1]. Also there are limitations to the applicability of FDDS for drugs that are irritant to gastric mucosa.

6. Conclusions The currently available polymer-mediated noneffervescent and effervescent FDDS, designed on the basis of delayed gastric emptying and buoyancy principles, appear to be an effective and rational approach to the modulation of controlled oral drug delivery. This is evident from the number of commercial products and a myriad of patents issued in this field. The FDDS become an additional advantage for drugs that are absorbed primarily in the upper segments of GI tract, i.e., the stomach, duodenum, and jejunum. Some of the unresolved, critical issues related to the rational development of FDDS include (1) the quantitative efficiency of floating delivery systems in the fasted and fed states; (2) the role of buoyancy in enhancing GRT of FDDS; and (3) the correlation between prolonged

B.N. Singh, K.H. Kim / Journal of Controlled Release 63 (2000) 235 – 259

GRT and SR / PK characteristics. Finally, with an increasing understanding of polymer behavior and the role of the biological factors mentioned above, it is suggested that future research work in the floating drug delivery systems should be aimed at discovering means to accurately control the drug input rate into the GI tract for the optimization of the pharmacokinetic and toxicological profiles of medicinal agents.

Acknowledgements Brahma Singh gratefully acknowledges St. John’s University, the College of Pharmacy and Allied Health Professions for the support he received as a doctoral fellow.

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