Expert Opinion Gastroretentive Drug Delivery Systems PDF

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Review Gastroretentive drug delivery systems Alexander Streubel†, Juergen Siepmann & Roland Bodmeier †Roche Diagnostics GmbH, Sandhofer Strasse 116, 68305 Mannheim, Germany 1. Introduction A controlled drug delivery system with prolonged residence time in the stom- 2. Bioadhesive drug delivery ach is of particular interest for drugs that i) are locally active in the stomach, systems ii) have an absorption window in the stomach or in the upper small intestine, 3. Size-increasing drug delivery iii) are unstable in the intestinal or colonic environment, or iv) exhibit low sol- systems ubility at high pH values. This article gives an overview of the parameters 4. Density-controlled drug delivery affecting gastric emptying in humans as well as on the main concepts used to Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Cornell University on 05/25/12 systems design pharmaceutical dosage forms with prolonged gastric residence times. 5. Drug delivery systems In particular, bioadhesive, size-increasing and floating drug delivery systems combining different concepts are presented and their major advantages and shortcomings are discussed. 6. Expert opinion Both single- and multiple-unit dosage forms are reviewed and, if available, results from in vivo trials are reported. Keywords: bioadhesion, controlled drug release, floating system, gastric retention Expert Opin. Drug Deliv. (2006) 3(2):217-233 1. Introduction For personal use only. The main function of the stomach is to temporarily store food, start its digestion and to release the resulting chyme slowly through the pylorus into the duodenum. Because of the small surface area of the stomach, absorption into the systemic circu- lation is restricted. The jejunum and ileum are the most important sites for absorp- tion of nutrients and drugs. In the colon, mainly water and ions are absorbed, as well as certain drugs (that show significant absorption due to the long residence time in the colon). The process of gastric emptying is characterised by a distinct cycle of electro- mechanical activity known as the interdigestive migrating myoelectric complex. This series of events that cycle through the stomach and small intestine every 1.5 – 2 h is divided into four consecutive phases : Phase I (45 – 60 min), the most quiescent, develops few or no contractions; Phase II (30 – 45 min) consists of intermittent action potentials and contractions, which gradually increase in intensity and frequency as the phase progresses; Phase III (5 – 15 min) is a short period of intense contractions and peristaltic waves, involving both the proximal and distal gastric regions (‘housekeeper waves’). In this phase, indigestible solids are removed from the fasted stomach; Phase IV (0 – 5 min) is a transition period of decreasing activity until the next cycle begins. In order to study the parameters affecting the process of gastric emptying, various methods have been applied, such as γ-scintigraphy, radiography, endoscopy, radio- telemetry and magnetic-marker monitoring [2-5]. Furthermore, indirect information on gastric emptying could be gained by comparing the pharmacokinetics of drugs administered in oral dosage forms of different size. Factors affecting the gastric emptying and, hence, the gastric retention time of oral dosage forms include: density, size and shape of the dosage form [6-9]; Ashley Publications www.ashley-pub.com concomitant ingestion of food and its nature, caloric content and frequency of intake [10-16]; 10.1517/17425247.3.2.217 © 2006 Ashley Publications ISSN 1742-5247 217  Gastroretentive drug delivery systems (simultaneous) administration of drugs acting as anti- 2. Bioadhesive drug delivery systems cholinergic agents (e.g., atropine, propantheline), opiates (e.g., codeine) and prokinetic agents (e.g., metoclopramide, Various types of polymers have been studied for their bio- cisapride) ; adhesive properties and several excellent review articles have biological factors, such as gender, posture, age, sleep, body been published on the fundamental aspects and potential mass index, physical activity and disease states (e.g., diabetes, applications of bioadhesive dosage forms [48-52]. Bioadhesive Crohn’s disease) [18-21]. polymers are usually macromolecular, hydrophilic gelling sub- stances with numerous hydrogen-bond forming groups, such The therapeutic interest to prolong the gastric residence as carboxyl, hydroxyl, amide and sulfate groups time of a pharmaceutical dosage form with time-controlled (e.g., crosslinked polyacrylic acids, sodium carboxymethyl cel- release kinetics can be significant, especially in the case of lulose, sodium alginate and carrageenan). In addition to drugs, which: hydrogen bondings, covalent and electrostatic interactions are are locally active in the stomach (e.g., misoprostol , ant- known to be of importance. Although the exact mechanisms Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Cornell University on 05/25/12 acids and antibiotics against Helicobacter pylori [24-26]); of bioadhesion are not yet completely understood, certain ele- have an absorption window in the stomach or in the upper ments of the process are known to be of significance, such as small intestine (e.g., L-DOPA [27,28], p-aminobenzoic acid spreading the bioadhesive over the substrate to increase the , furosemide [30,31] and riboflavin [32,33]); surface area of contact; diffusion/penetration of polymer are unstable in the intestinal or colonic environment chains of the bioadhesive into the substrate; and domination (e.g., captopril ); or of the attractive forces over the repulsive ones. exhibit low solubility at high pH values (e.g., diazepam, Several types of dosage forms have been proposed to allow chlordiazepoxide and verapamil HCl [36-38]). prolonged residence within the stomach based on bioadhesive polymers. For example, Akiyama and Nagahara developed Furthermore, as the total gastrointestinal transit time of the mucoadhesive microspheres consisting of a drug and Car- dosage form is increased by prolonging the gastric residence bopol® 934P (Noveon, Inc.; polyacrylic acid, polymerised in For personal use only. time, these systems can also be used as extended release benzene, highly crosslinked with allyl sucrose) being dispersed devices with a reduced frequency of administration and, thus, within a waxy matrix of polyglycerol esters of fatty acids. improved patient compliance. These systems were reported to adhere to the stomach mucosa In contrast, a prolonged residence time in the stomach is in rats and Mongolian gerbils, and to prolong the gastro- not desirable for drugs that: intestinal residence of the drug after oral administration. The cause gastric lesions (e.g., NSAIDs); adherence can probably be explained by the hydration and are unstable in the acidic pH of the stomach; or swelling of the Carbopol in the microspheres on contact with undergo a significant first-pass effect (i.e., metabolism in water. Importantly, parts of the polymer remained within the the liver prior to entering the systemic circulation; microspheres, whereas the rest was ‘anchored’ within the e.g., nifedipine). mucus layer. When furosemide (showing an absorption win- dow in the upper intestine) was administered to rats (and Most gastroretentive drug delivery systems are single-unit dos- riboflavin to human volunteers incorporated in these micro- age forms [40-42], which have in common the risk of losing spheres), enhanced absorption was observed compared with their effect too early due to their all-or-nothing emptying the administration of the respective furosemide/riboflavin sus- from the stomach. To overcome this restriction, multiple-unit pensions. Furthermore, amoxicillin-loaded microspheres of floating or bioadhesive systems have been proposed [43,44]. this type showed higher anti-H. pylori activity in the Mongo- These distribute uniformly within the gastric content and lian gerbil stomach compared with an amoxicillin suspension. gradually empty from the stomach, possibly resulting in Thus, this principle seems to work in vivo as well. longer-lasting effects and reduced intersubject variabilities. Microparticles consisting of amoxicillin-loaded ion- The main approaches used to increase the gastric residence exchange resin, encapsulated in mucoadhesive polymers (poly- time of pharmaceutical dosage forms include: carbophil and Carbopol 934) were prepared by a modified oil- in-oil solvent evaporation technique, aiming to increase the bioadhesive delivery systems, which adhere to mucosal efficacy of amoxicillin in the treatment of peptic ulcers. surfaces ; The in vitro release of the drug was rapid in the presence and delivery systems that rapidly increase in size once they are absence of the polymer coating. Interestingly, the gastric resi- in the stomach to slow the passage through the pylorus dence time in rats was longer, and the distribution of the ; microparticles on the mucosa apparently superior in the case of density-controlled delivery systems, which either float or uncoated systems. The authors concluded that the proposed sink in gastric fluids [46,47]. system failed to prolong the residence in the stomach. The major advantages and shortcomings of these concepts Jackson et al. observed extended gastric residence times will be reviewed in the following sections. of the positively charged ion-exchange resin colestyramine. In 218 Expert Opin. Drug Deliv. (2006) 3(2)  Streubel, Siepmann & Bodmeier addition, this substance had the ability to coat the gastric mucosa compared with the physical mixtures of tetracycline mucosa uniformly. The adherent behaviour was considered to and sucralfate (50 – 60 versus 25% after 3 h). The results of be responsible for the prolonged gastric residence. As the this in vitro study supported the observations in vivo. oppositely charged ion-exchange resin Amberlite IRP-69 did Schmitz et al. developed a stomach-targeted oral deliv- not possess the same characteristics, and as the coating of the ery system for low molecular-weight heparin based on mini- colestyramine with ethylcellulose (EC) reduced the effects, the tablets. Thiolated polycarbophil was used as the surface charge of the resin obviously plays a significant role in mucoadhesive carrier material and was compared with mucoadhesion and subsequent retention. These findings indi- hydroxyethylcellulose (HEC) as a non-mucoadhesive control. cate that colestyramine has an interesting potential for the The in vitro drug release profiles were similar, and near con- design of drug delivery systems aimed to topically treat the stant release rates were observed during 4 h with both poly- gastric mucosa. mers. In a gastric transit study in rats, the HEC formulations Hejazi and Amiji prepared tetracycline-loaded chitosan could not be observed in the gastric lumen at 4 h after admin- microspheres by ionic precipitation with sodium sulfate. istration, in contrast to thiolated polycarbophil-based delivery Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Cornell University on 05/25/12 Spherical particles with an average diameter of 2.0 – 3.0 µm systems. Further in vivo evaluation in rats revealed that the were formed. Depending on the preparation method, 8 – 69% relative bioavailability of oral formulations (compared with drug could be incorporated. However, the entire amount of subcutaneous administration) was significantly higher in the tetracycline was instantaneously released at pH 1.2 and 2.0 case of thiolated polycarbophil compared with HEC. due to the dissolution of the microspheres. At pH 3.5 and 5.0, Although the concept of bioadhesion gains increasing ∼ 70 and 90% of the drug was released after 3 and 8 h, respec- interest in alternative routes of administration (e.g., nasal, tively. The same authors studied the gastric residence of chi- buccal, ocular, vaginal and rectal), only a few successful tosan-based microspheres and the local tetracycline approaches to develop bioadhesive systems with prolonged concentrations following oral administration in gerbils. Of residence time in the stomach have been reported. The major the administered drug dose, ∼ 10% remained within the fasted challenge for such systems is the high turnover rate of the gas- stomach after 2 h. Most of the microspheres were found in the tric mucus and the resulting limited retention times. Further- For personal use only. colon 6 h after administration. Furthermore, the gastric resi- more, it is difficult to specifically target the gastric mucus with dence time of the chitosan-based microspheres was found to be bioadhesive polymers. For example, polycarbophil and Car- independent of the gastric pH within the range of 1.0 – 4.5. bopol stick to the various surfaces they come into contact However, the tetracycline concentration profile in the stom- with. An advantage of mucoadhesive dosage forms in the ach, following administration in the microsphere formulation, stomach (and in general) is the intimate contact with the was similar to that of an aqueous solution. The drug was pre- mucosa leading to short pathways for locally acting drugs, dominantly found in the colon and urine 6 h after administra- such as antibiotics against H. pylori. tion. Again, there was no significant difference in the tetracycline concentration profile when the gastric pH varied 3. Size-increasing drug delivery systems in the range of 1.0 – 4.5. Recently, chitosan-based microspheres with 85% tetra- Another approach to retain a dosage form in the stomach is cycline loading were prepared by ionic precipitation followed by increasing its size above the diameter of the pylorus, even by chemical crosslinking with glyoxal. Importantly, in the widest state during the housekeeper wave. Due to sig- increased residence times in the fasted gerbil stomach were nificant inter-individual variations, the cutoff size cannot be observed with these systems, compared with both tetracycline given exactly. Approximately, the dosage form should be solutions and non-crosslinked microspheres. After 2 h, 17% > 13 mm; however, even bigger units have been observed to of the crosslinked microspheres remained in the fasted stom- be emptied from the stomach. In order to facilitate swallow- ach, whereas only 10% of the non-crosslinked systems were ing, it is highly desirable to design dosage forms with an ini- retained. Furthermore, the tetracycline concentration in the tially small size, which, once they are in the stomach, stomach was higher in the case of crosslinked microspheres, significantly increase in size. The expanded state should be compared with oral solutions and non-crosslinked chitosan- achieved fairly quickly, in order to prevent premature empty- based systems at all investigated time points during 10 h. ing through the pylorus. On the other hand, the systems After 6 h, tetracycline could be detected in the stomach, the should also guarantee their clearance from the stomach after colon and the urine. predetermined time intervals, in order to avoid accumulation Higo et al. prepared a tetracycline–sucralfate complex following multiple administrations. Other characteristics of under acidic conditions and evaluated its mucoadhesive prop- an optimal size-increasing drug delivery system include: no erties both in vitro and in vivo. For this purpose, a novel effect on gastric motility and emptying pattern, no other in vitro gastric mucoadhesion test using ex vivo rat stomach local adverse effects (e.g., on the gastrointestinal wall), and was developed. Excellent mucoadhesive properties of the tetra- inexpensive industrial manufacture. cycline–sucralfate complex were demonstrated. Importantly, The increase in the system size can be based on several higher amounts of the complex were retained on the gastric principles, including unfolding in the stomach (to complex Expert Opin. Drug Deliv. (2006) 3(2) 219  Gastroretentive drug delivery systems geometric shapes); expanding due to swellable excipients; and expanding due to gas generation. Corner 3.1 Systems unfolding in the stomach Several geometric shapes, such as tetrahedron, ring, clover- leaf, disk, string and pellet/sphere, which can be packed tightly into a gelatin capsule and unfold after dissolution of the capsule shell, have been patented by Caldwell et al. Arm [202-205]. These systems consist of at least one erodible poly- mer (e.g., hydroxypropyl cellulose, Eudragit® E; Röhm Pharma GmbH), one nonerodible polymer (e.g., polyolefins, polyamides, polyurethanes), and a drug that is dispersed within the polymer matrix. The importance of the physical Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Cornell University on 05/25/12 characteristics of this type of systems, such as size, shape and flexibility on the resulting gastric emptying was studied in beagle dogs. Cloverleaf, disk, string and pellet shapes were moulded from silastic elastomer. Tetrahedron and rigid-ring shapes were fabricated from blends of low-density polyethyl- ene and ethylene:vinyl acetate copolymer. Furthermore, the devices contained barium sulfate in order to monitor their location by X-ray. These were folded, placed within gelatin capsules and administered to dogs. Interestingly, the tetra- hedron-shaped devices remained in the stomach for longer Figure 1. Tetrahedron-shaped drug delivery system formed periods of time than the other tested shapes (of similar size). by assembling two components: silastic corners and For personal use only. The gastric retention of rigid rings was significantly affected erodible arms. Reprinted from CARGILL R, ENGLE K, by their size. Disk- and cloverleaf-shaped systems showed GARDNER CR, PORTER P, SPARER RV, FIX JA: Controlled gastric only poor gastric retention. In addition, strings and pellets emptying. II. In vitro erosion and gastric residence times of an were eliminated fairly rapidly. Erodible tetrahedron-shaped erodible device in beagle dogs. Pharm. Res. (1989) 6:506-509 , with kind permission of Springer Science and Business Media. devices consisting of rods (‘arms’; made of poly[ortho ester]/ polyethylene blends) and ‘corners’ (based on silastic elas- tomer; Figure 1) showed prolonged gastric residence times in The same group studied the performance of levodopa-contain- beagle dogs. This could mainly be attributed to the con- ing multilayer films (5.0 × 2.5 cm in size) in beagle dogs. siderable size of the systems (∼ 2 cm) on unfolding. A reliable The systems consisted of an inner, drug-containing film layer exit from the stomach was ensured by the erosion of the (EC-levodopa, 1:1), covered on both sides by (outer) shielding drug-containing arms; the erosion rate being controlled by layers of enzymatically hydrolysed gelatin/Eudragit S/glycer- the polymer-blend ratio. In human volunteers, the gastric ine/glutaraldehyde blends (48:30:20:2), and a frame of rigid residence time of the tetrahedron-shaped dosage forms varied polymeric strips (L-poly[lactic acid]/EC, 9:1). Importantly, from 0.5 to 6 h. Other types of devices, which can be therapeutic levodopa concentrations (> 500 ng/ml) could be packed into gelatin capsules and considerably increase in size maintained over 9 h following the administration of one single following unfolding include Y-shaped systems and sheet- film. The mean absorption time of the drug was significantly like shaped devices , optionally with openings to reduce extended in comparison to non-gastroretentive controlled- the risk of pylorus obstruction. release particles and oral solutions. The performance of levo- Klausner et al. designed unfolding, multilayer, polymeric dopa-containing, multilayer films was also studied in humans films based on a drug-containing shellac matrix as the inner. Prolonged gastroretentivity (≥ 5 h) could be achieved due layer, covered on both sides with (outer) shielding layers com- to the rigidity and size of the dosage forms. The films rapidly posed of hydrolysed gelatin/Eudragit S (Röhm Pharma unfolded and maintained their mechanical integrity. The GmbH)/glycerine/glutaraldehyde. The system is optionally absorption period of the drug was significantly prolonged in framed with rigid polymeric strips composed of L-poly(lactic comparison to a non-gastroretentive controlled-release tablet. acid)/EC or EC-triethylcitrate. Such dosage forms placed into A tablet-shaped system with retention arms has been pat- gelatin capsules were administered to beagle dogs. Two factors ented by Curatolo and Lo [209,210]. The retention arms are ini- were found to influence the in vivo gastric retention behaviour: tially folded (e.g., fixed by a gelatin band), in order to facilitate the dimensions and the mechanical properties of the films. swallowing. Once in contact with gastric fluids, they expand With relatively large devices (surface ≥ 2.5 × 2.5 cm) and rigid and, thus, prevent rapid emptying through the pylorus. frames, prolonged residence times and improved absorption The major disadvantage of most systems that are unfolding properties could be achieved with the model drug riboflavin. in the stomach is their complex shape, making them difficult 220 Expert Opin. Drug Deliv. (2006) 3(2)  Streubel, Siepmann & Bodmeier to produce, and cost intensive on a larger scale. Furthermore, release mechanism. The gastric residence time in dogs their geometries could lead to mucosa irritation. exceeded 24 h, even under fasted conditions. Such an enzyme- digestible, swelling-hydrogel formulation was used to deliver 3.2 Systems expanding due to swellable excipients flavin mononucleotide, which is known to be absorbed only The significant swelling of this type of drug delivery system is from the upper small intestine. Importantly, the drug could be generally due to the presence of specific hydrogel formers, detected up to 50 h after administration in the blood, indicat- which drastically increase in size following contact with aque- ing the gastric retention of the hydrogel in the stomach. The ous media. Several devices based on this concept have been same group described a further, very promising, size-increas- patented [211-217]. ing gastroretentive drug delivery system [74-77] based on super- Urquhart and Theeuwes described a tablet-shaped sys- porous hydrogels with rapid swelling kinetics and tem consisting of a plurality of small, drug-containing pellets superabsorbent properties. Equilibrium swelling with these dispersed within a hydrogel-forming polymer matrix. This devices is attained in < 1 min. The swelling ratio (volume of device swelled 2- to 50-fold in the stomach, thus, potentially the swollen gel:volume of the dried form) can exceed 1000 in Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Cornell University on 05/25/12 providing extended gastric residence times. The pellets were some cases. The mechanical strength of the highly swollen, subsequently released from the system following the erosion of superporous hydrogels was increased by adding a composite the polymer matrix and the drug was released from the pellets material, such as croscarmellose sodium, which forms a dis- for gastric or intestinal absorption. persed phase within the continuous polymer matrix during Deshpande et al. developed a controlled-release gastric the synthesis (superporous hydrogel composites). Gastric retention system based on: i) a swellable core, consisting of retention experiments in dogs showed promising results. The the drug (chlorphenamine maleate or riboflavin 5′ phosphate) devices were placed in hard gelatin capsules for oral adminis- and the expanding agents polyvinyl pyrrolidone XL, tration. Even when the dog was maintained in the fasted con- Carbopol 934P and calcium carbonate, and ii) a permeable dition for 36 h before the experiment, the superporous coating, consisting of blends of Eudragit RL 30D and hydrogel composites remained in the stomach for 2 – 3 h NE 30D (Röhm Pharma GmbH) at different ratios. The tab- (after which they broke into pieces and emptied into the intes- For personal use only. lets swelled in ∼ 10 – 15 min to 2- to 4-times their original tine). On the other hand, when the initial fed state was main- volume, and drug release occurred during 15 – 18 h. The tained for the first few hours, the superporous hydrogel coating ensured the integrity of the tablet during the initial composites stayed in the stomach for > 24 h. Figure 2 shows swelling phase and subsequently controlled the release rate of the concept of the gastric retention of such a system. The the drug (the polymer-blend ratio and coating level being the superporous hydrogel composite swells to a few hundred most important parameters). The optimal ratio of Eudragit times of the original volume in a few minutes (Figure 2A). The RL 30D to NE 30D was found to be 70:30. The authors con- gastric contraction, which initially pushes the hydrogel to the cluded that this combination provides sufficient elasticity to pylorus (Figure 2B – D) slips over the surface of the system withstand the pressure of expansion during the initial swelling (Figure 2E) and pushes the hydrogel back into the body of the phase, and at the same time allows the breakdown of the stomach (Figure 2F). This process is repeated until the super- device following exhaustion of the drug. porous hydrogel composite breaks into smaller pieces. Recent A gastroretentive dosage form based on a bilayer tablet con- advances in the field led to so-called superporous hydrogel sisting of a collagen sponge, which is compressed onto a drug- hybrids, which are prepared by adding a water-soluble or containing polymer layer with controlled-release properties, water-dispersible polymer that can be crosslinked after the was developed by Cloer and Gröning. Following contact superporous hydrogel is formed. Examples for hybrid with aqueous fluids, the collagen sponge expanded to a length agents are polysaccharides, including sodium alginate, pectin, of 5 cm, which was assumed to be sufficient to prevent direct chitosan or synthetic water-soluble hydrophilic polymers, emptying through the pylorus. Drug release from this system such as poly(vinyl alcohol). Compared with conventional could be controlled by the composition of the second layer. A superporous hydrogels and superporous hydrogel composites, related device consisted of a three-layer tablet with two sus- superporous hydrogel hybrids are not easily breakable when tained-release layers at the top and one compressed collagen stretched because they possess highly elastic properties in the sponge at the bottom. swollen state, which can be very useful for the development of Park and colleagues described interesting enzyme-digestible gastrointestinal devices. hydrogels consisting of poly(vinyl pyrrolidone) crosslinked with albumin [71-73]. These hydrogels, which were especially 3.3 Systems expanding due to gas generation designed for gastroretentive dosage forms, swelled to a signifi- A drug-containing, carbon dioxide-generating, expandable cant extent (which was affected by the albumin content and system surrounded by a hydrophilic membrane has been degree of albumin alkylation). The hydrogels were degraded patented by Sinnreich. To provide an adequate control in the presence of pepsin either by bulk or by surface degrada- of drug release, a system containing drug-loaded pellets with tion. With increasing albumin alkylation, pepsin digestion extended-release surrounded by a polymer membrane was diminished and bulk degradation was the predominant (which expands reversibly due to the generation of carbon Expert Opin. Drug Deliv. (2006) 3(2) 221  Gastroretentive drug delivery systems A B C D E F Figure 2. Concept of the gastric retention of a highly swellable, gastroretentive drug delivery system proposed by Park and colleagues. A) The device significantly swells on contact with gastric fluids (to a few hundred times of the original volume); B – D) the gastric contraction pushes the hydrogel to the pylorus; E) the gastric contraction slips over the surface of the hydrogel; and F) the hydrogel is pushed back into the body of the stomach. Reprinted from CHEN J, BLEVINS WE, PARK H, PARK K: Gastric retention Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Cornell University on 05/25/12 properties of superporous hydrogel composites. J. Control. Release (2000) 64:39-51 , copyright (2000) with permission of Elsevier. dioxide following contact with gastric fluid), has been 4.2 Floating systems described by Asmussen et al.. Intragastric balloon Floating properties of drug delivery systems can be based on devices, which are deflated when introduced into the stom- several principles, including: inherent low density; low den- ach via a naso-gastric tube (followed by inflation from out- sity due to swelling; and low density due to gas generation side the body) have been patented for the purposes of and entrapment. appetite control, weight reduction and drug administration [221-223]. However, this is a very inconvenient procedure, 4.2.1 Floating drug delivery systems with inherent low which is not suitable for frequent use. density Usually, gas generation and entrapment does not only increase It is highly desirable to develop drug delivery systems that For personal use only. the size of the drug delivery system but also decreases its density, float immediately following contact with gastric fluids. This and possibly provides floating properties, thus, presenting a com- can only be achieved if the low density of the device is pro- bination of two principles to prolong the gastric residence time. vided from the beginning. Compared with systems initially However, the increase in size is the dominant mechanism of gas- settling down, the risk of premature emptying from the stom- tric retention of the systems discussed in this section, according ach is greatly reduced. Generally, inherent low density is pro- to the respective authors describing the devices. vided by entrapment of air (e.g., hollow chambers [80,224-227]) Size-increasing systems potentially present the hazard of or by the (additional) incorporation of low-density materials, permanent retention and could lead to serious life-threatening such as fatty substances or oils [228,229], or foam powder [81-83]. effects after multiple dosing. Consequently, these systems Desai and Bolton [84,230] developed a moulded agar gel tablet should consist of biodegradable materials or lose integrity with entrapped oil and air, which replaced evaporated water fol- after a desired time period. Until this happens, the systems lowing drying. Interestingly, the amount of agar needed to form should be sufficiently resistible in order to withstand the pow- the device was remarkably low (2% per tablet). In addition to erful waves from the stomach. An important shortcoming of density reduction, the oil may prevent the air entrapped within size-increasing systems is the risk to obstruct the pylorus. A the gel matrix from escaping when placed in gastric fluid due to major advantage is the independence of their performance on its hydrophobicity. The floating properties of this type of tablet the filling state of the stomach. were found to depend on the filling state of the stomach, and rel- atively constant saliva levels of the model drug theophylline were 4. Density-controlled drug delivery systems observed during the 24 h following administration in humans. Watanabe et al. described another single-unit, floating 4.1 High-density systems drug delivery system with inherent low density, consisting of As pointed out above, the density of a drug delivery system is a hollow core (empty, hard gelatin capsule or polystyrene an important factor influencing the gastric residence time. foam or pop rice grain) coated with two layers: a subcoat of High-density devices use their weight as a retention mecha- cellulose acetate phthalate, and an outer drug-containing nism. When the density of the system is larger than that of the coating of EC/hydroxypropyl methylcellulose (HPMC). This gastric juice, the device settles down to the bottom of the type of system is very interesting for low-dose drugs but may stomach, remaining located below the pylorus. However, so not be suitable if larger amounts of drug are needed for an far, no successful approach has been described for a gastro- effective therapy. retentive system being based only on high density. In contrast, Krögel and Bodmeier proposed a floating device con- it has been reported that such devices did not significantly sisting of two drug-loaded HPMC matrix tablets, which were extend the gastric residence time. placed within an impermeable, hollow polypropylene cylinder 222 Expert Opin. Drug Deliv. (2006) 3(2)  Streubel, Siepmann & Bodmeier Furthermore, a novel multiparticulate, gastroretentive drug delivery system based on low-density foam powder has been proposed and its performance demonstrated in vitro. Float- ing microparticles consisting of polypropylene foam powder; verapamil HCl as the model drug; and Eudragit RS (Röhm Pharma GmbH), EC or poly(methyl methacrylate) (PMMA) Low-density foam powder were prepared with an oil-in-water solvent extraction/evapora- tion method (Figure 4A). The drug and release-rate controlling Drug polymer were dissolved in methylene chloride. Polypropylene foam powder was then dispersed within this organic phase. Matrix-forming polymer(s) The resulting suspension was subsequently emulsified into an and, optionally, filler external aqueous, polyvinyl alcohol solution (adjusted to pH 12.5) and agitated with a stirrer to allow microparticle for- Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Cornell University on 05/25/12 mation. The microparticles were separated by sieving, then Figure 3. Schematic presentation of the structure of washed with water and dried in a desiccator. The effects of the low-density, floating matrix tablets proposed by Streubel et al. Reprinted from STREUBEL A, SIEPMANN J, BODMEIER R: various formulation and processing parameters on the internal Floating matrix tablets based on low density foam powder: effects and external particle morphology, drug loading, in vitro float- of formulation and processing parameters on drug release. Eur. J. ing behaviour, in vitro drug-release kinetics, particle-size distri- Pharm. Sci. (2003) 18:37-45 , copyright (2003) with bution, and physical state of the incorporated drug were permission of Elsevier. studied. The microparticles were irregular in shape and highly porous. The drug encapsulation efficiency was high and almost (open at both ends). Each matrix tablet closes one of the ends independent of the theoretical loading. Encapsulation efficien- of the cylinder so that an air-filled space is created inbetween, cies that were close to 100% could be achieved by varying providing a low, total-system density. The device remains either the amount of ingredients:volume of the organic-phase For personal use only. floating until at least one of the tablets has dissolved. ratio or the relative amount of Eudragit RS/EC/PMMA. In all A floating drug delivery system that is less dense than gastric cases, good in vitro floating behaviour was observed. The juice due to the incorporation of at least one porous structural release rate of the drug increased with raising drug loading and element, such as foam or a hollow body, has been patented by with decreasing Eudragit RS/EC/PMMA contents. The type Müller and Anders. Different types of dosage forms are of polymer that was used significantly affected the resulting described, including tablets. In the latter case, the hollow ele- drug-release rate, which increased in the following rank order: ments are distributed either within the matrix, compressed as a PMMA < EC < Eudragit RS. Importantly, a broad spectrum of second layer onto the tablet, or included as a core. release patterns could be obtained with the investigated formu- Recently, a single-unit, floating controlled-drug delivery lations. The size of the microparticles was found to be almost system (tablet) was proposed, consisting of polypropylene independent of the drug loading, but strongly depended on foam powder, matrix-forming polymer(s), drug and an the relative amount of Eudragit RS/EC/PMMA. Differential optional filler. The structure of this type of tablet is scanning calorimetry and X-ray measurements showed that the shown schematically in Figure 3. The highly porous foam drug was partly dissolved, and partly in the amorphous form powder provides a low density and, thus, excellent in vitro distributed throughout the system. floating behaviour of the system; all formulations kept float- Further studies focused on the development of a new prepa- ing for at least 8 h in 0.1 N HCl at 37°C. Different types of ration method for this type of low-density, foam-based, floating matrix-forming polymers were studied: HPMC, polyacryl- microparticles and on the demonstration of the systems’ per- ates, sodium alginate, corn starch, carrageenan, gum guar formance in vitro. Major advantages of a suggested novel and gum arabic. The tablets eroded on contact with the preparation technique include short processing times, no expo- release medium, and the relative importance of drug diffu- sure of the ingredients to high temperatures, the possibility to sion, polymer swelling and tablet erosion for the resulting avoid toxic organic solvents, and high encapsulation efficiencies release patterns varied significantly with the type of matrix- (close to 100%). Floating microparticles consisting of polypro- former. Importantly, the release rate could be effectively pylene foam powder, model drug (chlorphenamine maleate, adjusted by altering the matrix-forming polymer:foam pow- diltiazem HCl, theophylline or verapamil HCl), and a second der ratio, initial drug loading, tablet geometry (radius and polymer (Eudragit RS or PMMA) were prepared by soaking height), type of matrix-forming polymer, the use of polymer the microporous foam particles with an organic solution of the blends, and the addition of water-soluble or -insoluble fillers drug and polymer, and subsequent drying (Figure 4B). The (such as lactose or microcrystalline cellulose). Therefore, the effects of various formulation and processing parameters on the floating behaviour of the low-density drug delivery systems resulting in vitro floating behaviour, internal and external parti- could be successfully combined with an accurate control of cle morphology, drug loading, in vitro drug release and physical the drug release patterns. state of the incorporated drug were studied. Good in vitro Expert Opin. Drug Deliv. (2006) 3(2) 223  Gastroretentive drug delivery systems A B Teflon dish Polypropylene Polypropylene foam powder foam powder Organic solution Organic solution of of drug plus polymer drug plus polymer Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Cornell University on 05/25/12 Aqueous phase Soaking and solvent evaporation Microparticle suspension For personal use only. Drug-loaded microparticles Figure 4. Schematic presentation of the preparation of floating microparticles based on low density foam powder, using: A) a solvent evaporation method; B) a soaking method. Reprinted from. floating behaviour was observed in most cases, and a broad hydroxypropyl methylcellulose phthalate, HPMC or EC). variety of drug release patterns could be achieved by varying the The incorporation of HPMC within the outer shell showed drug loading and type of second polymer. In addition, the low- promising results concerning the control of drug release from density microparticles could be compressed into rapidly disin- the system at the pH of gastric fluids. With increasing HPMC tegrating tablets, providing an easily administrable oral dosage contents the amount of riboflavin released also increased; form. however, the floating properties of the microspheres Hollow microspheres (microballoons) consisting of decreased. The performance of these riboflavin-containing Eudragit S (an enteric polymer) containing the drug in the microballoons was also studied in vivo [94,95]. After oral polymeric shell were developed by Kawashima et al. [87-89]. administration to healthy volunteers, the intra-gastric behav- The preparation procedure and mechanism of microballoon iour was investigated by γ-scintigraphy and the urinary excre- formation is schematically illustrated in Figure 5. A solution of tion of riboflavin was followed. In the fed state, microballoons polymer and drug in ethanol/methylene chloride is poured were retained in the stomach for up to 5 h (Figure 6). In this into an agitated aqueous solution of polyvinyl alcohol. The experiment, each volunteer was given an aqueous solution of ethanol rapidly partitions into the external aqueous phase and indium-111 chloride prior to administration of the polymer precipitates around the methylene chloride drop- 99mTc-labelled samples for the purpose of outlining the stom- lets. The subsequent evaporation of the entrapped methylene ach, and a measure of inherent gastric emptying of liquid. chloride leads to the formation of internal cavities within the Importantly, the bioavailability of riboflavin was significantly microparticles. However, according to Lee et al. , many higher compared with a non-floating control formulation. drugs are not released in significant amounts from this type of Interestingly, microspheres with good floating properties but microparticles at the pH of gastric fluids. Modifications of low in vitro drug-release rates showed lower urinary excretion this system consisted of the addition of nonvolatile oil to the of riboflavin in the time period of 4 – 8 h after dosing, com- dispersed phase or the use of Eudragit S/RL mixtures. pared with microspheres with worse floating properties and The group of Kawashima also prepared hollow microspheres high in vitro drug release rates. Thus, it is important to select using mixtures of Eudragit S and other hydrophilic or hydro- an appropriate balance between the floating properties and phobic polymers (such as Eudragit L [Röhm Pharma GmbH], drug-release rates with this type of system. 224 Expert Opin. Drug Deliv. (2006) 3(2)  Streubel, Siepmann & Bodmeier Process Formation of emulsion Formation of shell Generation of gas phase Microballoon Mechanism EtOH CH2Cl2 Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Cornell University on 05/25/12 Oil/water emulsion Rapid diffusion of EtOH Evaporation and Hollow sphere diffusion of CH2Cl2 For personal use only. Figure 5. Preparation procedure (emulsion-solvent diffusion method) and mechanism of microballoon formation proposed by Kawashima et al. Reprinted from KAWASHIMA Y, NIWA T, TAKEUCHI H, HINO T, ITO Y: Hollow microspheres for use as a floating controlled drug delivery system in the stomach. J. Pharm. Sci. (1992) 81:135-140 with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. Another method for the preparation of hollow micro-