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Journal of Controlled Release 90 (2003) 143162

www.elsevier.com/locate/jconrel

Review

Expandable gastroretentive dosage formsa b a a ,*Eytan A. Klausner , Eran Lavy , Michael Friedman , Amnon Hoffman

aDepartment of Pharmaceutics,School of Pharmacy,Faculty of Medicine,The Hebrew University of Jerusalem POB 12065,

Jerusalem 91120,IsraelbClinical Sciences Department,The School of Veterinary Medicine,The Hebrew University of Jerusalem,Rehovot76100,Israel

Received 31 January 2003; accepted 16 April 2003

Abstract

Expandable gastroretentive dosage forms (GRDFs) have been designed for the past 3 decades. They were originally

created for possible veterinary use, but later the design was modified for enhanced drug therapy in humans. These GRDFs

are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong

their gastric retention time (GRT). After drug release, their dimensions are minimized with subsequent evacuation from the

stomach. Gastroretentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to

withstand the peristalsis and mechanical contractility of the stomach. Positive results were obtained in preclinical and clinical

studies evaluating GRT of expandable GRDFs. Narrow absorption window drugs compounded in such systems have

improved in vivo absorption properties. These findings are an important step towards the implementation of expandable

GRDFs in the clinical setting. The current review deals with expandable GRDFs reported in articles and patents, anddescribes the physiological basis of their design. Using the dog as a preclinical screening model prior to human studies,

relevant imaging techniques and pharmacokineticpharmacodynamic aspects of such delivery systems are also discussed.

2003 Elsevier Science B.V. All rights reserved.

Keywords:Controlled release; Gastroretentive; Expansion; Unfolding; Swelling; Narrow absorption window drugs

1. Introduction ever, this approach has not been suitable for a variety

of important drugs, characterized by a narrow ab-

Oral controlled release (CR) dosage forms (DFs) sorption window in the upper part of the gastroin-

have been developed for the past 3 decades due to testinal tract i.e. stomach and small intestine. This istheir considerable therapeutic advantages [1]. How- due to the relatively short transit time of the DF in

these anatomical segments. Thus, after only a short

period of less than 6 h, the CR-DF has already left

Abbreviations: CR, controlled release; DF, dosage form; GRT, the upper gastrointestinal tract and the drug isgastric retention time; GRDF, gastroretentive dosage form; released in nonabsorbing distal segments of theIMMC, interdigestive myoelectric motor complex; SPH, superpor- gastrointestinal tract. This results in a short absorp-ous hydrogel

tion phase that is often accompanied by lesser*Corresponding author. Tel.: 1972-2-675-8667; fax: 1972-2-

bioavailability.675-7246.E-mail address: [email protected](A. Hoffman). The medications that are included in the category

0168-3659/03/$ see front matter 2003 Elsevier Science B.V. All rights reserved.

doi:10.1016/S0168-3659(03)00203-7
mailto:[email protected]:[email protected]

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144 E.A.Klausner et al. /Journal of Controlled Release 90 (2003) 143162

of narrow absorption window drugs are mostly varies according to the amount of distention: up to

associated with improved absorption at the jejunum 1500 ml [9] following a meal; after food has

and ileum due to their enhanced absorption prop- emptied, a collapsed state is obtained with a resting

erties e.g. large surface area, in comparison to the volume of only 2550 ml [10]. The stomach is

colon; or because of the enhanced solubility of the composed of the following parts: fundus, above thedrug in the stomach as opposed to more distal parts opening of the esophagus into the stomach; body, the

of the gastrointestinal tract[2]. central part; and antrum. The pylorus is an ana-

It was suggested that compounding narrow absorp- tomical sphincter situated between the most terminal

tion window drugs in a unique pharmaceutical DF antrum and the duodenum[11].The fundus and the

with gastroretentive properties would enable an body store food temporarily, secrete digestive juices

extended absorption phase of these drugs. After oral and propulse chyme, a milky mixture of food with

administration, such a DF would be retained in the gastric juices, to the antrum. The antrum grinds and

stomach and release the drug there in a controlled triturates food particles and regulates the secretion of

and prolonged manner, so that the drug could be hydrochloric acid as well as the emptying of food

supplied continuously to its absorption sites in the [12].

upper gastrointestinal tract. This mode of administra- Fasting gastric pH is usually steady and approxi-

tion would best achieve the known pharmacokinetic mates 2, but there are short periods of 766 min

and pharmacodynamic advantages of CR-DFs for characterized by higher values. Food buffers and

these drugs[3]. neutralizes gastric acid, thus increasing the pH up to

The need for gastroretentive dosage forms about 6.5. After meal-ingestion is completed, the pH

(GRDFs) has led to extensive efforts in both rapidly falls back below 5 and then gradually

academia and industry towards the development of declines to fasting state values over a period of a few

such drug delivery systems [4]. These efforts re- hours[13]. In the elderly population approximately

sulted in GRDFs that were designed in large part 20% are hypochlorhydric i.e. with reduced but not

based on the following approaches [2]: (a) low absent gastric secretion, whereas the remainder have

density form of the DF that causes buoyancy above acid production similar to young people[14].

gastric fluid[5];(b) high density DF that is retained The pyloric sphincter has a diameter of 12.867

in the bottom of the stomach; (c) bioadhesion to the mm in humans[15,16]and acts as a sieve as well asstomach mucosa [6]; (d) slowed motility of the a mechanical stricture to the passage of large par-

gastrointestinal tract by concomitant administration ticles [12]. The duodenal pH is 6.1 [13] and its

of drugs or pharmaceutical excipients[7];(e) expan- epithelial surface contains transporters for peptides

sion by swelling or unfolding to a large size which [17] and metals [18,19]. The transit time in the

limits emptying of the DF through the pyloric duodenum is relatively short, less than 1 min[2].

sphincter. The current review deals with the expand- The small intestine has a large surface area, which is2

able GRDF approach that has recently become the comparable to the area of a basketball court, 463 m

leading methodology in this field. [20]. This is the main reason it is the primary

absorption site of water, ions, vitamins and nutrients

such as amino acids, fats and sugars. In addition, the

2. Biological aspects of GRDFs digestion of fats, peptides and sugars occurs in thissegment of the gastrointestinal tract[11].The pH of

2.1. Role of the gastrointestinal tract the small intestine is 67[21].The transit time in the

small intestine of 361 h[22], is relatively constant

To comprehend the considerations taken in the and is unaffected by food[21].

design of GRDFs and to evaluate their performance The colon has some absorption properties of water

the relevant anatomy and physiology of the gastroin- and ions [11]. Certain drugs [23] and especially

testinal tract must be fully understood. The stomach peptide molecules [24] are also absorbed. This is

is situated in the left upper part of the abdominal despite the lack of villi, which leads to small surface

cavity immediately under the diaphragm[8].Its size area[10].

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E.A.Klausner et al. /Journal of Controlled Release 90 (2003) 143162 145

2.2. Gastric motility and emptying of food from 50% emptying of 818 min. Solids empty much

the stomach more slowly than liquids. Digestible nonfat solids are

first ground for up to 1 h, then emptied in zero order

The motility of the stomach is mostly contractile, kinetics. Solid or semisolid fats, after being con-

which causes food grinding into smaller particles, sumed and warmed to body temperature in themixing with gastric juices, forward and backward stomach, are converted into a liquid. Due to a

movements of gastric contents and emptying, with nervous mechanism inhibiting gastric peristalsis and

all of the actions occurring together[8,11].There is a floating over gastric liquids, liquid fats empty much

marked difference between motility in the fasting more slowly than aqueous liquids[12].

state and the fed state: the motoric activity in the In cases where the stomach contractions during

fasting state, termed interdigestive myoelectric motor food digestion and in the second phase of IMMC

complex (IMMC), is a 2-h cycle of peristaltic activity are unable to empty undigested matter,

activity that is generated in the stomach and pro- including nondisintegrating DFs, through the relaxed

gresses aborally to the ileocecal junction. Its aim is pyloric sphincter, a retropulsion reflex is activated to

to clear the stomach and the small intestine of deliver the material from the pylorus and distal

indigested debris, swallowed saliva and sloughed antrum to the proximal antrum and stomach body

epithelial cells [12]. It is composed of four phases: [2931].Gastric emptying also depends upon post-

phase 1 lasts 4560 min, is quiescent, with rare low ure[32],gender, age[33],osmolarity and pH of food

amplitude contractions; phase 2 with a length of [10],mental stress and disease state[20].

3045 min, has intermediate amplitude contractions

[25],and involves bile secretion[26];phase 3 is also 2.3. Emptying of DFs from the stomach

termed housekeeper wave and extends for 515

min. It is initiated in the stomach in most cases When nondisintegrating DFs, like other indigest-

(71%), or in the duodenum[12].Very high amplitude ible solids, are administered in the fasting state, they

contractions, with a frequency of 45 per min[10], typically are not retained in the stomach for over 2 h

and maximal pyloric opening[27],characterize this due to the IMMC. On the other hand, in the fed

phase. This enables efficient evacuation of the stomach the gastric retention time (GRT) of non-

stomach contents; phase 4 has a length of less than 5 disintegrating DFs depends mostly on the DF size asmin and connects between the maximal amplitude well as the composition and the caloric value of food

contractions to the basal phase[25]. [34]: indigestible spheres smaller than 1 mm in

The motor activity in the fed state is induced 510 diameter freely pass into the intestine, often at rates

min after ingestion of a meal and persists as long as faster than solid nutritive food. Spheres with diame-

food remains in the stomach. The larger the amount ters of 12.4 mm pass with the calorie-containing

of food ingested, the longer the period of fed components of a solid meal[12].

activity, with usual time spans of 26 h, and more In general, the GRT of DFs and in particular large

typically, 34 h. Its phasic contractions are similar to DFs, is longer in the fed state in comparison to the

those seen during phase 2 of the IMMC. The fasting state. Large DFs are retropelled from the

stomach churns food while suspended fine particles, pyloric-antrum for further digestion and evacuation

typically in a size of less than 1 mm [12], are in the end of the fed state, or are retained until theemptied every 20 s to the duodenum [11]. This arrival of the subsequent housekeeper wave. In

controlled rate enables proper digestion and absorp- such cases, the GRT is a function of the length of the

tion of the food in the small intestine [28]. digestive process. Thus theoretically, continuous

Generally, the residence time of the food in the feeding can prolong GRT of the DF for more than 24

stomach depends upon its nutritive and physical h[20].

properties: emptying of liquid nutrients has a rate of Efforts were made to identify a cut-off size above21

200 kcal h , regardless of whether those calories which the DF will be retained in the stomach for

are in the form of fats, proteins or carbohydrates. prolonged periods of times. Large DFs, such as

Non-nutrient liquids empty rapidly, with a time to 13 mm diameter nondisintegrating tablets, were

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retained in the stomach for 171629 min, almost an emptying pattern, or other local adverse effects e.g.

hour more than 7-mm tablets, after a light breakfast on the gastrointestinal wall; prolonged shelf-life;

of 360 kcal[35].It was suggested that 7-mm tablets inexpensive industrial manufacture.

empty during the fed state while 13-mm tablets are

retained until arrival of the subsequent sweeping 3.2. Expandable GRDFshousekeeper wave. This emphasizes the need for

substantial size enlargement of the DF at the stomach 3.2.1. Underlying principle

in order to prolong GRT. The expandable GRDFs are usually based on three

In addition to some prolongation in GRT due to configurations: a small (collapsed) configuration

the retropulsion reflex, gastroretentivity may simply which enables convenient oral intake; expanded form

be achieved by large dimensions that are physically that is achieved in the stomach and thus prevents

unable to pass through the pyloric sphincter. The passage through the pyloric sphincter; and finally

dimensions which are desirable in order to prevent another small form that is achieved in the stomach

rapid evacuation of DFs from the human stomach when retention is no longer required i.e. after the

can be determined from reports on foreign bodies GRDF has released its active ingredient, thereby

retained in the stomach where medical intervention enabling evacuation.

was required to draw them out using gastroscopy The expansion can be achieved by swelling or by

(see Section 4.4). It has been suggested that the size unfolding in the stomach. Swelling usually occurs

is a length of more than 5 cm or a diameter larger because of osmosis. Unfolding takes place due to

than 3 cm[36].As opposed to foreign bodies, DFs mechanical shape memory i.e. the GRDF is fabri-

should be tailored to degrade, disintegrate, be mini- cated in a large size and is folded into a pharma-

mized in size or collapse in the stomach at a ceutical carrier e.g. a gelatin capsule, for convenient

plausible time interval i.e. before the subsequent intake. In the stomach, the carrier is dissolved and

dosing time. the GRDF unfolds or opens out, to achieve extended

The housekeeper wave does not always com- configuration. The unfolding occurs when polymeric

pletely clear the stomach from nondisintegrating DFs matrices, known or designed to have suitable me-

[28]. For instance, a radiotelemetric capsule for pH chanical properties, are used with some emphasis on

measurements (Heidelberg capsule, 2538 mm, appropriate storage conditions of the GRDF. Thelength3diameter) was randomly retained in the storage should maintain unfoldable properties for

stomach of one healthy subject from a group of eight extended time spans. As apparent from this review,

for over 12 h. During that time three housekeeper much artwork regarding expandable GRDFs, and this

waves were recorded[37].Other studies supported is true also for GRDFs based on other approaches,

that a radiotelemetric capsule is unable to induce fed has only been described in patents.

state motility[38].

3.2.2. Pioneering expandable GRDFs

The pioneering design of GRDFs based on unfold-

3. Pharmaceutical aspects of expandable GRDFs ing to a large configuration, was conducted by Laby

[39] for veterinary applications. These DFs were

3.1. Optimal GRDF constructed for ruminants and particularly for releas-ing in a controlled manner bloat-preventing surfac-

In designing GRDFs, the following characteristics tants in bovines. At a later time, drug delivery

should be sought: retention in the stomach according systems for clinical applications use many of the

to the clinical demand; convenient intake; ability to principles described in this invention.

load substantial amounts of drugs with different The device has a first configuration which enables

physicochemical properties and release them in a oral intake and a second configuration which pre-

controlled manner; complete degradation, preferably vents regurgitation, but still permits substantially free

in the stomach; FDA approved compounding in- movement of the DF in the rumen. Once in the

gredients; no effect on gastric motility including rumen, a special lobe termed obstructing means

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extends or protrudes from the drug-containing body able. Such devices for sheep typically weigh 8 g and

of the device thus inhibiting its evacuation. The contain 3.5 g of drug. Relevant drugs such as

mechanical property of resiliency induces opening of anthelmintics may be incorporated into the polymer

the obstructing means to its extended or protuber- sheet. Studies using devices which contained a

ant position (seeFig. 1). Since the unfolding of the nondegradable polymer, ethylene vinyl acetate co-DF to its large configuration is crucial for retention polymer, loaded with morantel citrate or levamisole

in the rumen, in cases where the mechanical prop- HCl showed in vitro release of the drug for a few

erties of the obstructing means do not induce months, with protection in sheep from worms for

opening to the second configuration, a special lobe similar times.

termed biasing means is added. The biasing A second generation of the above DFs[41],shown

means is comprised of hydrophilic and hydrophobic inFig. 2, had the same configuration but the DFs

materials connected together. In the presence of degraded after 612 weeks in the rumen due to

moisture such strips deform due to contraction or addition of degradable polymers to the matrices.

expansion of the hydrophilic material. Alternatively, Prolonged rumen retention as well as in vivo CR of

a strip which shrinks in the rumen milieu may induce an anthelmintic drug, parbendazole, for up to 6

opening. The device is designed to disintegrate in the weeks was proven by sacrificing sheep and measur-

rumen after ending its functional life. A ring-shape is ing the DFs drug contents.

the preferred configuration. The devices were shown

to protect cows against bloat, but their size of 1533

cm (length3diameter) was too large for human use.

Another unfolding DF for ruminants was de-

veloped by Brewer and Griffin [40]. This DF is

fabricated as an optionally multilayer insoluble poly-

meric sheet that opens from one configuration to the

other due to resiliency. The sizes vary according to

the ruminants species e.g. for sheep a size of 0.23

634 cm as thickness3length3width, may be suit-

Fig.2. Unfolding dosage form modified from Griffin and Brewer

Fig. 1. Unfolding dosage form modified from Laby [39], is [41],is designed for ruminants. The dosage form is composed of

designed for ruminants. Once the gelatin capsule (A) dissolves in an erodible sheet (A) which serves as a drug reservoir, attached to

the rumen, the hydrophobic/ hydrophilic strips (B) absorb water a nonerodible resilient sheet (B) which induces unfolding and

and deform, thus causing expansion to a size which prevents prolongs retention in the rumen. Gelatin strips (C) secure the

regurgitation. The drug diffuses through the permeable material dosage form in its folded configuration thus enabling administra-

(C) in a controlled manner. tion.

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Johnson and Rowe suggested the first GRDFs for the pyloric sphincter. After drug release, bioerosion

human use on the basis of expansion in the stomach or gradual diffusion of gas out of its compartment

[42]. The GRDF is a tablet comprised of thiolated enables achievement of collapsed state followed by

gelatin, a crosslinking agent and a drug. Once the DF expulsion from the stomach. The GRDF is adminis-

reaches the stomach the thiolated gelatin hydrates, tered in a gelatin capsule.swells and crosslinks to form a matrix too large to

pass through the pylorus. Optional additives for the 3.2.3. Swelling GRDFs

GRDF are a nondigestible hydrophilic colloidal Mamajek and Moyer [45] designed a GRDF

material which increases the swelling ratio i.e. the comprised of an envelope from an elastic or nonelas-

tablet swells to a larger size, and/ or a water soluble tic nonhydratable polymeric membrane, which is

salt which hastens the swelling rate. drug and body fluid permeable (see Fig. 4). The

Michaels[43,44]described swelling DFs intended envelope contains a drug reservoir and an expanding

for human use by constructing tubular GRDFs from agent i.e. a swellable resin or hydrocolloid which

a swelling retention arm bonded to a chamber which causes expansion by osmotic pressure. Such devices

contains a drug reservoir, a pressure generating of sizes larger than 1.531 cm were retained in the

compartment and a pressure responsive flexible dog stomach for prolonged periods of time, typically

bladder in between (see Fig. 3). The pressure more than 12 h. Models of drugs such as poldine

generating compartment contains a liquid with a methylsulfate and haloperidol, had prolonged phar-

boiling point close to body temperature or a solute macodynamic actions when administered in such

with a high osmotic pressure. In the stomach, the GRDFs in comparison to conventional DFs.

pressure inside the compartment is elevated due to Urquhart and Theeuwes [46] developed a DF,

creation of gas or diffusion of liquid thus its volume shown in Fig. 5, with a very high swelling ratio,

is increased. Thereby (a) pressure is exerted on the exhibiting a 250-fold volume increase. The pro-

bladder to reduce the volume of the drug reservoir posed mechanism of retention is not only due to

consequently inducing controlled drug release; and large dimensions, but also by maintaining the

(b) the retention arm is expanded to a size larger than stomach in the fed mode i.e. delaying the house-

keeper wave, presumably by mechanical sensation.

CR of the drug is achieved by incorporation into wax

Fig. 3. Swelling dosage form modified from Michaels[43].Oncethe gelatin capsule (A) reaches the stomach it dissolves and the

device (B) is exposed to the gastric milieu. Therefore, gas stored

in a liquified form in the pressure generating compartment (C)

causes vapor-pressure thus: the retention arm (D) swells and Fig.4. Swelling dosage form modified from Mamajek and Moyer

elevates retention in the stomach; pressure is exerted against the [45].Prior to administration the drug reservoir (A) is surrounded

pressure responsive bladder (E), which contains the drug reservoir by a swellable expanding agent (B) and the whole enclosed by

(F), and the medication is released in a controlled manner through elastic outer polymeric envelope (C), also controlling drug release

flow control means (G). At the end of the therapeutic regimen the rate. Postadministration, the pressure of the expanding agent (B)

bioerodible plug (H) erodes causing the pressure generating swells the elastic polymer (C). Drug is released from the dosage

compartment (C) to collapse. This enables evacuation from the form through the elastic polymeric envelope (C) as indicated by

stomach. the arrow.

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2.732.7 cm (length3diameter) in the dried state

swelled after 2.5 h in the stomach to a length of 3.6

cm and was retained there for more than 60 h.

Administration of riboflavin-5-phosphate containing

hydrogels to dogs maintained elevated blood con-centrations for up to 54 h, thus yielding a 3.7-fold

increase in bioavailability in comparison to oral

bolus.

3.2.4. Unfolding GRDFs

A study of unfolding devices characterized by

different erodibility, mechanical properties, sizes and

geometries was conducted by Caldwell and co-work-

ers[4951].The developed geometric configurations

were continuous stick, ring, tetrahedron, planar disc,

planar multilobe and string. These devices had the

following properties: sufficient resistance to forces

applied by the stomach, thus preventing rapid pas-

sage through the pylorus; allowance of free passage

of food while in residence in the stomach; and

desired in vivo circumference larger than 5 cm, to

ensure gastroretentivity.

In vivo results in beagle dogs showed that en-

hanced mechanical properties [52] and decreased

polymer erosion [53] increase gastroretentivity, as-

sessed as number of devices retained in the fasting

stomach at 24 h[52].The tetrahedron and the rigid

ring showed retention (.90%) of more than 24 hFig. 5. (i and ii) Dosage form which is retained in the stomach by[54]. The smaller geometrical figure, a 2-cm armsconcurrently swelling and keeping thestomach in the fed mode,tetrahedron, was further evaluated in Americanmodified from Urquhart and Theeuwes[46].(i) The dosage form,

seen in a view from the side and (ii) a cross-section of (i) in the foxhounds, larger dogs weighing 3040 kg, and indirection of the arrows. The dosage form comprises a body (A) humans. The results obtained in larger dogs and inshaped for oral administration and a hydrogel (B) which expands

humans were substantially different from the beaglein the presence of gastric fluids thereby releasing tiny pills (C) for

dog study. In American foxhounds, half of thecontrolled drug delivery.tetrahedra left the stomach in less than 2 h and only

17% of the tetrahedra were retained in the stomach

walled tiny pills dispersed throughout a hydrogel. for 24 h. In human volunteers, the tetrahedra left the

Bioerosion of the DF enables its evacuation from the stomach in the fasting state quickly with a median

stomach. The inventors did not address the feasibility GRT of 3 h and a range of 0.56 h. In the fed state,of an approach that repetitively affects normal most of the tetrahedra (90%) left the stomach in less

gastrointestinal motility as a consequence of DF than 10 h with a median GRT of 6.5 h and a range of

intake. 3.5 to more than 12 h.

Shalaby and co-workers [47,48] developed al- It was inferred that American foxhounds are a

bumincrosslinked polyvinylpyrrolidone hydrogels more predictive animal model for evaluating gas-

with swelling and degradation properties which can troretentivity of tetrahedra. While the differences in

be controlled by adjusting the degree of vinylic the outcomes of the human and beagle dog studies

functionality of the albumin crosslinker. A dog study are unequivocal, the results in human fed mode were

showed that a bulk-degrading hydrogel with a size of unsatisfactory for the researchers [54]. Lack of a

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control group under the same feeding conditions

makes evaluation of the devices performance tenta-

tive. Nevertheless, the median GRT achieved is

apparently prolonged and accordingly, may improve

drug therapy. Complete evacuation in less than 10 h,which was not achieved in this study, can be

regarded as a high safety profile whose consistency

is necessary for the clinical setting. However, these

devices did not contain drugs, and their loading

capacity seems limited.

A difficulty which might arise with unfolding

GRDFs is that the mechanical shape memory of their

polymeric constitution is not long enough. Thus the

prolonged stress applied during storage, reducesFig. 6. Unfolding dosage form modified from Sonobe et al.[56].resiliency and impedes the ability of the GRDFs toThe delivery system, having the shape, size and durability to

expand to the large configuration in the stomach.retain in the stomach for an extended time period, is composed of:This problem was addressed in connection with the (A) a shape memory material, which assures unfolding under

GRDFs developed by Caldwell et al., by Pogany and prolonged storage time spans; (B) an erodible material whichserves as a drug reservoir and whose rate of degradation controlsZentner[55]. They designed bioerodible thermosetthe gastric retention time; and (C) a part connecting A and B.covalently crosslinked elastomeric poly(ortho-esters)

with a prolonged shape memory. Thus, a three-

dimensional network structure induced dimensional stomach for more than 24 h. Exploratory nicardipine

stability and resiliency after compression for extend- CR tablets which were attached to such GRDFs had

ed periods of time. significantly higher bioavailability in comparison to

Sonobe et al.[56]developed unfolding DFs which identical CR tablets.

have the dimensions, shape and durability necessary The work of Curatolo and Lo [57] presents an

for prolonged gastroretentivity. The GRDFs contain unfolding spiral or coil configuration GRDF. It is

a material with prolonged shape memory, used to designed as a receptacle means that holds a drugprevent plastic deformation and ascertain elasticity, reservoir formed as a tablet or capsule, and one or

joined to or blended with an erodible material. Such more retention arms attached to it (seeFig. 7). The

shape memory polymers may have (a) a crosslinked retention arms, in the form of fibers or ribbons, have

structure and crystal structure below the melting the ability to stay in the stomach on their own. They

point, but an amorphous structure above the melting are characterized by: unfolding or uncoiling in the

point; or (b) glass transition (T ) at about room stomach to reach a circumference of more than 3 cm;gtemperature. The configurations may be constructed dissolution, degradation, disintegration, softening or

with at least three coplanar limbs extending from a detachment from the drug-containing device after

center, e.g. cylindrical-shape, cross-shape or Y-shape drug release; specific mechanical properties so as to

(seeFig. 6). The GRDF is folded at the site of the be flexible enough not to puncture the gastrointesti-

shape memory material. In order to fold the GRDF, nal wall and stiff enough to prevent evacuation froman external force is applied at a temperature higher the stomach.

than the melting point or glass transition of the shape GRDFs according to this invention, which had

memory substance e.g. 40 8C, to form the desired four short retention arms arranged concentrically

shape. The GRDF is then cooled to room tempera- around a tablet, were retained for more than 24 h

ture. The drug may be mixed with the erodible when administered to fasting beagle dogs, which

material. The rate of degradation of the erodible were fed their normal food 7 h postadministration.

material controls the GRT, as the shape memory On the other hand, devices having a single long

material can exit from the stomach on its own. retention arm arranged concentrically around the

Such GRDFs were retained in the beagle dogs fed tablet were not consistently retained in the stomach.

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after a period of several e.g. 12 h. In contrast, inside

the SPHs water flows through an open channel

system with pores of a few hundred micrometers, by

capillary effect. The rapid swelling occurring within

20 min, prevents premature emptying from thestomach by housekeeper wave. While SPHs are

characterized by low mechanical strength, addition

of a superdisintegrant e.g. croscarmellose sodium

(Ac-Di-Sol ), increases effective crosslinking den-

sity by physical entanglement, and yields a SPH

composite. Such a GRDF maintained its mechanical

strength and structural integrity in vitro. An in vivo

beagle dog study showed that SPH composite,

previously demonstrated to swell in simulated gastric

fluid to a size of 3.532.4 cm (length3diameter), wasFig. 7. Partially unfolded dosage form modified from Curatoloretained and maintained intact in the fed stomach for

and Lo[57]. The retention arms (A), which have the ability toretain in the stomach on their own, are adhered to a receptacle (B) more than 24 h. Administration to a fasting dogthat holds a controlled release tablet (C). The arms induce showed rapid evacuation.gastroretentivity of the dosage form.

Mechanical properties of the SPH composites

were tested using a bench comparator. The ultimate

compression pressure of the hydrogel composites,

Thus, successful retention relies on the configuration measured as 150 cmH O, was designed to be higher2of the attached retention arms which form the than values reported as applied in the stomach of

expanded coil. Administration of glipizide CR tablets 50130 cmH O. Following administration to fed2incorporated into such GRDFs to fasting beagle dogs, disintegration occurred after only a few hours,

dogs, which were fed 12 h postdose, showed eleva- followed by evacuation from the stomach. A sug-

tion of almost 2-fold in the bioavailability when gested explanation was that the pressure, abrasion

compared to identical CR tablets. and shear forces applied in the stomach were higherAnother finding was that resilient polyethylene than values reported in the literature. Using SPHs

fibers with dimensions of 1030.1 cm (length3 with substantially higher ultimate compression pres-

diameter) were retained in the stomach of beagle sure of 370 cmH O, prevented in vivo disintegration2dogs for more than 24 h. However, attachment of and the GRDFs were retained for more than 24 h

identical fibers to tablets shortened the GRT of the after eating.

combination to that of tablets alone. The approach of Klausner and co-workers[6265]designed rectan-

developing a GRDF which is retained in the stomach gular shaped unfolding GRDFs, which use a combi-

due to stealthing from gastric sensation has not yet nation of rigid components with large dimensions

been evaluated, probably due to the low payload of e.g. 532 cm, to enhance gastroretentivity. The

such DFs. GRDFs are compounded from thin polymeric mem-

branes: a drugpolymer matrix is surrounded by3.2.5. Recent developments in the field of rigid polymeric strips, all covered from both sides in

expandable GRDFs a sandwich form, by identical membranes, which

Chen and co-workers [5861] designed unique connect and maintain them intact. Each separate

superporous hydrogel (SPH) composites which com- component is designed to evacuate from the stomach

bine a high swelling rate and a ratio of more than rapidly while the combination of them all in this

100 times the original weight of the dried matrix platform yields prolonged GRT [66]. The GRDFs

with substantial mechanical strength. Conventional were retained in the stomach of dogs and of humans

hydrogels have relatively small pore sizes, and reach for prolonged and comparable time spans of at least

by diffusion of aqueous media equilibrium-swelling 5 h. In both species nondisintegrating tablets and

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large dimension low rigidity DFs were used as five of the ten subjects the tablets were retained for 6

control groups. h or more. In four of these five subjects the tablets

The drug payload in these GRDFs is a few were retained for 10 h or more[69].An experiment

hundred milligrams. Compounding of both soluble or on other swelling GRDFs in accordance with this

poorly soluble drugs in this platform, has shown in invention showed mean GRT values of less than 5.9vitro CR. Pharmacokinetic evaluation in dogs, of and mean upper gastrointestinal tract transit time of

riboflavin [62]and levodopa [63] incorporated into less than 9.5 h [71]. The lack of a control group

the GRDFs, has shown increased bioavailability in makes the evaluation of these GRDFs less definitive.

comparison to nongastroretentive CR-DFs. More- Pharmacokinetic performances of metformin and

over, studies in healthy volunteers demonstrated ciprofloxacin swelling GRDFs were compared to

enhanced pharmacodynamic actions i.e. diuresis and immediate release tablets following a standard break-

natriuresis, of furosemide [67]; and an extended fast of 500 kcal in healthy volunteers. Ciprofloxacin

absorption phase of levodopa in comparison to a GRDF showed equal bioavailability, longert andmax

nongastroretentive CR-DF, Sinemet CR , by about 2 lower C [72]. Metformin GRDFs released themaxh[68]. drug for 6 or 9 h in vitro. They had a diameter of 9

In order to overcome the difference between dog mm and swelled in vitro to 150% of their original

and human in basal gastric acidity during fasting size within 15 min. The in vivo findings showed that

state (see Section 4.1), 400 ml of acidic buffer were metformin GRDFs had a 17% or less increased mean

administered to the dogs via an oralgastric tube bioavailability, lowerC and about 2 h longertmax maxprior to DF administration. This had some delaying when compared to the immediate release tablet[70].

effect on gastric emptying, which did not interfere Another recent GRDF is a pouch with internal

with discrimination between GRDFs and control DFs dimensions of 232 cm to 2.532.5 cm, administered

[62].It is important to note that as conducted in this while incorporated into a capsule. After intake of a

research, it is preferred that studies involving healthy high fat meal these pouches were retained in the

volunteers are performed in the fed state, as patients human stomach for over 16 h[73].

cannot be expected to fast during the GRDFs Additional new developments in the field of

prolonged stay in the stomach. However, the amount expandable GRDFs are described in US Patents

of food administered should be such that differences 5651985, 6290989 and 6488962 and Internationalbetween GRDFs and nongastroretentive DFs may Application WO02085112. They are not detailed

still be observed unequivocally. here as their performances in vivo were not reported.

The GRDFs developed by Shell and co-workers

[6972]are swelling tablets which take advantage of 3.2.6. Safety of expandable GRDFs

the physiological fact that the fed mode prolongs In terms of safety, the following conditions must

GRT of DFs. They are administered with food, swell be met prior to implementation in the clinical setting:

to a size that promotes gastric retention and remain (a) the expandable GRDF should not intervene with

intact while releasing the drug in a controlled gastric motility; (b) the GRDF should have blunt

manner. edges to prevent gastrointestinal mucosal damage; (c)

Studies in fasting beagle dogs of GRDFs fabri- no local damage should be associated with prolonged

cated according to this invention, with dimensions of retention of the GRDF in the stomach as determined1938 mm (length3diameter) showed rapid evacua- by extensive histological examination of gastroin-

tion of less than 90 min from the stomach, while testinal tissue. For this purpose, a relatively fast

administration with 50 g food prolonged GRT to 45 biodegradation process would enhance the safety

h. A study involving human subjects evaluated GRT profile of the GRDF; and (d) the time for collapse

of swelling tablets with dimensions of 434 mm or of GRDF in the stomach should be reproducible.

636 mm (length3diameter) and showed brisk emp- It is preferred that the expandable GRDF leaves

tying of less than 1 h in the fasting state. However, the stomach before administration of the subsequent

following a heavy breakfast of 1500 kcal, 80% of the dose. This is important in order to prevent multiple

contents of all tablets were retained for 4 h, and in DF accumulation. GRDF accumulation is a major

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clinical concern, as shown in previous reports on overall there are enough similarities to make the dog

large enteric coated tablets of 13-mm diameter, that a useful screening tool. Moreover, the dog is more

had rare incidents of accumulation in the stomach suitable than other laboratory animals for such

with repetitive doses[74].In these cases, dozens of studies. For example, the GRT of enteric coated

tablets were found in the stomach[75]which led to tablets in pig was found to be days to weeks[77].hazardous situations. To ensure consistent gas- A comparison between gastrointestinal tract

troretentivity, expandable GRDFs are expected to characteristics of both species is presented inTable

have larger dimensions in the stomach than hitherto 1. It is seen that the fasting gastric motility i.e.

achieved by other DFs, including enteric-coated periodicity of the IMMC, including duration of the

tablets. Therefore, problems of accumulation might housekeeper wave of dog and human are very

have even more serious implications. This further similar.

emphasizes the advantage of GRDF degradation The two major differences in the stomach activity

inside the stomach, rather than in the intestine. are the gastric emptying time after eating and the pH

in the fasting state: the gastric emptying time of food

[85] and of DFs in the fed state is significantly

4. In vivo aspects of expandable GRDFs longer in dogs than in humans [86]. In the dog,

following a small meal, 8-mm tablets are retained for

4.1. Using a dog model for preclinical evaluation more than 8 h[80];and IMMC is abolished for about

of expandable GRDFs 8 h [87]. To prevent overestimation of the GRDF

performance in dog studies conducted as a prelimin-

While rats are the most common laboratory ani- ary screening prior to human studies, a fasting state

mals for absorption analysis [76], dogs are the should be maintained.

commonly used animals for evaluation of oral CR- The fasting human stomach is known to be acidic

DFs [21]. When developing expandable GRDFs, with pH 2 during most of the time[13].In contrast,

prior to clinical evaluation, dog studies are usually there is numerous evidence for instability, unpredic-

carried out, either for direct evaluation of gas- tability and relatively high pH of e.g. 5.56.9, for

troretentivity, for pharmacokinetic /pharmacodynam- prolonged periods of times in the fasting dog

ic proof-of-concept, or both. Despite some basic stomach[88].These pH values were detected usingdifferences between human and dog digestive tracts, various measurement techniques[89,90].The differ-

Table 1

Comparison between gastrointestinal characteristics of dog and human

Dog, 10 kg Human, 70 kg

Volume of stomach (ml) 480[78] 1500[9]21

Basal acid output (mequiv h )[79] 0.1 3.762.1 male,

2.261.8 female21

Peak acid output (mequiv h )[79] 3965 2367 male,

1865female

Gastric pH in the fasting state 17[80] 2[13]

Periodicity of housekeeper wave(min)[22] 113611 10668Length of phase 3 activity (min) [79] 1962 18.664

Gastric destructive forces (N) 3.2[81] Fasting 1.5,

Fed 1.9[82]

Duodenal diameter, autopsy (cm)[83] 22.5 34

Small intestinal transit time (min) [22] 111617 180660

Total gastrointestinal transit time (h)[21] 68 2030

Cut-off size for prolonged gastric retention (mm) 2 7[22] .1113[35]

Size which does not empty from the 1.4 diameter Longer than5 or

stomach, e.g. foreign body (cm) [84] larger than 3[36]

Numbers in square brackets indicate the references.

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Table 2ence can be attributed to a more significant reflux ofDrugs incorporated into GRDFsintestinal juice to the stomach which accompaniesAcyclovir[101,102]the housekeeper wave[80]in the dog[91],or to itsAlendronate[103]lower basal acid output [79]. Other reports foundAtenolol[104]

similar values e.g. pH 1.1 and 1.8 for human and Captopril[105]dog, respectively[92]. Cinnarizine[106]

Overcoming the pH difference may be unneces- Ciprofloxacin[72]Cisapride[107]sary in evaluating nongastroretentive CR-DFs due toFurosemide[67,108,109]their inherently short GRT. However, assessment ofGanciclovir[101]

GRDFs may demand intervention. Such gastricG-CSF[110]

acidification may be carried out by: pentagastrin Glipizide[57]intramuscular injection [93]; gastric acidifying tab- Ketoprofen[111]

Levodopa[63,112,113]lets e.g. glutamic acid hydrochloride, acidulin [94];Melatonin[114]or direct swallowing of acid[95].Metformin[69,70,115]

Recent studies have measured the gastric destruc-Minocyclin[116]

tive forces, known to be applied by the stomachMisoprostol[117]wall on its contents, using a tablet with a brittle outer Nicardipine[56]Riboflavin[48,62,109]layer which releases a marker drug when a forceSotalol[118]larger than its predetermined crushing strength isTetracycline[119]

applied[82].It was found that the forces in humansVerapamil[120]

are substantially less strong than in dogs regardless Vitamin E[121]of feeding state[81]. These results are similar to a

Numbers in square brackets indicate the references.previous study [96]. Thus if a DF is expected to

withstand destruction forces and maintain a specific

size for gastroretentivity, failure in a dog study might in gastric milieu and have either a narrow absorption

be misleading, as the same DF may be rigid enough window, or be used for gastroduodenal local

to maintain its dimensions in the human stomach. therapy. The following pharmacodynamic aspects

Recently, comprehensive articles comparing drug may further substantiate the potential benefits fromabsorption [97] and pharmacokinetics [98]between such compounding[1,3]

dogs and humans were published.

(A) Reduced fluctuations in drug effects: continuous4.2. Drugs proposed for GRDFs: input of the drug following GRDF administra-

pharmacodynamic considerations tion narrows the range of blood drug concen-

trations. Thus, fluctuations in drug effects are

Most drugs are not significantly absorbed in the minimized and concentration dependent adverse

stomach, due to a combination of short retention effects that are associated with peak concen-

time e.g. in comparison to the colonic transit time of trations can be prevented. This feature is of

dozens of hours[28],and small surface area of 3.5 special importance for narrow therapeutic index2

m [2]. Exceptions are furosemide [99] and sal- drugs.butamol[100].It is important to note that prolonged (B) Improved selectivity in receptor activation:

GRT may widen the stomachs potential as a drug minimization of fluctuations in the drug con-

absorbing organ. Examples of drugs evaluated when centration enables certain selectivity in the

incorporated into GRDFs are shown in Table 2. elicited pharmacodynamic effects of drugs that

Drugs with narrow absorption window are listed activate different types of receptors at various

elsewhere[122]. concentrations.

Identifying drugs or drug candidates which may (C) Reduced counter-activity of the body: in many

benefit from compounding into GRDFs involves cases the pharmacodynamic response, which

various considerations. Such drugs should be stable intervenes with the natural physiologic pro-

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cesses, provokes a rebound activity of the body ment of a novel gastroretentive drug carrier. In many

that minimizes drug action i.e. causes tolerance. of the studies involving GRDFs, immediate release

Slow input of the drug e.g. furosemide, from a DFs were used as a reference for assessing effect of

GRDF into the body has been shown to mini- gastrorentivity on the pharmacokinetics of the drug,

mize the counteractivity[67]. e.g. atenolol [104]. The absorption phase length of(D) Extended time over critical (effective) concen- immediate release mode of administration is inher-

tration: for certain drugs that have nonconcen- ently short and associated with elevated peak drug

tration dependent pharmacodynamics e.g. b-lac- concentration (C ) that might lead to adversemaxtam antibiotics, the clinical response is not effects. This pharmacokinetic profile may differ

associated with peak concentration, but rather, significantly from the corresponding GRDF and

with the time span where drug levels are over a therefore is less suitable as a reference group than

critical therapeutic concentration. GRDF may CR-DF.

extend the duration of time over an effective Pharmacokinetic parameters developed for CR-

concentration and thus improve therapy. DFs e.g. C and t , were recently suggestedapical apical(E) Minimized adverse activity at the colon: pro- for the evaluation of GRDFs[63].These parameters

longed GRT of DF minimizes the amount of better describe pharmacokinetics of CR-DFs as they

drug that reaches the colon. Thus, undesirable take into account multiple concentrationtime peaks,

activities in the colon may be prevented. For common for such profiles [124]. The standard re-

example, this pharmacodynamic aspect provides spective parameters,C andt , are single pointmax maxan additional rationale for GRDF of b-lactam parameters and accordingly also have a stronger

antibiotics that are absorbed only from the small dependency upon sampling schedule[125].

intestine, as their presence in the colon leads to

the development of microorganisms resistance. 4.4. Imaging and direct observation techniques for

evaluation of expandable GRDF properties

4.3. Pharmacokinetic evaluation of GRDFs

In order to optimize the performance of expand-

Pharmacokinetic evaluation of GRDFs should able GRDFs, a thorough in vivo characterization

acknowledge the fact that the continuous and pro- should be conducted. It may include evaluation oflonged input of the drug from the GRDF in the the kinetics and extent of expanding; effects of

stomach may have different implications. It could prolonged GRT on the mechanical integrity, dimen-

improve the bioavailability of certain drugs e.g. sions and biodegradation of the GRDF; and mecha-

riboflavin [48,62].However, GRDFs may also lead nisms of prolonged gastroretentivity and evacuation.

to lowered bioavailability, which may be attributed To characterize GRDFs, the following techniques,

to: (a) pharmaceutical rationale i.e. incomplete drug some of which were recently introduced for pharma-

leaching in the absorbing upper gastrointestinal tract ceutical applications, have been proposed:

due to slow release of the drug during the GRDFs

stay there; or (b) biological rationale i.e. continuous (A) g-Scintigraphy: using g-emitting radioisotopes

supply of the drug to the metabolic enzymes in the compounded into CR-DFs has become the state-

intestinal wall improves their efficacy and thus of-art for evaluation of gastrointestinal transitaugments the loss of the drug during the first pass times in healthy volunteers [126]. A small

152metabolism[123]. amount of a stable isotope e.g. Sm, is

The ultimate proof-of-concept for the phar- compounded into the DF during its preparation.

macokinetic advantages of the GRDF technology Prior to the study the DF is irradiated in a

usually will be superiority in the absorption phase neutron source to convert the isotope into a153

length, over nongastroretentive CR-DF, rather than g-emitting material e.g. Sm[127].Additional

immediate release DF. This approach, previously uses of the method are identification of intragas-

shown for e.g. glipizide[57], may reveal the most tric location of the DF[128] and dissolution/

convincing pharmacokinetic rationale for develop- disintegration properties of the DF [129]. A

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major advantage of this technique is its high be used to inspect visually the effects of pro-

safety profile, as it is accompanied by relatively longed stay in the stomach milieu on the GRDF.

low doses of radiation[31]. Alternatively, the GRDF may be drawn out of

(B) Radiology: this method is the state-of-art in the stomach for more detailed evaluation. Using

preclinical evaluation of gastroretentivity. Its gastroscopy to assess GRTs is relatively limited,major advantages as compared to g-scintigraphy as conducting this procedure more than once per

are simplicity and cost. However, use of X-ray experiment is unlikely. Recently, gastroscopy

in biopharmaceutical studies involving healthy was used to evaluate the extent that unfolding

volunteers [130] has declined as the obvious GRDFs expanded in dogs[63].

risk dictates strict limitations, regarding the (D) Magnetic marker monitoring (MMM): this tech-

amount of exposure. A commonly used contrast nique, developed by Weitschies et al., follows

agent is barium sulfate, often used in high magnetically marked DFs by magnetic source

concentrations e.g. 40% or more, for exemplify- imaging and therefore requires very sensitive

ing tablets[131].In order to reduce the formula- biomagnetic measurement equipment. The

tive change while attaining in vivo imaging, method has no radiation exposure and is com-

contrast aluminium threads obtained from sur- pletely safe [136,137].It yields successive data

gical gauze pads have been compounded into regarding the location of the DF along the

GRDFs during their preparation. Moreover, gastrointestinal tract and enables assessment of

GRDF dimensions may be evaluated by measur- the intragastric location of the DF[138].

ing the distances between short radiopaque (E) Ultrasonography: ultrasonic waves reflected at

threads previously added in a specific order. substantially different acoustic impedances ac-

Disintegration properties may be assessed by ross an interface enable the imaging of some

observing the location of the threads in the abdominal organs [139]. Ultrasound is not

gastrointestinal tract and assuming that proximi- routinely used in oral biopharmaceutics because

ty in their position suggests intactness of the it does not delineate the intestine. Additionally,

GRDF[62].Accordingly, compounding threads most DFs do not have sharp acoustic mismat-

having different lengths may identify complete- ches across their interface with the physiologi-

ness of specific parts or lobes of the GRDF. cal milieu. However, a swelling hydrogel typeRadiopaque markers may be applied to study GRDF was previously imaged using ultrasound

the effects of GRDFs or experimental models of in the stomach of a dog, by repetitive adminis-

their evaluation on gastric emptying, including tration of a large volume of water via a gastric

negating obstructions[62].BIPS ,inert spheres tube. The characterization included assessment

having a density similar to food that provide of intragastric location of the hydrogel, solvent

quantitative information about the process of penetration into the gel and interactions between

solids emptying from the stomach of small gastric wall and the GRDF during peristalsis

animals [132], are particularly convenient for [31].

dog studies as their gastrointestinal transit times

have been previously thoroughly investigated 4.5. Methods to measure the impact of GRDF on

under various feeding states[133]. stomach motility(C) Gastroscopy: gastroscopy is peroral endoscopy,

used with fiberoptic or video systems. It is The in vivo characterization of GRDF perform-

applied for diagnosis e.g. of gastric ulcer; ance and safety may include assessment of the effect

therapy for example of upper gastrointestinal of its administration on stomach contractility and

tract bleeding; and removal of foreign bodies motility. In fact, some previous expandable GRDFs

[134].Its adverse effects are very rare[135].In were designed to slow gastric emptying as a mecha-

dogs, the procedure involves complete anes- nism of their prolonged retention [46]. The estab-

thesia while in humans it usually involves some lished measuring techniques of stomach contractions

sedation. It is suggested that gastroscopy may are manometry and electrogastrography[140].Alter-

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natively, similar data may be obtained by a recently swelling tablets have a better chance of implementa-

developed methodmagnetic field goniometry. It tion in the clinical setting.

uses an electronic compass to measure angular It is expected that extension of applications of

changes in the direction of a magnetic field generated imaging techniques, and recently developed methods

by a previously swallowed magnet. Its advantages for both imaging DFs and following gastric motility,are minimal invasiveness, ease of use and low cost may yield a deeper insight into the mechanisms of

[141]. gastroretentivity. This could lead to a more sys-

Recently, a novel method to assess gastric empty- tematic and intelligent design of GRDFs.

ing in humans, pellet gastric emptying test, has been Further investigations may concentrate on the

suggested. Gastric emptying is recognized by the following concepts:

first appearance of measurable drug concentration in

the blood, following its administration as an enteric Identification of a minimal cut-off size above

coated DF[142]. which DFs retained in the human stomach for

Effect of GRDF intake on frequency of the prolonged periods of time. This would permit a

housekeeper wave appearance may be assessed more specific control to be achieved in gas-

indirectly by using radioimmunoassay of motilin, a troretentivity.

hormone excreted from the duodenal epithelium. Design of an array of GRDFs, each having a

This is because increased motilin blood levels are narrow GRT for use according to the clinical need

usually accompanied by a housekeeper wave[143]. e.g. dosage and state of disease. This may be

achieved by compounding polymeric matrices

with various biodegradation properties.

Study of the effect of various geometric shapes

5. Conclusions and future perspectives which combine, in a more excessive manner than

previous studies [52,54], extended dimensions

Among the drugs currently in clinical use are with high rigidity, on gastroretentivity.

several narrow absorption window drugs that may Design of novel polymers with prolonged me-

benefit from compounding into a GRDF. Replacing chanical memory to ensure unfolding.

parenteral administration of drugs to oral pharmaco-therapy would substantially improve treatment. It is Despite significant progress in the field of GRDFanticipated that GRDF may enhance this possibility. design, there is still much work to be done beforeMoreover, it is expected that the GRDF approach expandable GRDFs, and GRDFs in general, are usedmay be used for many potential active agents with a in the clinical setting.narrow absorption window, whose development has

been halted due to the lack of appropriate pharma-

ceutical GRDF technologies. AcknowledgementsCombining high rigidity with extended dimensions

of unfolding DF was shown to yield prolonged GRT We thank Dr. Josh Backon for his constructivein healthy volunteers in comparison to nongas- remarks. Professor Amnon Hoffman and Professor

troretentive DFs [65]. There is additional evidence Michael Friedman are affiliated with the David R.for the viability of this approach regarding swelling Bloom Center for Pharmacy at The Hebrew Uni-GRDFs in fed dogs[59].These accumulated findings versity of Jerusalem.warrant additional research on swelling GRDFs

which combine large dimensions with high rigidity

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