Drug delivery to the upper small intestine window using gastroretentive technologies

Alexander Streubel1, Juergen Siepmann1,2 and Roland Bodmeier1

The bioavailability of drugs with an absorption window in the upper small intestine is generally limited with conventional pharmaceutical dosage forms. The residence time of such systems and, thus, of their drug release into the stomach and upper intestine is often short. To overcome this restriction and to increase the bioavailability of these drugs, controlled drug delivery systems with a prolonged residence time in the stomach can be used. Approaches to achieving prolonged residence times of the devices in the upper part of the gastrointestinal tract include the use of bioadhesive, sizeincreasing, and oating drug delivery systems.
Addresses 1 t Berlin, Kelchstr. 31, College of Pharmacy, Freie Universita 12169 Berlin, Germany 2 College of Pharmacy, University of Lille, 3 rue du Professeur Laguesse, 59006 Lille, France Corresponding author: Streubel, Alexander (alexander.streubel@roche.com)

from the stomach, the passage through this region is rapid, thus limiting the extent of absorption at this site. In order to increase the bioavailability of this type of drug, the residence time of the controlled-release dosage forms in the upper gastrointestinal tract needs to be prolonged. Various methods have been applied g-scintigraphy, radiology (X-rays), endoscopy, ultrasonography, radiotelemetry and magnetic marker monitoring in order to study the parameters affecting the process of gastric emptying [4,5]. The most important parameters affecting gastric emptying and, hence, the gastric retention time of oral dosage forms include: 1. Density, size and shape of the device [6,7]. 2. Concomitant ingestion of food and its nature, caloric content and frequency of intake [810]. 3. Simultaneous administration of drugs with impact on gastrointestinal transit time; for example, drugs acting as anticholinergic agents (e.g. atropine, propantheline), opiates (e.g. codeine) and prokinetic agents (e.g. metoclopramide, cisapride) [11]. 4. Biological factors such as gender, posture, age, sleep, body mass index, physical activity and disease states (e.g. diabetes, Crohns disease) [1214]. The main approaches to prolonging the gastric residence time of pharmaceutical dosage forms include bioadhesive delivery systems, which adhere to mucosal surfaces; devices that rapidly increase in size once they are in the stomach to retard the passage through the pylorus; and density-controlled delivery systems, which oat on gastric uids [1518,19]. Although many systems reported in the literature have not been studied using drugs showing an absorption window in the upper small intestine, they are all potentially applicable for this purpose. This review focuses on several examples for both singleand multiple-unit gastroretentive drug delivery systems and reports (if available) results from in vivo trials targeting an absorption window in the upper small intestine.

Current Opinion in Pharmacology 2006, 6:501508 This review comes from a themed issue on New technologies Edited by Alan Baird and David Brayden Available online 4th August 2006 1471-4892/$ see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2006.04.007

Introduction
Oral ingestion is the predominant and most preferable route for drug delivery. Importantly, it allows unassisted administration by the patient without the need for trained personnel (as this is the case with most parenterally administered dosage forms). Time-controlled oral drug delivery systems offer several advantages over immediate-release dosage forms, including the minimization of uctuations in drug concentrations in the plasma and at the site of action over prolonged periods of time, resulting in optimized therapeutic efciencies and reduced side effects; a reduction of the total dose administered (while providing similar therapeutic effects); and a reduction of the administration frequency, leading to improved patient compliance. However, standard controlled-release dosage forms offer only limited advantage for drugs that have an absorption window in the upper small intestine (e.g. levodopa [Ldopa] [1], furosemide [2] and riboavin [3]): once emptied
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Bioadhesive drug delivery systems

Akiyama and Nagahara [20] proposed the use of mucoadhesive microspheres consisting of a drug and Carbopol 934P (polyacrylic acid, polymerized in benzene and highly cross-linked with allyl sucrose), dispersed within a waxy matrix of polyglycerol esters of fatty acids. These systems were found to adhere to the stomach mucosa in rats and Mongolian gerbils and to prolong the drugs gastrointestinal residence time after oral administration.
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The adherence can be attributed to the hydration and swelling of Carbopol in the microspheres upon contact with water. Importantly, parts of the macromolecules remain within the microspheres, whereas the rest is anchored within the mucus layer. When furosemide was administered to rats, and riboavin to human volunteers, with the use of microspheres, enhanced levels in plasma were observed compared with the administration of furosemide or riboavin suspensions. The major challenge for bioadhesive drug delivery systems is the high turnover rate of the gastric mucus and the resulting limited retention times. Furthermore, it is difcult to target specically the gastric mucus with bioadhesive polymers. Most of the latter (e.g. polycarbophil, Carbopol and chitosan) will stick to various other surfaces that they come into contact with [21,22]. In addition, the possibility of oesophageal binding might present a challenge regarding safety aspects.

diameter of the pylorus (even in its widest state during a housekeeper wave). However, owing to signicant interindividual variations, the cut-off size cannot be determined exactly. Roughly, the dosage forms should be larger than 13 mm, but even bigger units have been found to be emptied from the stomach. In order to facilitate swallowing, it is highly desirable to design dosage forms with an initially small size that once in the stomach signicantly increase in size. The expanded state should be achieved rapidly in order to prevent premature emptying through the pylorus. Conversely, the systems should also guarantee their clearance from the stomach after predetermined time intervals to avoid accumulation upon multiple administrations. Klausner et al. [23] proposed unfolding multilayer, polymeric lms based on a drug-containing shellac matrix as the inner layer, covered on both sides with (outer) shielding layers composed of hydrolyzed gelatin, Eudragit S, glycerin and glutaraldehyde. The system is optionally framed with rigid polymeric strips composed of L-poly(lactic acid) and ethylcellulose, or ethylcellulose-triethylcitrate (Figure 1). Such dosage forms placed into gelatin

Size-increasing drug delivery systems

Another approach to retaining a pharmaceutical dosage form in the stomach is by increasing its size above the

Figure 1

Schematic presentation of the gastroretentive drug delivery system proposed by Klausner et al. [23]: multilayer polymeric films consisting of (a) shielding (outer) layers; (b) rigid (frame) strips; (c) polymer-drug matrix; and (d) anti-adhering layers (microcrystalline cellulose). Reprinted from [23] with kind permission of Springer Science and Business Media. Current Opinion in Pharmacology 2006, 6:501508 www.sciencedirect.com

Drug delivery to the upper small intestine window using gastroretentive technologies Streubel, Siepmann and Bodmeier 503

capsules were administered to beagle dogs. Two factors inuenced the in vivo gastric retention behavior: the dimensions and the mechanical properties of the lms. Prolonged residence times could be provided with relatively large devices (surface area  2.5 2.5 cm2) and rigid frames. The effects of the mode of riboavin-5phosphate administration on the resulting mean drug plasma concentrations and cumulative amounts of riboavin absorbed in dogs are illustrated in Figure 2. In contrast with both a non-gastroretentive control formulation (multilayer lm without rigid frame; 5.0 2.5 cm2) and an oral solution, which resulted in shorter time periods with elevated riboavin concentrations, the gastroretentive device (multilayer lm with rigid frame; 5.0

2.5 cm2) produced elevated plasma drug concentrations for at least 48 h. The absolute bioavailabilities were 17.1 3.5%, 3.9 0.4%, and 3.9 1% for the gastroretentive dosage form, control formulation and oral solution, respectively. The same working group studied the performance of L-dopa-containing multilayer lms (5.0 2.5 cm2 in size) in beagle dogs [24]. The systems consisted of an inner drug-containing lm layer (ethylcellulose levodopa, with a 1:1 ratio), covered on both sides by (outer) shielding layers of enzymatically hydrolyzed gelatin, Eudragit S, glycerin and glutaraldehyde blends (a ratio of 48:30:20:2) and a frame of rigid polymeric strips [Lpoly(lactic acid)ethylcellulose; ratio of 9:1]. Importantly, therapeutic L-dopa concentrations (>500 ng/ml) could be

Figure 2

Effects of the mode of administration of 100 mg riboflavin-5-phosphate on the resulting (a) mean riboflavin plasma concentration and (b) cumulative amount of riboflavin absorbed in dogs (n=6). DF, dosage form; GRDF, gastroretentive dosage form. Reprinted from [23] with kind permission of Springer Science and Business Media. www.sciencedirect.com Current Opinion in Pharmacology 2006, 6:501508

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maintained over 9 h upon administration of one single lm. The mean absorption time of the drug was signicantly extended in comparison with non-gastroretentive controlled-release particles and oral solutions. The performance of L-dopa-containing, multilayer lms was also studied in humans [25]. Prolonged gastroretention (5 h) could be achieved owing to the rigidity and size of the dosage forms. Importantly, the lms rapidly unfolded and maintained their mechanical integrity. The time-period during which the drug was absorbed signicantly increased compared with non-gastroretentive controlled-release tablets. However, the downside of this type of system is their rather complex structure, making them difcult to manufacture. Furthermore, their clearance from the stomach after predetermined time intervals might present a challenge. Enzyme-digestible hydrogels, consisting of poly(vinyl pyrrolidone) cross-linked with albumin, were described by Park and co-workers [2628]. These specially designed hydrogels swell to a signicant extent, which is a function of the albumin content and degree of albumin alkylation. The polymers are degraded in the presence of pepsin either via bulk or surface erosion. With increasing albumin alkylation, pepsin digestion is diminished and bulk erosion becomes predominant. In dogs, the gastric residence time exceeded 24 h, even under fasted conditions. Such an enzyme-digestible swelling hydrogel formulation was used to deliver riboavin to the upper small intestine of these animals. Importantly, the drug could be detected for up to 54 h after administration in the blood, indicating gastric retention of the hydrogel in the stomach. The same research group described another promising size-increasing gastroretentive drug delivery system based on superporous hydrogels with very fast swelling kinetics and super-absorbent properties [2932]. Equilibrium swelling with these devices is attained in less than 1 min. The swelling ratio (volume of the swollen gel/volume of the dried form) can exceed 1000 in some cases. The mechanical strength of the highly swollen superporous hydrogels can be increased by adding a so-called composite material (e.g. croscarmellose sodium), which forms a dispersed phase within the continuous polymer matrix during the synthesis (superporous hydrogel composites). Gastric retention experiments in dogs, in which the devices were placed in hard gelatin capsules for oral administration, showed very promising results. Even when the dogs were maintained in a fasted condition for 36 h before the experiment, the superporous hydrogel composites remained in the stomach for 23 h, after which they broke into pieces and were emptied into the intestine. Conversely, when the initial fed state was maintained for the rst couple of hours, the superporous hydrogel composites stayed in the stomach for more than 24 h. Recent advances in the eld led to superporous hydrogel hybrids, which are prepared by adding a water-soluble
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or water-dispersible polymer that can be cross-linked after the superporous hydrogel is formed [33]. Examples of hybrid agents include polysaccharides (e.g. sodium alginate, pectin, chitosan) or synthetic water-soluble hydrophilic polymers such as polyvinyl alcohol. Compared with conventional superporous hydrogels and superporous hydrogel composites, superporous hydrogel hybrids do not easily break when stretched owing to their high elasticity in the swollen state. In general, size-increasing drug delivery systems potentially present the hazard of permanent retention in the stomach and could lead to life-threatening effects upon multiple administration. To avoid this risk, the systems should consist of biodegradable materials or have the ability to lose their integrity after a desired time period. However, the systems also need to be sufciently resistant in order to withstand the powerful mechanical contractions within the stomach. A major advantage of size-increasing systems is the (a priori) independence of their performance on the lling state of the stomach.

Floating drug delivery systems

Drug delivery systems that oat immediately upon contact with gastric uids present promising approaches for increasing the bioavailability of drugs with absorption windows in the upper small intestine. However, immediate oating can only be achieved if the density of the device is low at the very beginning. Devices with an initially high density (which decreases with time) rst settle down in the stomach and, thus, undergo the risk of premature emptying. Inherent low density can, for example, be provided by the entrapment of air (e.g. hollow chambers [34]) or by the (additional) incorporation of lowdensity materials (e.g. fatty substances or oils [35], or foam powder [3638]). Recently, a single-unit, oating, controlled drug delivery system (tablet) was proposed consisting of polypropylene foam powder, matrix-forming polymer(s), drug and (optional) ller [36]. The highly porous foam powder provides an inherent low density and, thus, excellent in vitro oating behavior of the system from the very beginning. All formulations kept oating for at least 8 h in 0.1 N HCl at 37 8C. Importantly, the good oating behavior of these systems could successfully be combined with accurate control of the resulting drug-release patterns. Varying the formulation and processing parameters allows a broad spectrum of release proles. Furthermore, a novel multi-particulate gastroretentive drug delivery system based on low-density foam powder has been proposed and its performance demonstrated in vitro [37]. Floating microparticles consisting of polypropylene foam powder, verapamil HCl (as the model drug) and Eudragit RS, ethylcellulose or poly(methyl methacrylate) (PMMA) were prepared with an oil-in-water
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Drug delivery to the upper small intestine window using gastroretentive technologies Streubel, Siepmann and Bodmeier 505

Figure 3

Schematic presentation of the preparation of floating microparticles based on low-density foam powder, using (a) the solvent evaporation method or (b) the soaking method. Reprinted from Streubel A: Oral delivery systems with modified drug release. Ph.D. Thesis 2002.

solvent extraction/evaporation method (Figure 3a). The drug and release-rate-controlling polymer were dissolved in methylene chloride. Polypropylene foam powder was then dispersed within this organic phase. The resulting suspension was subsequently emulsied into an external aqueous poly(vinyl alcohol) solution and agitated with a stirrer to allow microparticle formation. The microparticles were separated by being sieved, washed with water and dried in a desiccator; they were irregular in shape and highly porous. Importantly, the drug encapsulation efciency was high and almost independent of the theoretical loading of the system. In all cases, good in vitro oating behavior was observed. Interestingly, a broad spectrum of release patterns could be obtained with the investigated formulations. Further studies focused on the development of an improved preparation method for this type of low-density, foam-based, oating microparticle, and also on the demonstration of the systems performances in vitro [38]. Major advantages of the suggested novel preparation technique include short processing times, no exposure of the ingredients to high temperatures, the ability to avoid toxic organic solvents, and high encapsulation efciencies (close to 100%). Floating microparticles consisting of polypropylene foam powder, model drug (chlorpheniramine maleate, diltiazem HCl, theophylline or verapamil HCl), and a second polymer [Eudragit RS or poly(methyl methacrylate)] were prepared by soaking microporous
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foam particles with an organic solution of the drug and polymer, and subsequent drying (Figure 3b). Good in vitro oating behavior was observed in most cases, and a broad variety of drug release patterns could be achieved by varying the drug loading and type of second polymer. In addition, the low-density microparticles could be compressed into rapidly disintegrating tablets, providing an easily administrable oral dosage form [38]. Kawashima and colleagues [3941] proposed hollow microspheres (so-called microballoons) based on Eudragit S (an enteric polymer), containing the drug in the polymeric shell. The preparation procedure and mechanism of microballoon formation is schematically illustrated in Figure 4. A solution of polymer and drug in ethanol/ methylene chloride is poured into an agitated aqueous solution of poly(vinyl alcohol). The ethanol rapidly partitions into the external aqueous phase and the polymer precipitates around methylene chloride droplets. The subsequent evaporation of the entrapped methylene chloride leads to the formation of internal cavities within the microparticles. However, according to Lee et al. [42], many drugs fail to be released in signicant amounts from this type of microparticle at the low pH of the stomach because of the shell consisting of an enteric polymer. To overcome this restriction, non-volatile oil [43] or highly porous calcium silicate powder pre-loaded with drug [44] can be added to the dispersed phase, or Eudragit S/RL mixtures can be used [45]. The research group of
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Figure 4

Preparation technique (emulsion-solvent diffusion method) and mechanism of microballoon formation proposed by Kawashima et al. [40]. Redrawn from [40] with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

Kawashima also prepared hollow microspheres based on blends of Eudragit S and other hydrophilic or hydrophobic polymers, such as Eudragit L, hydroxypropyl methylcellulose phthalate (HPMCP), HPMC or ethylcellulose [46]. Incorporation of HPMC within the outer shell showed promising results concerning the control of drug release from the system at the pH of gastric uids. With increasing HPMC content, riboavin release was accelerated; however, the oating ability of the microspheres decreased. Importantly, the performance of these riboavin-containing microballoons was also studied in vivo [47,48]. Upon oral administration to healthy volunteers, the intra-gastric behavior was investigated by g-scintigraphy and the urinary excretion of riboavin was monitored. In the fed state, the microballoons were retained in the stomach for up to 5 h. Interestingly, microspheres with good oating properties but low in vitro drug-release rates showed lower urinary excretion of riboavin in the time period of 4 8 h after administration than microspheres with worse oating properties and high in vitro drug-release rates. Thus, it is important to choose an appropriate balance between the oating properties and drug-release rates with this type of gastroretentive drug delivery system. A major drawback of low-density, oating drug delivery devices is that their performance is strongly dependent upon the lling state of the stomach. Nevertheless, this approach can successfully prolong the gastric retention time of drugs [49], and has already led to pharmaceutical products that are commercially available on the market [50].
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Conclusions
A controlled drug delivery system with prolonged residence time in the stomach can be of great practical importance for drugs with an absorption window in the upper small intestine. Adequate control of the gastric residence time combined with time-controlled drug release patterns can signicantly increase the bioavailability of the drug and, thus, the efciency of the medical treatment. Bioadhesive, size-increasing and oating drug delivery systems show the most promising potential of achieving this goal. The major challenge for bioadhesive systems is the high turnover rate of the gastric mucus. Recent improvements in the eld of size-increasing drug delivery systems led to devices that can easily be swallowed but rapidly increase in size once they reach the stomach, assuring prolonged gastric residence times. Importantly, their performance is independent of the lling state of the stomach and, after predetermined time intervals, they break into smaller pieces, guaranteeing their removal from the stomach. In contrast, the performance of lowdensity, oating drug delivery systems is strongly dependent upon the lling state of the stomach. In conclusion, promising in vitro and in vivo results have been reported with several different types of gastroretentive drug delivery systems. In the future, it is expected that they will become of increasing importance, ultimately leading to improved efciencies of various types of pharmacotherapies.
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Drug delivery to the upper small intestine window using gastroretentive technologies Streubel, Siepmann and Bodmeier 507

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:  of special interest  of outstanding interest 1. Erni W, Held K: The hydrodynamically balanced system: a novel principle of controlled drug release. Eur Neurol 1987, 27(Suppl 1):21-27. zdemir N, Ordu S, O zkan Y: Studies of oating dosage forms O of furosemide: in vitro and in vivo evaluations of bilayer tablet formulations. Drug Dev Ind Pharm 2000, 26:857-866. Hoffman A, Stepensky D, Lavy E, Eyal S, Klausner E, Friedman M: Pharmacokinetic and pharmacodynamic aspects of gastroretentive dosage forms. Int J Pharm 2004, 277:141-153. Wilding IR, Coupe AJ, Davis SS: The role of g-scintigraphy in oral drug delivery. Adv Drug Deliv Rev 2001, 46:103-124. nnikes H, Trahms L: Magnetic marker Weitschies W, Kosch O, Mo monitoring: an application of biomagnetic measurement instrumentation and principles for the determination of the gastrointestinal behavior of magnetically marked solid dosage forms. Adv Drug Deliv Rev 2005, 57:1210-1222. Khosla R, Davis SS: The effect of tablet size on the gastric emptying of non-disintegrating tablets. Int J Pharm 1990, 62:R9-R11. s AJ: Factors controlling the buoyancy and Timmermans J, Moe gastric retention capabilities of oating matrix capsules: new data for reconsidering the controversy. J Pharm Sci 1994, 83:18-24. OReilly S, Wilson CG, Hardy JG: The inuence of food on the gastric emptying of multiparticulate dosage forms. Int J Pharm 1987, 34:213-216. Khosla R, Feely LC, Davis SS: Gastrointestinal transit of non-disintegrating tablets in fed subjects. Int J Pharm 1989, 53:107-117.

20. Akiyama Y, Nagahara N: Novel formulation approaches to oral muco-adhesive drug delivery systems. In Bioadhesive Drug Delivery Systems Fundamentals, Novel Approaches and Development. Edited by Mathiowitz E, Chickering III DE, Lehr CM. New York: Dekker; 1999:477-505. 21. Khosla R, Davis SS: Effect of polycarbophil on the gastric emptying of pellets. J Pharm Pharmacol 1987, 39:47-49. kkinen M, Marvola J, Kanerva H, Lindevall K, Lipponen M, 22. Sa Kekki T, Ahonen A, Marvola M: Gamma scintigraphic evaluation of the fate of microcrystalline chitosan granules in human stomach. Eur J Pharm Biopharm 2004, 57:133-143. 23. Klausner EA, Lavy E, Stepensky D, Friedman M, Hoffman A: Novel gastroretentive dosage forms: evaluation of gastroretentivity and its effect on riboavin absorption in dogs. Pharm Res 2002, 19:1516-1523. 24. Klausner EA, Eyal S, Lavy E, Friedman M, Hoffman A: Novel levodopa gastroretentive dosage form: in-vivo evaluation in dogs. J Control Release 2003, 88:117-126. 25. Klausner EA, Lavy E, Barta M, Cserepes E, Friedman M, Hoffman A: Novel gastroretentive dosage forms: evaluation of gastroretentivity and its effect on levodopa absorption in humans. Pharm Res 2003, 20:1466-1473. 26. Shalaby WSW, Park K: Biochemical and mechanical characterization of enzyme-digestible hydrogels. Pharm Res 1990, 7:816-823. 27. Shalaby WSW, Blevins WE, Park K: Gastric retention of enzymedigestible hydrogels in the canine stomach under fasted and fed conditions. In Polymeric Drugs and Drug Delivery Systems. Edited by Dunn RL, Ottenbrite RM. Washington: ACS Symposium Series; 1991:237-248. 28. Shalaby WSW, Blevins WE, Park K: In vitro and in vivo studies of enzyme-digestible hydrogels for oral drug delivery. J Control Release 1992, 19:131-144. 29. Chen J, Park H, Park K: Synthesis of superporous hydrogels: hydrogels with fast swelling and superabsorbent properties. J Biomed Mater Res 1999, 44:53-62. 30. Chen J, Park K: Synthesis of fast-swelling, superporous sucrose hydrogels. Carbohydrate Polymers 2000, 41:259-268. 31. Chen J, Blevins WE, Park H, Park K: Gastric retention properties of superporous hydrogel composites. J Control Release 2000, 64:39-51. 32. Chen J, Park K: Synthesis and characterization of superporous hydrogel composites. J Control Release 2000, 65:73-82. 33. Omidian H, Rocca JG, Park K: Advances in superporous  hydrogels. J Control Release 2005, 102:3-12. Very interesting expanding/swelling system. gel I, Bodmeier R: Development of a multifunctional matrix 34. Kro drug delivery system surrounded by an impermeable cylinder. J Control Release 1999, 61:43-50. 35. Sriamornsak P, Thirawong N, Puttipipatkhachorn S: Emulsion gel beads of calcium pectinate capable of oating on the gastric uid: effect of some additives, hardening agent or coating on release behavior of metronidazole. Eur J Pharm Sci 2005, 24:363-373. 36. Streubel A, Siepmann J, Bodmeier R: Floating matrix tablets based on low density foam powder: effects of formulation and processing parameters on drug release. Eur J Pharm Sci 2003, 18:37-45. 37. Streubel A, Siepmann J, Bodmeier R: Floating microparticles based on low density foam powder. Int J Pharm 2002, 241:279-292. 38. Streubel A, Siepmann J, Bodmeier R: Multiple unit gastroretentive drug delivery systems: a new preparation method for low density microparticles. J Microencapsul 2003, 20:329-347. 39. Kawashima Y, Niwa T, Takeuchi H, Hino T, Ito Y: Preparation of multiple unit hollow microspheres (microballoons) with acrylic resin containing tranilast and their drug release Current Opinion in Pharmacology 2006, 6:501508

2.

3.

4. 5.

6.

7.

8.

9.

10. Abrahamsson B, Alpsten M, Hugosson M, Jonsson UE, lli J: Absorption, gastrointestinal Sundgren M, Svenheden A, To transit, and tablet erosion of felodipine extended-release (ER) tablets. Pharm Res 1993, 10:709-714. 11. Nimmo J, Heading RC, Tothill P, Prescott LF: Pharmacological modication of gastric emptying: effects of propantheline and metoclopramide on paracetamol absorption. Br Med J 1973, 1:587-589. 12. Bennett CE, Hardy JG, Wilson CG: The inuence of posture on the gastric emptying of antacids. Int J Pharm 1984, 21:341-347. 13. Mojaverian P, Vlasses PH, Kellner PE, Rocci ML Jr: Effects of gender, posture, and age on gastric residence time of an indigestible solid: pharmaceutical considerations. Pharm Res 1988, 5:639-644. 14. Coupe AJ, Davis SS, Evans DF, Wilding IR: Nocturnal scintigraphic imaging to investigate the gastrointestinal transit of dosage forms. J Control Release 1992, 20:155-162. 15. Hwang SJ, Park H, Park K: Gastric retentive drug-delivery systems. Crit Rev Therap Drug Carrier Syst 1998, 15:243-284. 16. Lee JW, Park JH, Robinson JR: Bioadhesive-based dosage forms: the next generation. J Pharm Sci 2000, 89:850-866. 17. Klausner E, Lavy E, Friedman M, Hoffman A: Expandable gastroretentive dosage forms. J Control Release 2003, 90:143-162. 18. Bardonnet PL, Faivre V, Pugh WJ, Piffaretti JC, Falson F: Gastroretentive dosage forms: overview and special case of helicobacter pylori. J Control Release 2006, 111:1-18. 19. Streubel A, Siepmann J, Bodmeier R: Gastroretentive drug  delivery systems. Expert Opin. Drug Deliv. 2006, 3:217-233. Comprehensive review of gastric retentive drug delivery systems. www.sciencedirect.com

508 New technologies

characteristics (in vitro) and oating behavior (in vivo). J Control Release 1991, 16:279-290. 40. Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y: Hollow microspheres for use as a oating controlled drug delivery system in the stomach. J Pharm Sci 1992, 81:135-140. 41. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H: Physicochemical properties to determine the buoyancy of hollow microspheres (microballoons) prepared by the emulsion solvent diffusion method. Eur J Pharm Biopharm 2003, 55:297-304. 42. Lee JH, Park TG, Choi HK: Development of oral drug delivery system using oating microspheres. J Microencapsul 1999, 16:715-729. 43. Lee JH, Park TG, Lee YB, Shin SC, Choi HK: Effect of adding non-volatile oil as a core material for the oating microspheres prepared by emulsion solvent diffusion method. J Microencapsul 2001, 18:65-75. 44. Jain SK, Awasthi AM, Jain NK, Agrawal GP: Calcium silicate based microspheres of repaglinide for gastroretentive oating drug delivery: preparation and in vitro characterization. J Control Release 2005, 107:300-309.

45. El-Kamel AH, Sokar MS, Al Gamal SS, Naggar VF: Preparation and evaluation of ketoprofen oating oral delivery system. Int J Pharm 2001, 220:13-21. 46. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H: In vitro evaluation of oating and drug releasing behaviors of hollow microspheres (microballoons) prepared by the emulsion solvent diffusion method. Eur J Pharm Biopharm 2004, 57:235-243. 47. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H, Fujibayashi Y: Pharmacoscintigraphic evaluation of riboavin-containing microballoons for a oating controlled drug delivery system in healthy humans. J Control Release 2004, 98:75-85. 48. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H: In vitro and in vivo evaluation of riboavin-containing microballoons for a oating controlled drug delivery system in healthy humans. Int J Pharm 2004, 275:97-107. 49. Talukder R, Fassihi R: Gastroretentive delivery systems: a mini review. Drug Dev Ind Pharm 2004, 30:1019-1028. 50. Singh BN, Kim KH: Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J Control Release 2000, 63:235-259.

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