Floating DDS Main

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Journal of Controlled Release 63 (2000) 235259

www.elsevier.com/locate/jconrel

Review

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

*Brahma N. Singh, Kwon H. KimDrug Delivery Systems Research Laboratory, College of Pharmacy and Allied Health Professions, St. Johns 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 achieving more predictable and increased bioavail-

ability of drugs. However, the development process

The de novo design of an oral controlled drug is precluded by several physiological difficulties,

delivery system (DDS) should be primarily aimed at 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 empty-Abbreviations: CR, controlled-release; DDS, drug delivery ing process. It can be anticipated that, dependingsystem; F, floating; FDDS, floating drug delivery systems; FT,

upon the physiological state of the subject and thefloating or floatation time; GET, gastric emptying time(s); GRT,

design of pharmaceutical formulation, the emptyinggastric residence time(s); GI, gastrointestinal; HBS, hydro-dynamically balanced systems; HPC, hydroxypropylcellulose; process can last from a few minutes to 12 h. ThisHPMC, hydroxypropylmethylcellulose; MMC, migrating variability, in turn, may lead to unpredictable bio-myoelectric complex; NF, non-floating; PK, pharmacokinetic; availability and times to achieve peak plasma levels,PAA, polyacrylic acid; PMA, polymethacrylic acid; PVA, poly-

since the majority of drugs are preferentially ab-vinyl alcohol; SR, sustained-release

sorbed in the upper part of the small intestine [1].*Corresponding author. Tel.: 11-718-990-6063; fax: 11-718-990-6316. Furthermore, the relatively brief GET in humans,

0168-3659/ 00/ $ see front matter 2000 Elsevier Science B.V. All rights reserved.

P I I : S 0 1 6 8 - 3 65 9 ( 9 9 ) 0 0 2 0 4 - 7


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236 B.N. Singh, K.H. Kim / Journal of Controlled Release 63 (2000) 235259

which normally averages 23 h through the major contractions. Phase II is a period of similar duration

absorption zone (stomach or upper part of the consisting of intermittent action potentials and con-

intestine), can result in incomplete drug release from tractions that gradually increase in intensity and

the DDS leading to diminished efficacy of the frequency as the phase progresses. Phase III is a

administered dose. Thus, control of placement of a short period of intense, large regular contractionsDDS in a specific region of the GI tract offers lasting from 4 to 6 min. It is this phase, which gives

numerous advantages, especially for drugs exhibiting the cycle the term housekeeper wave, since it

an absorption window in the GI tract or drugs with a serves to sweep undigested materials out of the

stability problem. Overall, the intimate contact of the stomach and down the small intestine. As phase III

DDS with the absorbing membrane has the potential of one cycle reaches the end of the small intestine,

to maximize drug absorption and may also influence phase III of the next cycle begins in the duodenum.

the rate of drug absorption [2,3]. These considera- Phase IV is a brief transitional phase that occurs

tions have led to the development of oral controlled- between phase III and phase I of two consecutive

release (CR) dosage forms possessing gastric re- cycles. In the fed state, the gastric emptying rate is

tention capabilities. As the first part in this series of slowed since the onset of MMC is delayed [7]. In

reviews on contemporary gastroretentive systems, other words, feeding results in a lag time prior to thethe current technological developments in FDDS, onset of gastric emptying.

including patented and clinically available products, Scintigraphic studies involving measurements of

formulation development strategy, and their advan- gastric emptying rates in healthy human subjects

tages and future potential for oral controlled drug have revealed that an orally administered CR dosage

delivery are discussed. form is mainly subject to two physiological adver-

sities: the short GRT and the variable (unpredictable)

GET. Yet another major adversity encountered

2. Basic physiology, problems, and approaches through the oral route is the first-pass effect, which

leads to reduced systemic bioavailability of a large2.1. Gastric emptying and problems number of drugs. Overall, the relatively brief GI

transit time of most drug products, which is approxi-

It is well recognized that the stomach may be used mately 812 h, impedes the formulation of a onceas a depot for sustained-release (SR) dosage forms, daily dosage form for most drugs. These problems

both in human and veterinary applications. The can be exacerbated by alterations in gastric emptying

stomach is anatomically divided into three parts: that occur due to factors such as age, race, sex, and

fundus, body, and antrum (or pylorus). The proximal disease states, as they may seriously affect the

stomach, made up of the fundus and body regions, release of a drug from the DDS. It is, therefore,

serves as a reservoir for ingested materials while the desirable to have a CR product that exhibits an

distal region (antrum) is the major site of mixing extended GI residence and a drug release profile

motions, acting as a pump to accomplish gastric independent of patient related variables.

emptying [4].

The process of gastric emptying occurs both 2.2. Approaches to gastric retention

during fasting and fed states; however, the pattern ofmotility differs markedly in the two states. In the Over the last three decades, various approaches

fasted state, it is characterized by an interdigestive have been pursued to increase the retention of an oral

series of electrical events which cycle both through dosage form in the stomach, including floating

the stomach and small intestine every 23 h [5]. This systems [8], swelling and expanding systems [9,10],

activity is called the interdigestive myoelectric cycle bioadhesive systems [3,1113], modified-shape sys-

or migrating myoelectric complex (MMC), which is tems [1419], high-density systems [2022], and

often divided into four consecutive phases. As other delayed gastric emptying devices [23,24].

described by Wilson and Washington [6], phase I is a FDDS or hydrodynamically balanced systems have a

quiescent period lasting from 40 to 60 min with rare bulk density lower than gastric fluids and thus


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B.N. Singh, K.H. Kim / Journal of Controlled Release 63 (2000) 235259 237

remain buoyant in the stomach without affecting the These factors include density, size, and shape of

gastric emptying rate for a prolonged period of time. dosage form, concomitant intake of food and drugs

While the system is floating on the gastric contents, such as anticholinergic agents (e.g., atropine, propan-

the drug is released slowly at a desired rate from the theline), opiates (e.g., codeine) and prokinetic agents

system. After the release of drug, the residual system (e.g., metoclopramide, cisapride), and biologicalis emptied from the stomach. This results in an factors such as gender, posture, age, body mass

increase in the GRT and a better control of fluctua- index, and disease states (e.g., diabetes, Crohns

tions in plasma drug concentrations in some cases. disease). Most of these factors have been described

Swelling type dosage forms are such that after here in the context of FDDS.

swallowing, these products swell to an extent that FDDS are retained in the stomach for a prolonged

prevents their exit from the stomach through the period of time by virtue of their floating properties,

pylorus. As a result, the dosage form is retained in which can be acquired by several means. Generally

the stomach for a long period of time. These systems speaking, in order for a HBS dosage form to float in

may be referred to as plug type systems since they the stomach, the density of the dosage form should

exhibit a tendency to remain lodged at the pyloric be less than the gastric contents. A density of less

sphincter. Bioadhesive systems are used to localize a than 1.0 g/ ml has been reported in the literature.delivery device within the lumen and cavity of the However, the floating force kinetics of such dosage

body to enhance the drug absorption process in a forms has shown that the bulk density of a dosage

site-specific manner [11]. The approach involves the form is not the most appropriate parameter for

use of bioadhesive polymers that can adhere to the describing its buoyant capabilities. The buoyant

epithelial surface of the GI tract. The proposed capabilities are better represented and monitored by

mechanism of bioadhesion is the formation of hydro- resultant-weight measurements and swelling experi-

gen- and electrostatic bonding at the mucus-polymer ments [29]. This is because the magnitude of floating

boundary [6]. Rapid hydration in contact with the strength may vary as a function of time and usually

muco-epithelial surface appears to favor adhesion, decreases after immersion of the dosage form into

particularly if water can be excluded at the reactive the fluid as a result of the development of its

surfaces [6]. Modified-shape systems are nondisin- hydrodynamic equilibrium [30].

tegrating geometric shapes molded from silastic While considering the role of specific gravity inelastomer or extruded from polyethylene blends, GRT, the potential of food in modifying GRT should

which extend the GRT depending on size, shape and not be overlooked (Table 1). One of the earlier inflexural modulus of the drug delivery device [14 vivo evaluations of FDDS by Muller-Lissner et al.

19]. High-density formulations include coated pel- [34] demonstrated that a GRT of 410 h could be

lets, which have a density greater than that of the achieved after a fat and protein test meal. Further-3

stomach contents (|1.004 g / cm ). This is accom- more, food affects the GRT of dosage forms depend-

plished by coating the drug with a heavy inert ing on its nature, caloric content and the frequency

material such as barium sulfate, zinc oxide, titanium of intake [3537]. For example, Oth et al. [35]

dioxide, iron powder, etc. Other delayed gastric reported that the mean GRT of a bilayer floating

emptying approaches of interest include sham feed- capsule of misoprostol was 199669 min after a

ing of indigestible polymers [2527] or fatty acid single light meal (breakfast). However, after asalts [23,24,28] that change the motility pattern of succession of meals, the data showed a remarkable

the stomach to a fed state, thereby decreasing the prolongation of the mean GRT, to 6186208 min. In

gastric emptying rate and permitting considerable another study, Iannuccelli et al. [38] reported that in

prolongation of drug release. the fed state after a single meal, all the floating units

had a floating time (FT) of about 5 h and a GRT2.3. Factors affecting gastric retention prolonged by about 2 h over the control. However,

after a succession of meals, most of the floating units

There are several factors that can affect gastric showed a FT of about 6 h and a GRT prolonged by

emptying (and hence GRT) of an oral dosage form. about 9 h over the control, though a certain vari-


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Table 1a

Effects of food on GRTs of floating and non-floating (control) dosage forms

Dosage forms Non-floating Floating

[References]

Fasted Fed Fasted Fed

Isradipine caps [31] 1.59 (n55) 2.15 (n54) 1.0 (n55) 3.60 (n54)b

Radiolabeled tabs [22] 1.65 (n54) 4.43 (n54) 0.82 (n54) 5.25 (n54)c c

3.37 (n58) 7.0 (n58)b

Radiolabeled tabs [32] 1.1 (n57) 1.32 (n57) 1.1 (n57) 7.15 (n57)

Radiolabeled tabs [33] 2.53 (n54) 6.27 (n54) 2.2 (n54) 6.77 (n54)

Theophylline [7] 2.32 (n53) 7.54 (n53) 1.57 (n53) 7.15 (n53)

aValues are represented as mean (h); n5number of healthy human volunteers.

bResults are expressed as gastric emptying times (GET).

cFloating capsules.

ability of the data owing to mixing with heavy solid capsule left the stomach. Thus, in view of foregoing

food ingested after the dosing was observed. Obvi- discussions, it may be concluded that althoughously, when the gastroretentive properties of a floating systems possess an inherent ability for

floating dosage form is independent of meal size, it gastric retention, they rely more on the presence of a

can be suggested that the dosage form will be meal to retard their emptying.

suitable for patients with a wide range of eating From the results presented in Table 1, there does

habits [39]. not appear to be large difference between the GRT of

Interestingly, most of the studies related to effects the F and NF dosage forms. This consistency can be

of food on GRT of FDDS share a common viewpoint explained based on the fact that the gastric emptying

that food intake is the main determinant of gastric depends on the onset of the MMC. Therefore, the

emptying, while specific gravity has only a minor GRT is significantly increased under fed conditions,

effect on the emptying process [22,31,33,40]. Stated since the onset of MMC is delayed [7]. Nevertheless,

otherwise, the presence of food, rather than the efficiency of intragastric buoyant dosage forms in

buoyancy, is the most important factor affecting the fed stomach is questionable because of theGRT and floating does not invariably increase GRT. intensive contractile activity of the stomach and the

In fact, studies have shown that the GET for both density of the viscous chyme. Moreover, in the

floating (F) and non-floating (NF) single units are fasted stomach the amount of liquid is not sufficient

shorter in fasted subjects (less than 2 h), but are for the drug delivery buoy and the stomachs entire

significantly prolonged after a meal (around 4 h) contents are emptied down the small intestine within

[22,40]. In a similar study, Agyilirah et al. [32] 23 h because of the typical phase III activity [41].

found that in the fed state, balloon (floating) tablets Concern regarding the role of food in the

prolonged the GET by an average of 6 h over that of prolongation of the GRT has also provided insights

uncoated, nondisintegrating tablets; however, in the into other determinants of gastric retention. For

fasted state, the balloon tablets did not significantly instance, studies have shown that the GRT of a

prolong GET and both tablets had much shorter dosage form in the fed state can also be influencedemptying times compared to the fed state. Studies of by its size. Small-size tablets are emptied from the

Mazer et al. [31] suggested that the release and stomach during the digestive phase, while larger-size

absorption kinetics of a lipophilic drug (isradipine) units are expelled during the housekeeping waves

from a floating modified-release capsule might be [35]. Timmermans et al. [42] studied the effect of

affected by intragastric interaction with the lipid size on the GRT of F and NF units using g-sci-

phase of a high-fat meal. Further, for the modified- ntigraphy. They found that F units with a diameter

release capsule, GRT was regarded as the duration of equal to or less than 7.5 mm had longer GRTs

intragastric release to reach 90% release, since no compared to NF units. However, the GRTs were

further intragastric release could occur after the 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, buoyancy and non-buoyancy of the forms lead to

which remain buoyant on gastric contents, are distinct intragastric behaviors [47]. It was also

protected against gastric emptying during digestive concluded that depending on the subject posture,

phases. On the other hand, NF units lie in the antrum either standing or supine, the gastric residence period

region and are propelled during the digestive process of a dosage form is function of either its buoyancy orby peristalsis. the diametric size of the matrix. Recently, a triple

The prolongation of the GRT by food is expected radionuclide scintigraphic technique has been de-

to maximize drug absorption from a FDDS. This scribed for intragastric monitoring that allowed the

may be rationalized in terms of increased dissolution measurement of the effects on GRT of galenic

of drug and longer residence at the most favorable parameters (size, density of matrices), as well as of

sites of absorption. However, there may be rare physiological parameters such as subject posture

exceptions, where the presence or absence of food in [48]. Studies were conducted in nonfasting human

the stomach has no effect on the absorption of a drug volunteers either in upright or in supine posture, who

from HBS type dosage forms [43]. The effects of concurrently were given one optimized F and one NF

food on various aspects of drug absorption have been hydrophilic matrix capsules of the same size, and

extensively discussed in a separate publication [44]. three different sizes (small,[

5; medium,[

0; large,Apart from food and buoyancy effects, there are [000). In upright subjects, all the F forms stayed

other biological factors that can influence the GRT. continuously above the gastric contents irrespective

Sangekar et al. [33] concluded that the increase in of their size, whereas the NF units sank rapidly after

retention time of HBS may also be due to effects ingestion and never rose back to the surface there-

such as adhesion to the gastric mucosa, rather than after. Thus, in upright subjects the F forms were

the effect of floating per se. Mojaverian et al. [45] protected against postprandial emptying. Conse-

investigated the effects of gender, posture, and age quently, the F forms showed prolonged and more

on the GRT of an indigestible solid, the Heidelberg reproducible GRTs compared to the NF forms. The

capsule. As a result of this study, authors found that significance and extent of this prolongation when

the mean ambulatory GRT in the males was sig- compared with NF units were the most marked for

nificantly faster than in their age (63 years)- and the small size units (P,0.001) but gradually les-

race-matched female counterparts (3.460.6 vs. sened as the dosage form size increased (P,0.05 for4.661.2 h, P,0.01). Further, the data indicated that the medium size units), to become insignificant for

women emptied their stomach slower than men, the large size units (P.0.05). However, there was no

regardless of weight, height, body surface area and significant difference between the mean GRTs of the

even when the hormonal changes due to the menstru- small, medium, and large F units (P.0.05). These

al cycle were normalized. The mean GRT for findings indirectly confirm that the intragastric

volunteers in the supine state was not statistically buoyancy of the F forms is the main factor determin-

significant from that in the upright, ambulatory state ing their prolonged GRTs and protecting them from

(3.460.8 vs. 3.560.7 h, P.0.05). In the case of random gastric emptying related to antral peristaltism

elderly, the GRT was prolonged, especially in sub- [49]. Similar results were reported in a recent study

jects .70 years old (mean GRT55.8 h; n53). [50]. The mean GRTs of the NF forms were much

Another confounding factor is the variability of GI more variable and highly dependent on their size,transit within and between individuals. Studies by which were in the order of small,medium,large

Coupe et al. [46] revealed that variability in gastric units, P,0.05. Moreover, in supine subjects, a size

emptying of single- and multiple-unit systems was effect influenced the GRT of both the F and NF

large compared to that in small intestinal transit forms (P,0.05). The F forms were more often

times; however, the intrasubject variation was less emptied before the NF forms but size for size, the

than intersubject for both gastric and small intestinal mean GRTs did not differ in the aggregate. Bennett

transit times. et al. [51] have also demonstrated the role of posture

A comparative evaluation of the gastric transit of in gastric emptying. They observed that an alginate

F and NF matrix dosage forms indicated that raft emptied faster than food in subjects lying on


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their left side or on their backs and slower in subjects preparations include hollow microspheres (mi-

lying on their right side with the raft positioned in croballoons), granules, powders, capsules, tablets

the greater curvature of the stomach. This is because (pills), and laminated films. Most of the floating

when the subjects laid on their left side, the raft was systems reported in literature are single-unit systems,

presented to the pylorus ahead of the meal and so such as the HBS and floating tablets. These systemsemptied faster [6]. are unreliable and irreproducible in prolonging resi-

dence time in the stomach when orally administered,

owing to their fortuitous (all-or-nothing) emptying

3. Technological developments in FDDS process [53]. On the other hand, multiple-unit dosage

forms appear to be better suited since they are

The concept of FDDS was described in the claimed to reduce the intersubject variability in

literature as early as 1968 [52], when Davis dis- absorption and lower the probability of dose-dump-

closed a method for overcoming the difficulty ex- ing [54]. A list of drugs used in the development of

perienced by some persons of gagging or choking FDDS thus far is given in Tables 2 and 3.

while swallowing medicinal pills. The author sug- Based on the mechanism of buoyancy, two dis-

gested that such difficulty could be overcome by tinctly different technologies, i.e., noneffervescentproviding pills having a density of less than 1.0 g / ml and effervescent systems, have been utilized in the

so that pill will float on water surface. Since then development of FDDS. The various approaches used

several approaches have been used to develop an in and their mechanisms of buoyancy are discussed

ideal floating delivery system. The various buoyant in the following subsections.

Table 2a

List of drugs explored for various floating dosage forms

Microspheres Tablets/Pills

Aspirin, griseofulvin Acetaminophen [71,72]

and p-nitroaniline [55] Acetylsalicylic acid [73]

Ibuprofen [56] Amoxycillin trihydrate [74]Terfenadine [57] Ampicillin [75]

Tranilast [53,56] Atenolol [76,77]

Chlorpheniramine maleate [8]

Granules Cinnarizine [61]

Diclofenac sodium [58] Diltiazem [78]

Indomethacin [59] Fluorouracil [79]

Prednisolone [60] Isosorbide mononitrate [80]

Isosorbide dinitrate [81]

Films p-Aminobenzoic acid [81,82]

Cinnarizine [61] Piretanide [77]

Drug delivery device [62] Prednisolone [83]

Quinidine gluconate [32]

Powders Riboflavin-59-phosphate [8,84]

Several basic drugs [63] Sotalol [85]Theophylline [4,7,86]

Capsules Verapamil HCl [8789]

Chlordiazepoxide HCl [64]

Diazepam [34,64,65]

Furosemide [66]

L-Dopa and benserazide [67]

Misoprostol [35,68]

Propranolol HCl [69]

Ursodeoxycholic acid [70]

aNumbers in parentheses indicate the references.


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Table 3a

Comparison of GRTs of floating and non-floating solid dosage forms

Drugs Dosage forms GRT (h) References

NFDS FDDS

Diazepam Capsules 1.01.5 4.010.0 [34,64,65]

Ethmozine (Moricizine HCl) Tablets 11.5 .6 [90]

Gentamycin sulfate Tablets 12 .4 [91]b b

Isradipine Capsules 0.512.87 2.44.8 [31]

Metoprolol tartrate Tablets 11.5 56 [92]

Miocamycin Tablets 34 .7 [93]b

Pepstatin Minicapsules NR 35 [94]

Salbutamol sulfate Capsules NR 89 [95]

Tranilast Microballoons NR .3 [53]

aGRT, gastric residence time; NFDS, non-floating delivery system; FDDS, floating drug delivery system.

bValues obtained in fed state; NR, not reported.

3.1. Noneffervescent FDDS capsule containing a mixture of a drug and hydro-

colloids. Upon contact with gastric fluid, the capsule

The most commonly used excipients in noneffer- shell dissolves, the mixture swells and forms a

vescent FDDS are gel-forming or highly swellable gelatinous barrier thereby remaining buoyant in the

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 main-

tains a relative integrity of shape and a bulk densityof 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 ofsolvent-in and drug-out of the dosage form. As the

exterior surface of the dosage form goes into solu-

tion, 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 boundaryFig. 1. Working principle of the hydrodynamically balanced

within the gel structure [64]. The working principlesystem (HBS). The hard gelatin capsule contains a special

of the HBS is more clearly illustrated in Fig. 1. formulation of hydrocolloids, which swell into a gelatinous massSheth and Tossounian [97] developed a HBS upon contact with gastric fluids. Adapted from Bogentoft [96].


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gastric juice for an extended period of time. Ushi- developed floating ampicillin tablets using a formula

maru et al. [98] developed SR capsules containing a and procedure similar to those of Desai [4]. How-

mixture of a drug, a cellulose derivative or starch ever, the former formula included a buffer system

derivative which forms a gel in water, and a higher that was expected to improve the stability of ampicil-

fatty acid glyceride or higher alcohol or a mixture lin in the acidic medium, especially in the slowthereof which is solid at room temperature. The release tablets. In this study, sodium citrate was used

capsules were prepared by filling capsules with the as a buffering agent, which maintained a pH of about

above mixture, then heating them to a temperature 6.0 in the microenvironment of the ampicillin mole-

above the melting point of the fat/ oil component and cules in the tablets; the drug was most stable at pH

finally cooling and solidifying the mixture. 6.5 in non-buffered solution. Moreover, the buffering

A recent patent issued to G.D. Searle and Co. agent did not affect the dissolution rate of ampicillin.

described a bilayer buoyant dosage form consisting The results of this study also demonstrated that

of a capsule, which included a non-compressed calcium gluconate increased the hardness of tablets

bilayer formulation. One layer was a drug release reasonably.

layer containing misoprostol and other was a buoyant Dennis et al. [63] described a buoyant CR powder

or floating layer. Each layer included a hydrocolloid formulation, which may be either filled into capsulesgelling agent such as hydroxypropylmethylcellulose or compressed into tablets. The formulation con-

(HPMC), gums, polysaccharides and gelatin, which sisted of a drug of basic character, a pH-dependent

upon contact with gastric fluid formed a gelatinous polymer, which was a water-soluble salt of alginic

mass, sufficient for cohesively binding the drug acid (such as sodium or potassium alginate), and a

release layer and floating layer. The dosage form was pH-independent hydrocolloid gelling agent (such as

shown to be buoyant in gastric fluid for a period up HPMC, methyl cellulose, HPC, or a mixture of two

to about 13 h, whereby a substantial amount of drug or more), and binder. The formulation was consid-

was released in the stomach [68]. ered unique in the sense that it released the drug at a

Desai and Bolton [7,99] developed CR floating controlled rate regardless of the pH of the environ-

tablets of theophylline using agar and light mineral ment, being free of calcium ion and CO producing2oil. Tablets were made by dispersing a drug/ mineral material, and had drug release properties similar to a

oil mixture in a warm agar gel solution and pouring tablet of identical composition. Other authors havethe resultant mixture into tablet molds, which on also prepared tablets with alginate and HPMC that

cooling and air drying formed floatable CR tablets. were able to float on gastric contents and provided

Interestingly, the amount of agar needed to form the SR characteristics [22,34,64].

floating tablet was remarkably low (2% per tablet). Sheth and Tossounian [73,101] developed SR

The light mineral oil was essential for the floating floating tablets that were hydrodynamically balanced

property of the tablet since relatively high amounts in the stomach for an extended period of time until

of drug (75%) were used. Secondly, the light mineral all the drug-loading dose was released. Tablets were

oil in the formulation may prevent the air entrapped comprised of an active ingredient, 080% by weight

in the gel matrix from escaping when placed in of inert materials, and 2075% by weight of one or

gastric fluid owing to its inherent hydrophobicity; more hydrocolloids such as methylcellulose, HPC,

however, the mechanism is not yet clear [7]. The air HPMC, hydroxyethylcellulose, and sodium carboxy-entrapped in the tablet gel network may reduce the methylcellulose, which upon contact with gastric

density and contribute towards the buoyancy of the fluid provided a water impermeable colloid gel

tablet. Their study also indicated the importance of barrier on the surface of tablets (Figs. 2 and 3).

an agar gel network in providing tablet binding Mitra [62] described a multilayered, flexible,

properties to these non-compressed tablets, which sheet-like medicament device that was buoyant in the

gives the desired hardness and friability, and in gastric juice of the stomach and had SR characteris-

controlling the drug release characteristics. In tics. The device consisted of at least one dry, self-

another study, these authors developed a similar supporting carrier film made up of a water-insoluble

formulation without using an oil [100]. Gupta [75] polymer matrix having a drug dispersed or dissolved


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h. Further, the drug release profiles from the mi- ability from the air trapped in the pores of calcium

croballoons exhibited enteric behavior, and drug silicate when they were coated with a polymer.

release rates were controlled by changing the ratio of Whitehead et al. [105] developed a multiple-unit

polymer to drug in the balloon. floating dosage form from freeze-dried calcium

A patent assigned to Eisai Co. Ltd. of Japan alginate. Spherical beads of approximately 2.5 mm indescribed a floatable coated shell, which consisted diameter were produced by dropping a sodium

essentially of a hollow globular shell made from alginate solution into aqueous calcium chloride.

polystyrene. The external surface of the shell was After the internal gelation was complete, beads were

coated with an under-coating and a final coating. separated from the solution and snap-frozen in liquid

While the former was a layer of a cellulose acetate nitrogen before being freeze-dried at 2408C for 24

phthalate, the latter consisted of a layer of ethyl h. The results of resultant-weight measurements

cellulose and HPMC in combination with an effec- suggested that these beads maintained a positive

tive amount of a pharmaceutically active ingredient floating force for over 12 h. In their subsequent study

selected from the group consisting of a gastric acid [39], the gastroretentive properties of F beads were

secretion inhibitor, a gastric acid neutralizer and an investigated in fed healthy male subjects, using the

anti-pepsin inhibitor. Although these capsules were technique ofg

-scintigraphy, and compared with thatbuoyant, because of the air present in the empty of NF beads made from identical material. A pro-

capsule shell, and were able to achieve prolonged longed GRT of over 5.5 h was achieved in all

residence in the stomach, it was difficult to incorpo- subjects for the F formulations, whereas the NF

rate drugs into such a system [103]. beads displayed short GRTs, with a mean onset

Harrigan [104] described a floating system, known emptying time of 1 h.

as an intragastric floating drug delivery device. The Iannuccelli and co-workers [38,106] described a

device comprised of a drug reservoir encapsulated in multiple-unit system that contained an air compart-

a microporous compartment having pores along its ment. The units forming the system were composed

top and bottom surfaces. The peripheral walls of the of a calcium alginate core separated by an air

drug reservoir compartment were completely sealed compartment from a membrane of calcium alginate

to prevent any physical contact of the undissolved or calcium alginate/ PVA. The porous structure gen-

drug with the stomach walls (Fig. 4). The floatation erated by leaching of the PVA, which was employedchamber caused the system to float in the gastric as a water-soluble additive in the coating composi-

fluid. Yuasa et al. [58] developed intragastric floating tion, was found to increase the membrane per-

and SR granules of diclofenac sodium using a meability, preventing the collapse of the air compart-

polymer solution of hydroxypropylcellulose L grade ment. The in vitro results suggested that the floating

(HPC-L) and ethylcellulose, and calcium silicate as a ability increased with an increase in PVA concen-

floating carrier, which has a characteristically porous tration and molecular weight.

structure with numerous pores and a large individual A synergism between a bioadhesive system and a

pore volume. The coated granules acquired floating 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 release pills as seeds surrounded by double layers

that were cross-linked polymers of methacrylic acid (Fig. 5a). The inner layer was an effervescent layer

(PMA) and acrylic acid (PAA). Floating tablets of containing both sodium bicarbonate and tartaric acid.

isosorbide mononitrate were prepared and then dip- The outer layer was a swellable membrane layer

coated with Carbopol suspensions or 0.5% suspen- containing mainly polyvinyl acetate and purifiedsion of these bioadhesive polymers in 0.5% shellac. Moreover, the effervescent layer was divided

Carbopol gel, and finally air-dried. The results into two sublayers to avoid direct contact between

showed that tablets coated with bioadhesive poly- sodium bicarbonate and tartaric acid. Sodium bicar-

mers had better adhesive properties at pH 1.0 as bonate was contained in the inner sublayer and

compared to those coated with suspensions of tartaric acid was in the outer layer. When the system

Carbopol . Further, the coated tablets had lower was immersed in a buffer solution at 378C, it sank at

densities, indicating that the polymer coat might once in the solution and formed swollen pills, like

confer buoyancy to these tablets. Such studies pro- balloons, with a density much lower than 1 g/ ml.

vide a rational basis to further improve gastroreten- The reaction was due to carbon dioxide generated by

tive systems. neutralization in the inner effervescent layers with

the diffusion of water through the outer swellable3.2. Effervescent FDDS 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 [107109].

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 upwardmotion 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 that Fig. 5. (a) A multiple-unit oral floating dosage system. Re-2produced with permission from Ichikawa et al. [82]. (b) Stages ofwas trapped in the hydrating gel network on expo-floating mechanism: (A) penetration of water; (B) generation ofsure to an acidic environment.CO and floating; (C) dissolution of drug. Key: (a) conventional2Recently a multiple-unit type of floating pill,SR pills; (b) effervescent layer; (c) swellable layer; (d) expanded

which generates carbon dioxide gas, has been de- swellable membrane layer; (e) surface of water in the beakerveloped [82]. The system consisted of sustained- (378C). Reproduced with permission from Ichikawa et al. [82].


12/25


float completely within 10 min and approximately film layer comprising a polymer, which allowed

80% remained floating over a period of 5 h irre- gastric juice to pass therethrough and expand by

spective of pH and viscosity of the test medium. foam produced by the reaction between the gastric

While the system was floating, a drug (p-amino- juice and the foamable layer. Moreover, the foam-

benzoic acid) was released. A variant of this ap- able layer was divided into two sublayers: an innerproach utilizing citric acid (anhydrous) and sodium layer containing bicarbonate and an outer layer

bicarbonate as effervescing agents and HPC-H grade containing an organic acid.

as a release controlling agent has also been reported It is worth mentioning here that carbonates, in

[79]. In vitro results indicated a linear decrease in the addition to imparting buoyancy to these formula-

FT of the tablets with an increase in the amount of tions, provide the initial alkaline microenvironment

effervescing agents in the range of 1020%. At- for polymers to gel [8]. Moreover, the release of CO2tempts have also been made to develop SR floating helps to accelerate the hydration of the floating

tablets using a mixture of sodium bicarbonate, citric tablets, which is essential for the formation of a

acid and chitosan. Inouye et al. [83] used two types bioadhesive hydrogel [87]. This provides an addi-

of chitosan with different degrees of deacetylation tional mechanism (bioadhesion) for retaining the

(chitosan H and L) and prednisolone as a model dosage form in the stomach, apart from floatation.drug. Although both chitosans provided SR of drug Based on this approach, Asrani [87] developed a

in acidic dissolution medium, and imparted quick novel floating bioadhesive DDS using verapamil HCl

buoyancy to the preparations, the drug release from as the model drug. In the study, tablet buoyancy was

the preparation using chitosan L was slower than that found to be affected by the amount of sodium

from the preparation of chitosan H. In a follow up bicarbonate added and the type of polymer used in

study by the same group, the release properties were the formulations. Further, these formulations were

controlled by regulating the chitosan content of the capable of sustaining release up to 24 h. As a matter

granules, or the chitosan L membrane thickness of of fact, there are several factors that influence the

the laminated preparations [60]. Chitosan based SR buoyancy of floating tablets. These include nature of

floating granules for indomethacin have also been excipients, viscosity grades of the polymers, tablet

developed [59]. weight, tablet density, tablet diameter and pH of the

Umezawa [94] developed floating minicapsules dissolution medium [71,72,113]. Similar formulationhaving a diameter in the range of 0.12.0 mm. The variables are known to affect the in vitro perform-

core (center) of minicapsules was comprised of a ance of floating capsules. These variables include

granule of sodium bicarbonate admixed with lactose polymer excipients, contents of the polymer, weight

and polyvinylpyrrolidone, coated by repeated spray- of the filled powdered mixture (i.e., density of the

ing with a 2% methanol solution of HPMC in a capsules), and the amount of the effervescent added

coating pan. The center was then outer coated with [89].

pepstatin. The CO that was liberated on contact Atyabi and co-workers [114116] developed a2with gastric acid caused the minicapsules to float and floating system utilizing ion exchange resins. The

permitted pepstatin to stay longer in the stomach. It system consisted of resin beads, which were loaded

was claimed that oral administration of an amount with bicarbonate and a negatively charged drug that

containing 50200 mg pepstatin per dose could was bound to the resin. The resultant beads wererelease enough pepstatin to suppress the pepsin then encapsulated in a semipermeable membrane to

activity in patients being treated for gastric and overcome rapid loss of CO . Upon arrival in the2duodenal ulcers. acidic environment of stomach, an exchange of

Ichikawa et al. [112] described a similar capsule, chloride and bicarbonate ions took place, as was

which contained a plurality of granules having expected. As a result of this reaction, CO was2different residence times in the stomach. The released and trapped in the membrane, thereby

granules were comprised of a core containing the carrying beads toward the top of gastric contents and

drug, coated by double layers. The inner coat was a producing a floating layer of resin beads. In contrast,

foamable layer, and the outer layer was an expansive the uncoated beads sank quickly. Radioactivity mea-


13/25


surement by scintigraphy showed that gastric resi- second contained a volatile liquid, such as cyclopen-

dence was substantially prolonged, compared with a tane or ether that vaporizes at physiological tempera-

control, when the system was given after a light, ture to produce a gas, enabling the drug reservoir to

mainly liquid meal. Furthermore, the system was float. To enable the unit to exit from the stomach, the

capable of slow release of drug, a property which device contained a bioerodible plug that allowed thewidens the scope of such floating system for SR vapor to escape (Figs. 6 and 7). Although this type

preparation of drugs possessing negative charge of sophisticated dosage form might be used to

since they can be easily bound to the resin in administer a drug at a controlled rate for a prolonged

combination with bicarbonate ions. Todd and Fryers period of time, it could not be recommended for

[117] described a similar formulation, which con- smokers because of safety reasons [6].

tained anhydrous cholestyramine (an anionic ex- Floating dosage forms with an in situ gas generat-

change resin), low viscosity grade alginic acid/ so- ing mechanism are expected to have greater

dium alginate, citric acid, and sufficient sodium buoyancy and improved drug release characteristics.

carbonate or bicarbonate mixtures thereof to neutral- However, the optimization of the drug release may

ize the acid groups of the alginic and citric acids. alter the buoyancy and, therefore, it is sometimes

Two patents on FDDS issued to the Alza Corpora- necessary to separate the control of buoyancy fromtion disclosed drug delivery devices for the con- that of drug release kinetics during formulation

trolled and continuous administration of medicinal optimization [1]. Mitchell and Phadke (Drug release

agents [108,109]. As an osmotically controlled float- modulation in a press-coated hydrophilic polymer

ing system, the device comprised of a hollow matrix containing an effervescent core, Marion Mer-

deformable unit that was convertible from a col- rell Dow Inc., Kansas City, MO, unpublished data)

lapsed to an expanded position and returnable to a investigated the release of pseudoephedrine HCl

collapsed position after an extended period of time. from press-coated tablets where the core was com-

A housing was attached to the deformable unit and it posed of an effervescent mixture (anhydrous citric

was internally divided into a first and second acid and sodium bicarbonate) and HPMC formed the

chamber with the chambers separated by an im- outer coat. Their results demonstrated that by press

permeable, pressure responsive movable bladder. coating the hydrophilic polymer and drug matrix

The first chamber contained an active drug, while the 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 where it is practically insoluble and is poorly ab-

matrix, allowing slower initial release and more sorbed. The HBS system maximizes the dissolution

complete release than could be obtained with a single of the drug by prolonging the GRT. Moreover,layer polymer matrix tablet. It is noteworthy here pharmacokinetic data have demonstrated the blood

that release kinetics for effervescent floating systems level equivalence of once per day dosing with the

significantly deviate from the classical Higuchi HBS capsule to three times daily dosing from

model and approach zero-order kinetics systems conventional, 5-mg Valium tablets [64].

[82,89,110]. This deviation in drug release behavior Floating liquid alginate preparations, e.g., Liquid

has been attributed to the air entrapped in the matrix Gaviscon, are used to suppress gastroesophageal

[118], which is considered a barrier to diffusion, and reflux and alleviate the symptoms of heart burn.

matrix relaxation [89]. In contrast, noneffervescent The formulation consists of a mixture of alginate,

floating systems obey the Higuchi model, indicating which forms a gel of alginic acid, and a carbonate or

that drug release occurs via a diffusion mechanism bicarbonate component (e.g., sodium bicarbonate),

[7,69,89,95]. which reacts with gastric acid and evolve CO2bubbles. The gel becomes buoyant by entrapping the

3.3. Marketed products of FDDS gas bubbles, and floats on the gastric contents as a

viscous layer, which has a higher pH than the gastric

The last three decades of intensive research work contents [119].

have resulted in the development of five commercial Topalkan is a third-generation aluminummag-

FDDS. Madopar HBS (Prolopa HBS) is a commer- nesium antacid that involves not only its antacid

cially available product used in Europe and other properties but an even greater degree the availability

countries, but not available in the US. It contains 100 of alginic acid in its formula. It has antipeptic and

mg levodopa and 25 mg benserazide, a peripheral protective effects with respect of the mucous mem-

dopa decarboxylase inhibitor. This CR formulation brane of the stomach and esophagus, and provides,

consists of a gelatin capsule that is designed to float together with the magnesium salts, a floating layer of

on the surface of the gastric fluids. After the gelatin the preparation in the stomach [120]. Almagate Flot-shell dissolves, a mucus body is formed that consists Coat is another novel antacid formulation that

of the active drugs and other substances. The drugs confers a higher antacid potency together with a

diffuse as successively hydrated boundary layers of prolonged GRT and a safe as well as extended

the matrix dissipate [67]. delivery of antacid drug [121]. It is obvious that

Valrelease is a second example of a floating these newer formulations differ from the standard

capsule, marketed by Hoffmann-LaRoche, that con- antacid products, which are either rapidly neutralized

tains 15 mg diazepam; the latter is more soluble at to water-soluble ions or sediment to the fundus of the

low pH. Thus, diazepam (pK53.4) absorption is stomach, and are evacuated into the duodenum byamore desirable in the stomach, not in the intestine normal peristalsis [121].


15/25


4. Development and evaluation of FDDS ments of various excipients, these authors concluded

that higher molecular weight polymers and slower4.1. Formulation development rates of polymer hydration are usually associated

with enhanced floating behavior. Therefore, the

For the optimum design of a CR oral dosage form, selection of high molecular weight and less hydro-the key step is to understand the principles of GI philic grades of polymers seems to improve floating

dynamics such as gastric emptying, small intestinal characteristics [29]. However, there are certain unde-

transit, colonic transit, etc. [122]. Acquiring knowl- sirable properties associated with hydrophilic poly-

edge about the rate and extent of drug absorption mers. For instance, a capsule containing hydrophilic

from different sites of GI tract, and factors that can minimatrices (minitablets) has a stronger tendency

alter or limit the absorption further aid in designing to quickly form a single cohesive mass in vivo, due

the type of dosage form that is needed for a to the imbibed gastric fluids, which would be emp-

particular drug. For instance, with drugs such as tied from the stomach as such [127]. In fact, such

sulpiride, furosemide, theophylline and albuterol capsules exhibit a tendency to adhere to one another

which are predominantly absorbed from the upper before being administered orally, which is due to the

part of the GI tract, designing a gastroretentive inherent nature of gelatin capsule shells and thedosage form is a logical strategy for improving and hydration of the minitablets on storage. Rouge et al.

extending their limited oral bioavailabilities [54] have described two different approaches to

[7,32,123,124]. With the advent of g-scintigraphy, it circumvent this problem: (1) addition of a protective

is now possible to understand the various physiologi- filler excipient into the capsule, and (2) coating the

cal and pharmaceutical factors involved in oral drug minitablets with Eudragit NE30D (ethyl acrylate/

delivery [125]. One of the most reliable and novel methylmethacrylate), which is insoluble in gastric

approaches includes the use of the InteliSiteE Cap- juice but permeable and swellable. Thus, prevention

sule, which provides quick assessment of the oral of aggregation improves the dispersion of minitab-

absorption of drugs within specific regions of the GI lets, thereby increasing the contact surface area of

tract. The method is simple, operator-controlled, tablets with the medium, which may increase the

non-invasive, and leads to cost-effective develop- drug release.

ment of novel oral DDS [126]. Further, as the Fforms show prolonged and more reproducible GRTs 4.2. In vitro and in vivo evaluation

compared to NF [49], the former would be a

preferred choice for a gastroretentive dosage form. The various parameters that need to be evaluated

For the formulation of a HBS dosage form, three for their effects on GRT of buoyant formulations can

major conditions must be met [64]: (i) it must have mainly be categorized into following different

sufficient structure to form a cohesive gel barrier; (ii) classes.

it must maintain an overall specific gravity lower

than that of gastric contents (reported as 1.0041.01 1. Galenic parameters: diametral size (cut-off

g/ cc); and (iii) it should dissolve slowly enough to size), flexibility and density of matrices.

serve as a reservoir for the delivery system. 2. Control parameters: floating time, dissolution,

The task of designing a dosage form to achieve a specific gravity, content uniformity, and hardnessconsistent and controlled residence in the stomach and friability (if tablets).

begins with selection of potential excipients that 3. Geometric parameters: shape.

allow the formulation of matrices having sustained 4. Physiological parameters: age, sex, posture, food,

delivery characteristics and a bulk density of less and bioadhesion.

than unity. Ideally water-soluble cellulose derivatives

are best suited for such purposes. Gerogiannis and The test for buoyancy and in vitro drug release

co-workers [29,113] have described the floating and studies are usually carried out in simulated gastric

swelling characteristics of commonly used excipi- and intestinal fluids maintained at 378C. In practice,

ents. From the results of resultant-weight measure- floating time is determined by using the USP dis-


16/25


integration apparatus containing 900 ml of 0.1 N blades were positioned at the surface of the dissolu-

HCl as a testing medium maintained at 378C. The tion medium. The results obtained with this modified

time required to float the HBS dosage form is noted paddle method showed reproducible biphasic-release

as floating (or floatation) time. dissolution profiles when paddle speeds were in-

Dissolution tests are performed using the USP creased from 70 to 100 rpm and the dissolutiondissolution apparatus. Samples are withdrawn medium pH was varied from 6.0 to 8.0. The dissolu-

periodically from the dissolution medium, re- tion profile was also unaltered when the bile acid

plenished with the same volume of fresh medium concentration in the dissolution medium was in-

each time, and then analyzed for their drug contents creased from 7 to 14 mM. In contrast, the standard

after an appropriate dilution. Recent methodology as paddle or basket methods as described in the BP

described in USP XXIII states The dosage unit is (1993) were unable to provide either sufficient

allowed to sink to the bottom of the vessel before mixing of the dissolution medium to disperse oily

rotation of the blade is started. A small, loose piece rapid release material or sufficient mechanical ero-

of nonreactive material such as not more than a few sion of the SR component of the formulation.

turns of a wire helix may be attached to the dosage In additional studies [129], the authors modified a

units that would otherwise float. However, standard standard dissolution vessel for more reliable assess-dissolution methods based on the USP or British ment of the performance of floating dosage forms,

Pharmacopoeia (BP) have been shown to be poor particularly those which rely on an erosion mecha-

predictors of in vitro performance for floating dosage nism for drug release. The results showed a more

forms [128,129]. Pillay and Fassihi [128] investi- reproducible dissolution profile while eliminating the

gated the application of the helical wire sinker to the need for the positioning of the paddle blades at the

swellable floating system containing theophylline (a surface of the dissolution medium, thereby simplify-

sparingly water-soluble drug). They observed that ing sampling procedures and preventing adhesion of

the procedure tends to inhibit the three-dimensional dosage forms to the paddle blades. Nevertheless, the

swelling process of the dosage form and conse- method retained its ability to differentiate between

quently drug release from the formulation was acceptable and unacceptable dissolution perform-

suppressed. Based on their observations, the authors ance.

proposed an alternative method in which the float- The specific gravity of FDDS can be determinedable delivery system was fully submerged under a by the displacement method using analytical grade

ring / mesh assembly. The results showed significant benzene as a displacing medium [33]. Timmermansincrease in drug release (.20%). In addition, the and Moes [30] recommended that the initial (dry

proposed method was found to provide reproducible state) bulk density of the dosage form and changes in

hydrodynamic conditions and consistent release pro- the floating strength with time should be character-

files. However, in the case of a swellable floating ized prior to in vivo comparison between F and NF

system, which contained diltiazem (a highly water- units. Further, the optimization of floating formula-

soluble drug), the authors did not find any difference tions should be realized in terms of stability and

in release between the proposed method and the USP durability of the floating forces produced, thereby

method. These finding led to the conclusion that drug avoiding unforeseeable variations in floating capa-

release from swellable floating systems depends on bility that might occur during in vivo studies. Thesefull surface exposure, unhindered swelling and the investigators have also described a method for

drug solubility in water. determining the buoyant capabilities of the F forms

Another attempt to modify official dissolution and the sinking characteristics of the NF forms

methods was made by Burns et al. [130] who [131,132]. The method involves the use of a special-

developed and validated an in vitro dissolution ly designed apparatus for measuring the total force

method for a floating dosage form which had both acting vertically on an object immersed in a liquid.

rapid release and SR properties. The method, al- The technical details of the apparatus used in this

though based on the standard BP (1993) / USP (1990) method have been described elsewhere [131,133].

apparatus 2 method, was modified such that paddle The in vivo gastric retentivity of a floating dosage


17/25


form is usually determined by g-scintigraphy [42] or Madopar formulation is essentially complete in less

roentgenography [53,81,95]. Studies are done both than 30 min [67]. Pharmacokinetic (PK) studies in

under fasted and fed conditions using F and NF Parkinsonian patients and healthy volunteers have

(control) dosage forms. It is also important that both also revealed that Madopar HBS behaves as a

dosage forms are nondisintegrating units, and human controlled / slow-release formulation of L-dopa andsubjects are young and healthy. benserazide [43,134]. In comparison with standard

Madopar , the rate of absorption was reduced,

providing lower peak concentrations of L-dopa.

5. Advantages, future potential, and limitations Further, the drug was released and absorbed over a

of FDDS period of 45 h, thus maintaining substantial plasma

concentrations for 68 h after dosing [43].5.1. Sustained drug delivery Desai and Bolton [7] compared the dissolution

profiles of floating theophylline CR tablet (300 mg)

As mentioned earlier, drug absorption from oral and a commercial SR tablet (Theo-Dur ; 300 mg).

CR dosage forms is often limited by the short GRT They found that floating tablets showed a more

available for absorption. However, HBS type dosage gradual release of the drug. The initial release rateforms can remain in the stomach for several hours was found to be comparatively faster, with a slower

and, therefore, significantly prolong the GRT of rate after 8 h. On the other hand, the release rate of

numerous drugs (Table 3). These special dosage Theo-Dur was slower initially but increased later.

forms are light, relatively large in size and do not However, these differences were not statistically

easily pass through the pylorus, which has an significant, and two formulations were regarded as

opening of approximately 0.91.9 cm [18]. It is bioequivalent.

worth noting here that a prolonged GRT is not

responsible for the slow absorption of a lipophilic 5.2. Site-specific drug delivery

drug such as isradipine that has been achieved with a

floating modified-release capsule [31]. This is A floating dosage form is a feasible approach

because the major portion of drug release from the especially for drugs such as furosemide and ribo-

modified-release capsule took place in the colon, flavin, which have limited absorption sites in therather than in the stomach. However, the assumed upper small intestine. In fact, the absorption of

prolongation in the GRT is postulated to cause furosemide has been found to be site-specific, the

sustained drug-release behavior [41]. stomach being the major site of absorption, followed

A recent study by a Chinese group indicated that by the duodenum [123]. This property prompted the

the administration of diltiazem floating tablets twice development of a monolithic floating dosage form

a day may be more effective compared to normal for furosemide, which could prolong the GRT, and

tablets in controlling the blood pressure of hyperten- thus its bioavailability was increased [66]. Recently,

sive patients [78]. Although there was no significant a bilayer floating capsule has been used to achieve

difference between the two formulations in terms of local delivery of misoprostol at the gastric mucosa

maximal decreases in systolic and diastolic pressure, level [35]. It is a synthetic prostaglandin E analog1

the duration of hypotensive effects was longer with approved and marketed in the US (as Cytotec ) forfloating tablets than that with normal ones. Further, prevention of gastric ulcers caused by non-steroidal

the t (6.464.4 h) and C (56623 ng/ ml) were anti-inflammatory drugs (NSAIDs). Basically it re-1 / 2 maxlonger and lower for floating tablets than those of plenishes the GI-protective prostaglandins that are

normal tablets (2.361.1 h and 96630 ng/ml, P, depleted by NSAIDs. Thus, the controlled, slow

0.01), respectively; however, the two formulations delivery of misoprostol to the stomach provides

were bioequivalent. sufficient local therapeutic levels and limit the

In case of Madopar HBS, the formulation has systemic and intestinal exposure to the drug. This

been shown to release levodopa for up to 8 h in reduces the side effects that are caused by the

vitro, whereas the release from the standard presence of the drug in the blood circulation


18/25


(uterotonic activity), or a combination of intestinal Pharmacokinetic studies by Miyazaki et al. [59]

and systemic exposure (diarrhea), while maintaining demonstrated that floating granules of indomethacin

its antiulcer efficacy. In addition, the prolonged prepared with chitosan were superior to the conven-

gastric availability of the misoprostol from a site- tional commercial capsules in terms of the decrease

directed delivery system may also reduce the dosing in the peak plasma concentration and maintenance offrequency [135]. Floating tablets containing 2050 indomethacin concentration in plasma. The values of

mg of 5-fluorouracil have been successfully evalu- various bioavailability parameters are shown in

ated in four patients with stomach neoplasms in Table 4. There are only few instances in which the

which tablets remained floating in the stomach for a relative bioavailability of a floating dosage form is

period of 2 h after administration [79]. reduced compared to the conventional dosage form.

An illustrative example is that of SR floating tablets5.3. Pharmacokinetic advantages and future of amoxycillin trihydrate the in vivo evaluation of

potential which in healthy fasted males indicated that the

relative bioavailability was reduced to 80.5% when

As sustained release systems, floating dosage compared with the conventional capsules; other

forms offer various potential advantages evident pharmacokinetic parameters indicated no improvedfrom several recent publications. Drugs that have efficacy even though the tablets remained buoyant

poor bioavailability because their absorption is re- for 6 h and had a satisfactory release pattern in vitro

stricted to the upper GI tract can be delivered [74]. However, the lower bioavailability of drugs

efficiently thereby maximizing their absorption and could be balanced in part by potential clinical

improving their absolute bioavailabilities. For in- advantages of FDDS, and may be compensated by

stance, a significant increase in the absolute bioavail- taking a higher daily dose. For instance, in patients

ability of the floating dosage form of furosemide has with advanced Parkinsons disease, who experienced

been obtained (42.9%), compared to the commercial- pronounced fluctuations in symptoms while on stan-

ly available tablet (Lasix ; 33.4%) and enteric dard L-dopa treatment, a HBS dosage form provided

product (Lasix long; 29.5%) (Table 4). Further- a better control of motor fluctuations [136,137] (for

more, among these three dosage forms, only the review, see Ref. [138]), although its bioavailability

floating dosage form yielded satisfactory in vitro had been found to be 50 to 60% of the standardresults that were significantly correlated (P,0.05) formulation [134,139]. There were significant im-

with in vivo absorption kinetics. The findings of this provements with regard to both akinetic and

study were based on a previous postulation that dyskinetic phenomena.

site-specific absorption and longer GRT could pos- The reduced fluctuations in the plasma levels of

sibly increase the bioavailability of furosemide drugs result from delayed gastric emptying. After

[123]. Similar observations were made by Ichikawa oral dosing the bioavailability of standard Madopar

et al. [81] who found that floating pills containing has been found to be 6070%; the difference in

p-aminobenzoic acid, a drug with a limited absorp- bioavailabilities of standard and HBS formulations

tion site in the GI tract, had 1.61 times greater AUC seems to be due to incomplete absorption rather than

than the control pills (32.2966.06 vs. 20.1065.81 an altered disposition of the drug [43]. Cook et al.

mg?h/ ml). These authors, however, did not find any [140] demonstrated that a HBS capsule containingsignificant difference in bioavailabilty of isosorbide- iron salts has an increased efficacy and reduced side

5-nitrate when floating and control pills were com- effects. Floating dosage forms with SR characteris-

pared. This difference in results could be explained tics can also be expected to reduce the variability in

by the fact that isosorbide-5-nitrate is well absorbed transit performance [50] and various phar-

from both the stomach and small intestine. Thus, macokinetic parameters [134]. It might be expected

prolonging the GRT of a dosage form appears to that developing HBS dosage form for tacrine might

offer no advantage (in terms of bioavailability) for provide a better delivery system and reduce its GI

drugs with multiple absorption sites in the GI tract side effects in Alzeihmers patients. In addition,

[1]. buoyant delivery systems might provide a beneficial


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Table 4a

Comparative pharmacokinetic parameters for floating (F) and non-floating (NF) dosage forms

Drugs Numbers Oral dose C (mg/ ml) AUC (mg?h/ml) t (h) t (h)max u` max 1 / 2

of subjects (mg)

F NF F NF F NF F NF

b c c cAcetaminophen [72] 6 500 2.027 10.399 27.025 32.348 3.00 0.67 NR NR

(0.692.787) (7.73614.086) (8.72544.267) (11.25945.872) (0.55.0) (0.51.0)d d d

1.467 20.283 3.50

(0.5601.944) (3.76241.103) (2.05.0)

e f c f c f cAmoxycillin [74] 6 500 2.933 6.833 15.283 18.967 3.667 1.917 NR NR

(0.763) (1.989) (5.043) (4.167) (1.862) (1.068)

g c c c cAtenolol [76] 6 25 0.091 0.167 1.021 1.228 5.3 2.6 11.3 7.1

(0.032) (0.053) (0.507) (0.354) (1.5) (0.9) (8.1) (1.5)d d d d

0.068 0.876 3.7 9.9

(0.023) (0.174) (1.2) (5.2)

h F,f f f f f Furosemide [66] 6 30 0.323 0.127 0.982 0.66 1.05 2.01 2.05 3.33

(0.102) (0.026) (0.186) (0.121) (0.22) (0.43) (0.44) (1.19)c c c c c

40 0.431 1.02 0.53 3.07

(0.071) (0.051) (0.12) (0.714)

i j c j c j cIndomethacin [59] 3 25 3.62 5.76 11.63 9.39 1.52 0.51.5 NR NR

(1.75) (2.11) (3.12) (2.51)k f k f k f

2.23 2.59 10.65 9.37 36 12 NR NR

(0.33) (0.35) (2.30) (1.56)

l g g g g g g gIsradipine [31] 5 10 0.00082 0.0132 0.0114 0.0283 24 1.5 13.5 NR

(0.000660.00107) (0.003870.0182) (0.01060.015) (0.01390.0357) (24) (11.5) (7.726.5)m m m m m m

0.64 24.5 0.42 21.7 0.5 1.0

(0.38 24.6 ) (15.6 105) (0.16 8.59 ) (7.35 66.2) (0.25 0.75 ) (0.5 1.25)

b f f f Theophylline [7] 6 300 3.04 3.69 105.77 92.19 10.83 8.0 NR NR

(0.77) (1.28) (54.48) (46.45) (7.86) (0.0)

f c f c f cUrsodeoxycholic 12 450 5.65 5.53 29.3 30.5 3.67 3.0 NR NR

nacid [70] (0.65) (1.16) (3.4) (4.9) (0.99) (0.86)

d,f d,f d,f 8.67 39.5 4.17

(2.07) (8.5) (1.35)

aValues represented as mean (6S.D. or range) except for isradipine in which median value is listed for each parameter; NR, not reported.

bData obtained from saliva of healthy human volunteers (fasted).

cImmediate release formulations.

dHigh density formulations.

eAUC

0 1 2 hf

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 .

jDrugchitosan ratio51:0.5

kDrugchitosan ratio51:2

lAUC

0 2 4 hm

Data obtained from gastric juice of healthy human volunteers (fasted), C as mg /g and AUC as mg?h/g).max 0 24 hn

C as mmol / l and AUC as mmol?h/l.max 0 8 h

strategy for the treatment of gastric and duodenal development of various anti-reflux formulations.

cancers. Washington et al. [141] investigated the gastric

The concept of FDDS has also been utilized in the distribution and residence time of a pectin-containing


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formulation. They observed that the formulation was can be expected that topical delivery of a narrow-

able to float and form a discrete phase on top of the spectrum antibiotic through a FDDS may result in

stomach contents. Indeed, the product emptied from complete removal of the organisms in the fundal area

the stomach more slowly than the food (P,0.05), of the gastric mucosa due to bactericidal drug levels

and more than 50% of the formulation remained in being reached in this area, and might lead to betterthe fundal region for 3 h. Atyabi et al. [114] reported treatment of peptic ulcer disease.

a floating system prepared from anionic exchange

resins that could also be used as a protective barrier 5.4. Limitations

(floating seal) against gastroesophageal reflux.

Todd and Fryers [117] have described a similar One of the disadvantages of floating systems is

pharmaceutical composition that could be used in the that they require a sufficiently high level of fluids in

treatment of biliary gastritis, which results from the stomach for the drug delivery buoy to float

duodeno-gastric reflux of bile into the stomach. therein and to work efficiently. However, this limita-

Apart from aforementioned advantages, floating sys- tion can be overcome by coating the dosage form

tems are particularly useful for acid-soluble drugs with bioadhesive polymers, thereby enabling them to

[6], drugs which are poorly soluble or unstable in adhere to the mucous lining of the stomach wallintestinal fluids [142], and those which may undergo [80]. Alternatively, the dosage form may be adminis-

abrupt changes in their pH-dependent solubility due tered with a glass full of water (200250 ml).

to factors such as food, age and pathophysiological Floating systems are not feasible for those drugs that

conditions of the GI tract. have solubility or stability problems in gastric fluids.

Developing controlled release systems for such Drugs such as nifedipine, which is well absorbed

drugs as bromocriptine might lead to potential along the entire GI tract and which undergoes

treatment of Parkinsons disease. After oral adminis- significant first-pass metabolism, may not be desir-

tration, approximately 30% of the dose is absorbed able candidates for FDDS since the slow gastric

from the GI tract [143]. However, its low absorption emptying may lead to reduced systemic bioavail-

potential, which often results from low dose usage, ablity [1]. Also there are limitations to the ap-

might be improved by a HBS dosage form, which plicability of FDDS for drugs that are irritant to

could significantly enhance its therapeutic efficacy. gastric mucosa.Furthermore, the co-delivery of bromocriptine and

metoclopramide based on a dual delivery concept

similar to that of the Madopar HBS might further 6. Conclusions

improve the therapeutic efficacy of the HBS dosage

form. The use of metoclopramide, a standard an- The currently available polymer-mediated nonef-

tiemetic agent, is justifiable since it can prevent the fervescent and effervescent FDDS, designed on the

side effects caused especially by high doses of basis of delayed gastric emptying and buoyancy

bromocriptine [144]. principles, appear to be an effective and rational

Another therapeutic area in which FDDS can be approach to the modulation of controlled oral drug

explored is the eradication of Helicobacter pylori, delivery. This is evident from the number of com-

which is now believed to be the causative bacterium mercial products and a myriad of patents issued infor chronic gastritis and peptic ulcers. Although the this field. The FDDS become an additional advan-

bacterium is highly sensitive to most antibiotics, its tage for drugs that are absorbed primarily in the

eradication from patients requires high concentra- upper segments of GI tract, i.e., the stomach,

tions of drug be maintained within the gastric duodenum, and jejunum. Some of the unresolved,

mucosa for a long duration [145]. Recently critical issues related to the rational development of

Katayama et al. [146] developed a SR liquid prepara- FDDS include (1) the quantitative efficiency of

tion of ampicillin using sodium alginate that spreads floating delivery systems in the fasted and fed states;

out and adheres to the gastric mucosal surface (2) the role of buoyancy in enhancing GRT of

whereby the drug is continuously released. Thus, it FDDS; and (3) the correlation between prolonged


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Floating DDS Main

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