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Review
Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention
Brahma N. Singh, Kwon H. Kim*
Drug Delivery Systems Research Laboratory, College of Pharmacy and Allied Health Professions, St. John s University, Jamaica, NY 11439, USA Received 19 January 1999; accepted 19 August 1999
Abstract In recent years scientic and technological advancements have been made in the research and development of rate-controlled oral drug delivery systems by overcoming physiological adversities, such as short gastric residence times (GRT) and unpredictable gastric emptying times (GET). Several approaches are currently utilized in the prolongation of the GRT, including oating drug delivery systems (FDDS), also known as hydrodynamically balanced systems (HBS), swelling and expanding systems, polymeric bioadhesive systems, modied-shape systems, high-density systems, and other delayed gastric emptying devices. In this review, the current technological developments of FDDS including patented delivery systems and marketed products, and their advantages and future potential for oral controlled drug delivery are discussed. 2000 Elsevier Science B.V. All rights reserved.
Keywords: Intragastric oating systems; Hydrodynamically balanced systems; Gastroretentive systems; Microballoons; Buoyant delivery systems
1. Introduction The de novo design of an oral controlled drug delivery system (DDS) should be primarily aimed at
Abbreviations : CR, controlled-release; DDS, drug delivery system; F, oating; FDDS, oating drug delivery systems; FT, oating or oatation time; GET, gastric emptying time(s); GRT, gastric residence time(s); GI, gastrointestinal; HBS, hydrodynamically balanced systems; HPC, hydroxypropylcellulose; HPMC, hydroxypropylmethylcellulose; MMC, migrating myoelectric complex; NF, non-oating; PK, pharmacokinetic; PAA, polyacrylic acid; PMA, polymethacrylic acid; PVA, polyvinyl alcohol; SR, sustained-release *Corresponding author. Tel.: 11-718-990-6063; fax: 11-718990-6316.
achieving more predictable and increased bioavailability of drugs. However, the development process is precluded by several physiological difculties, such as an inability to restrain and localize the DDS within desired regions of the gastrointestinal (GI) tract and the highly variable nature of gastric emptying process. It can be anticipated that, depending upon the physiological state of the subject and the design of pharmaceutical formulation, the emptying process can last from a few minutes to 12 h. This variability, in turn, may lead to unpredictable bioavailability and times to achieve peak plasma levels, since the majority of drugs are preferentially absorbed in the upper part of the small intestine [1]. Furthermore, the relatively brief GET in humans,
0168-3659 / 00 / $ see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 99 )00204-7
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which normally averages 23 h through the major absorption zone (stomach or upper part of the intestine), can result in incomplete drug release from the DDS leading to diminished efcacy of the administered dose. Thus, control of placement of a DDS in a specic region of the GI tract offers numerous advantages, especially for drugs exhibiting an absorption window in the GI tract or drugs with a stability problem. Overall, the intimate contact of the DDS with the absorbing membrane has the potential to maximize drug absorption and may also inuence the rate of drug absorption [2,3]. These considerations have led to the development of oral controlledrelease (CR) dosage forms possessing gastric retention capabilities. As the rst part in this series of reviews on contemporary gastroretentive systems, the current technological developments in FDDS, including patented and clinically available products, formulation development strategy, and their advantages and future potential for oral controlled drug delivery are discussed.
contractions. Phase II is a period of similar duration consisting of intermittent action potentials and contractions that gradually increase in intensity and frequency as the phase progresses. Phase III is a short period of intense, large regular contractions lasting from 4 to 6 min. It is this phase, which gives the cycle the term housekeeper wave, since it serves to sweep undigested materials out of the stomach and down the small intestine. As phase III of one cycle reaches the end of the small intestine, phase III of the next cycle begins in the duodenum. Phase IV is a brief transitional phase that occurs between phase III and phase I of two consecutive cycles. In the fed state, the gastric emptying rate is slowed since the onset of MMC is delayed [7]. In other words, feeding results in a lag time prior to the onset of gastric emptying. Scintigraphic studies involving measurements of gastric emptying rates in healthy human subjects have revealed that an orally administered CR dosage form is mainly subject to two physiological adversities: the short GRT and the variable (unpredictable) GET. Yet another major adversity encountered through the oral route is the rst-pass effect, which leads to reduced systemic bioavailability of a large number of drugs. Overall, the relatively brief GI transit time of most drug products, which is approximately 812 h, impedes the formulation of a once daily dosage form for most drugs. These problems can be exacerbated by alterations in gastric emptying that occur due to factors such as age, race, sex, and disease states, as they may seriously affect the release of a drug from the DDS. It is, therefore, desirable to have a CR product that exhibits an extended GI residence and a drug release prole independent of patient related variables.
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remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is oating on the gastric contents, the drug is released slowly at a desired rate from the system. After the release of drug, the residual system is emptied from the stomach. This results in an increase in the GRT and a better control of uctuations in plasma drug concentrations in some cases. Swelling type dosage forms are such that after swallowing, these products swell to an extent that prevents their exit from the stomach through the pylorus. As a result, the dosage form is retained in the stomach for a long period of time. These systems may be referred to as plug type systems since they exhibit a tendency to remain lodged at the pyloric sphincter. Bioadhesive systems are used to localize a delivery device within the lumen and cavity of the body to enhance the drug absorption process in a site-specic manner [11]. The approach involves the use of bioadhesive polymers that can adhere to the epithelial surface of the GI tract. The proposed mechanism of bioadhesion is the formation of hydrogen- and electrostatic bonding at the mucus-polymer boundary [6]. Rapid hydration in contact with the muco-epithelial surface appears to favor adhesion, particularly if water can be excluded at the reactive surfaces [6]. Modied-shape systems are nondisintegrating geometric shapes molded from silastic elastomer or extruded from polyethylene blends, which extend the GRT depending on size, shape and exural modulus of the drug delivery device [14 19]. High-density formulations include coated pellets, which have a density greater than that of the stomach contents (|1.004 g / cm 3 ). This is accomplished by coating the drug with a heavy inert material such as barium sulfate, zinc oxide, titanium dioxide, iron powder, etc. Other delayed gastric emptying approaches of interest include sham feeding of indigestible polymers [2527] or fatty acid salts [23,24,28] that change the motility pattern of the stomach to a fed state, thereby decreasing the gastric emptying rate and permitting considerable prolongation of drug release.
These factors include density, size, and shape of dosage form, concomitant intake of food and drugs such as anticholinergic agents (e.g., atropine, propantheline), opiates (e.g., codeine) and prokinetic agents (e.g., metoclopramide, cisapride), and biological factors such as gender, posture, age, body mass index, and disease states (e.g., diabetes, Crohns disease). Most of these factors have been described here in the context of FDDS. FDDS are retained in the stomach for a prolonged period of time by virtue of their oating properties, which can be acquired by several means. Generally speaking, in order for a HBS dosage form to oat in the stomach, the density of the dosage form should be less than the gastric contents. A density of less than 1.0 g / ml has been reported in the literature. However, the oating force kinetics of such dosage forms has shown that the bulk density of a dosage form is not the most appropriate parameter for describing its buoyant capabilities. The buoyant capabilities are better represented and monitored by resultant-weight measurements and swelling experiments [29]. This is because the magnitude of oating strength may vary as a function of time and usually decreases after immersion of the dosage form into the uid as a result of the development of its hydrodynamic equilibrium [30]. While considering the role of specic gravity in GRT, the potential of food in modifying GRT should not be overlooked (Table 1). One of the earlier in vivo evaluations of FDDS by Muller-Lissner et al. [34] demonstrated that a GRT of 410 h could be achieved after a fat and protein test meal. Furthermore, food affects the GRT of dosage forms depending on its nature, caloric content and the frequency of intake [3537]. For example, Oth et al. [35] reported that the mean GRT of a bilayer oating capsule of misoprostol was 199669 min after a single light meal (breakfast). However, after a succession of meals, the data showed a remarkable prolongation of the mean GRT, to 6186208 min. In another study, Iannuccelli et al. [38] reported that in the fed state after a single meal, all the oating units had a oating time (FT) of about 5 h and a GRT prolonged by about 2 h over the control. However, after a succession of meals, most of the oating units showed a FT of about 6 h and a GRT prolonged by about 9 h over the control, though a certain vari-
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Table 1 Effects of food on GRTs of oating and non-oating (control) dosage forms a Dosage forms [References] Isradipine caps [31] Radiolabeled tabs b [22] Radiolabeled tabs b [32] Radiolabeled tabs [33] Theophylline [7]
a b
Non-oating Fasted 1.59 (n 55) 1.65 (n 54) 1.1 (n 57) 2.53 (n 54) 2.32 (n 53) Fed 2.15 (n 54) 4.43 (n 54) 1.32 (n 57) 6.27 (n 54) 7.54 (n 53)
Floating Fasted 1.0 (n 55) 0.82 (n 54) 3.37 (n 58)c 1.1 (n 57) 2.2 (n 54) 1.57 (n 53) Fed 3.60 (n 54) 5.25 (n 54) 7.0 (n 58)c 7.15 (n 57) 6.77 (n 54) 7.15 (n 53)
Values are represented as mean (h); n 5number of healthy human volunteers. Results are expressed as gastric emptying times (GET). c Floating capsules.
ability of the data owing to mixing with heavy solid food ingested after the dosing was observed. Obviously, when the gastroretentive properties of a oating dosage form is independent of meal size, it can be suggested that the dosage form will be suitable for patients with a wide range of eating habits [39]. Interestingly, most of the studies related to effects of food on GRT of FDDS share a common viewpoint that food intake is the main determinant of gastric emptying, while specic gravity has only a minor effect on the emptying process [22,31,33,40]. Stated otherwise, the presence of food, rather than buoyancy, is the most important factor affecting GRT and oating does not invariably increase GRT. In fact, studies have shown that the GET for both oating (F) and non-oating (NF) single units are shorter in fasted subjects (less than 2 h), but are signicantly prolonged after a meal (around 4 h) [22,40]. In a similar study, Agyilirah et al. [32] found that in the fed state, balloon (oating) tablets prolonged the GET by an average of 6 h over that of uncoated, nondisintegrating tablets; however, in the fasted state, the balloon tablets did not signicantly prolong GET and both tablets had much shorter emptying times compared to the fed state. Studies of Mazer et al. [31] suggested that the release and absorption kinetics of a lipophilic drug (isradipine) from a oating modied-release capsule might be affected by intragastric interaction with the lipid phase of a high-fat meal. Further, for the modiedrelease capsule, GRT was regarded as the duration of intragastric release to reach 90% release, since no further intragastric release could occur after the
capsule left the stomach. Thus, in view of foregoing discussions, it may be concluded that although oating systems possess an inherent ability for gastric retention, they rely more on the presence of a meal to retard their emptying. From the results presented in Table 1, there does not appear to be large difference between the GRT of the F and NF dosage forms. This consistency can be explained based on the fact that the gastric emptying depends on the onset of the MMC. Therefore, the GRT is signicantly increased under fed conditions, since the onset of MMC is delayed [7]. Nevertheless, the efciency of intragastric buoyant dosage forms in the fed stomach is questionable because of the intensive contractile activity of the stomach and the density of the viscous chyme. Moreover, in the fasted stomach the amount of liquid is not sufcient for the drug delivery buoy and the stomachs entire contents are emptied down the small intestine within 23 h because of the typical phase III activity [41]. Concern regarding the role of food in the prolongation of the GRT has also provided insights into other determinants of gastric retention. For instance, studies have shown that the GRT of a dosage form in the fed state can also be inuenced by its size. Small-size tablets are emptied from the stomach during the digestive phase, while larger-size units are expelled during the housekeeping waves [35]. Timmermans et al. [42] studied the effect of size on the GRT of F and NF units using g-scintigraphy. They found that F units with a diameter equal to or less than 7.5 mm had longer GRTs compared to NF units. However, the GRTs were similar for F and NF units having a larger diameter
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of 9.9 mm. This study also demonstrated that F units, which remain buoyant on gastric contents, are protected against gastric emptying during digestive phases. On the other hand, NF units lie in the antrum region and are propelled during the digestive process by peristalsis. The prolongation of the GRT by food is expected to maximize drug absorption from a FDDS. This may be rationalized in terms of increased dissolution of drug and longer residence at the most favorable sites of absorption. However, there may be rare exceptions, where the presence or absence of food in the stomach has no effect on the absorption of a drug from HBS type dosage forms [43]. The effects of food on various aspects of drug absorption have been extensively discussed in a separate publication [44]. Apart from food and buoyancy effects, there are other biological factors that can inuence the GRT. Sangekar et al. [33] concluded that the increase in retention time of HBS may also be due to effects such as adhesion to the gastric mucosa, rather than the effect of oating per se. Mojaverian et al. [45] investigated the effects of gender, posture, and age on the GRT of an indigestible solid, the Heidelberg capsule. As a result of this study, authors found that the mean ambulatory GRT in the males was signicantly faster than in their age ( 63 years)- and race-matched female counterparts (3.460.6 vs. 4.661.2 h, P ,0.01). Further, the data indicated that women emptied their stomach slower than men, regardless of weight, height, body surface area and even when the hormonal changes due to the menstrual cycle were normalized. The mean GRT for volunteers in the supine state was not statistically signicant from that in the upright, ambulatory state (3.460.8 vs. 3.560.7 h, P .0.05). In the case of elderly, the GRT was prolonged, especially in subjects .70 years old (mean GRT55.8 h; n 53). Another confounding factor is the variability of GI transit within and between individuals. Studies by Coupe et al. [46] revealed that variability in gastric emptying of single- and multiple-unit systems was large compared to that in small intestinal transit times; however, the intrasubject variation was less than intersubject for both gastric and small intestinal transit times. A comparative evaluation of the gastric transit of F and NF matrix dosage forms indicated that
buoyancy and non-buoyancy of the forms lead to distinct intragastric behaviors [47]. It was also concluded that depending on the subject posture, either standing or supine, the gastric residence period of a dosage form is function of either its buoyancy or the diametric size of the matrix. Recently, a triple radionuclide scintigraphic technique has been described for intragastric monitoring that allowed the measurement of the effects on GRT of galenic parameters (size, density of matrices), as well as of physiological parameters such as subject posture [48]. Studies were conducted in nonfasting human volunteers either in upright or in supine posture, who concurrently were given one optimized F and one NF hydrophilic matrix capsules of the same size, and three different sizes (small, [5; medium, [0; large, [000). In upright subjects, all the F forms stayed continuously above the gastric contents irrespective of their size, whereas the NF units sank rapidly after ingestion and never rose back to the surface thereafter. Thus, in upright subjects the F forms were protected against postprandial emptying. Consequently, the F forms showed prolonged and more reproducible GRTs compared to the NF forms. The signicance and extent of this prolongation when compared with NF units were the most marked for the small size units (P ,0.001) but gradually lessened as the dosage form size increased (P ,0.05 for the medium size units), to become insignicant for the large size units (P .0.05). However, there was no signicant difference between the mean GRTs of the small, medium, and large F units (P .0.05). These ndings indirectly conrm that the intragastric buoyancy of the F forms is the main factor determining their prolonged GRTs and protecting them from random gastric emptying related to antral peristaltism [49]. Similar results were reported in a recent study [50]. The mean GRTs of the NF forms were much more variable and highly dependent on their size, which were in the order of small,medium,large units, P ,0.05. Moreover, in supine subjects, a size effect inuenced the GRT of both the F and NF forms (P ,0.05). The F forms were more often emptied before the NF forms but size for size, the mean GRTs did not differ in the aggregate. Bennett et al. [51] have also demonstrated the role of posture in gastric emptying. They observed that an alginate raft emptied faster than food in subjects lying on
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their left side or on their backs and slower in subjects lying on their right side with the raft positioned in the greater curvature of the stomach. This is because when the subjects laid on their left side, the raft was presented to the pylorus ahead of the meal and so emptied faster [6].
3. Technological developments in FDDS The concept of FDDS was described in the literature as early as 1968 [52], when Davis disclosed a method for overcoming the difculty experienced by some persons of gagging or choking while swallowing medicinal pills. The author suggested that such difculty could be overcome by providing pills having a density of less than 1.0 g / ml so that pill will oat on water surface. Since then several approaches have been used to develop an ideal oating delivery system. The various buoyant
preparations include hollow microspheres (microballoons), granules, powders, capsules, tablets (pills), and laminated lms. Most of the oating systems reported in literature are single-unit systems, such as the HBS and oating tablets. These systems are unreliable and irreproducible in prolonging residence time in the stomach when orally administered, owing to their fortuitous (all-or-nothing) emptying process [53]. On the other hand, multiple-unit dosage forms appear to be better suited since they are claimed to reduce the intersubject variability in absorption and lower the probability of dose-dumping [54]. A list of drugs used in the development of FDDS thus far is given in Tables 2 and 3. Based on the mechanism of buoyancy, two distinctly different technologies, i.e., noneffervescent and effervescent systems, have been utilized in the development of FDDS. The various approaches used in and their mechanisms of buoyancy are discussed in the following subsections.
Table 2 List of drugs explored for various oating dosage forms a Microspheres Aspirin, griseofulvin and p -nitroaniline [55] Ibuprofen [56] Terfenadine [57] Tranilast [53,56] Granules Diclofenac sodium [58] Indomethacin [59] Prednisolone [60] Films Cinnarizine [61] Drug delivery device [62] Powders Several basic drugs [63] Capsules Chlordiazepoxide HCl [64] Diazepam [34,64,65] Furosemide [66] L-Dopa and benserazide [67] Misoprostol [35,68] Propranolol HCl [69] Ursodeoxycholic acid [70]
a
Tablets / Pills Acetaminophen [71,72] Acetylsalicylic acid [73] Amoxycillin trihydrate [74] Ampicillin [75] Atenolol [76,77] Chlorpheniramine maleate [8] Cinnarizine [61] Diltiazem [78] Fluorouracil [79] Isosorbide mononitrate [80] Isosorbide dinitrate [81] p -Aminobenzoic acid [81,82] Piretanide [77] Prednisolone [83] Quinidine gluconate [32] Riboavin-59-phosphate [8,84] Sotalol [85] Theophylline [4,7,86] Verapamil HCl [8789]
B.N. Singh, K.H. Kim / Journal of Controlled Release 63 (2000) 235 259 Table 3 Comparison of GRTs of oating and non-oating solid dosage forms a Drugs Dosage forms GRT (h) NFDS Diazepam Ethmozine (Moricizine HCl) Gentamycin sulfate Isradipine Metoprolol tartrate Miocamycin Pepstatin Salbutamol sulfate Tranilast
a b
241
References FDDS 4.010.0 .6 .4 2.44.8 b 56 .7 35 b 89 .3 [34,64,65] [90] [91] [31] [92] [93] [94] [95] [53]
GRT, gastric residence time; NFDS, non-oating delivery system; FDDS, oating drug delivery system. Values obtained in fed state; NR, not reported.
capsule containing a mixture of a drug and hydrocolloids. Upon contact with gastric uid, the capsule shell dissolves, the mixture swells and forms a gelatinous barrier thereby remaining buoyant in the
Fig. 1. Working principle of the hydrodynamically balanced system (HBS). The hard gelatin capsule contains a special formulation of hydrocolloids, which swell into a gelatinous mass upon contact with gastric uids. Adapted from Bogentoft [96].
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gastric juice for an extended period of time. Ushimaru et al. [98] developed SR capsules containing a mixture of a drug, a cellulose derivative or starch derivative which forms a gel in water, and a higher fatty acid glyceride or higher alcohol or a mixture thereof which is solid at room temperature. The capsules were prepared by lling capsules with the above mixture, then heating them to a temperature above the melting point of the fat / oil component and nally cooling and solidifying the mixture. A recent patent issued to G.D. Searle and Co. described a bilayer buoyant dosage form consisting of a capsule, which included a non-compressed bilayer formulation. One layer was a drug release layer containing misoprostol and other was a buoyant or oating layer. Each layer included a hydrocolloid gelling agent such as hydroxypropylmethylcellulose (HPMC), gums, polysaccharides and gelatin, which upon contact with gastric uid formed a gelatinous mass, sufcient for cohesively binding the drug release layer and oating layer. The dosage form was shown to be buoyant in gastric uid for a period up to about 13 h, whereby a substantial amount of drug was released in the stomach [68]. Desai and Bolton [7,99] developed CR oating tablets of theophylline using agar and light mineral oil. Tablets were made by dispersing a drug / mineral oil mixture in a warm agar gel solution and pouring the resultant mixture into tablet molds, which on cooling and air drying formed oatable CR tablets. Interestingly, the amount of agar needed to form the oating tablet was remarkably low (2% per tablet). The light mineral oil was essential for the oating property of the tablet since relatively high amounts of drug (75%) were used. Secondly, the light mineral oil in the formulation may prevent the air entrapped in the gel matrix from escaping when placed in gastric uid owing to its inherent hydrophobicity; however, the mechanism is not yet clear [7]. The air entrapped in the tablet gel network may reduce the density and contribute towards the buoyancy of the tablet. Their study also indicated the importance of an agar gel network in providing tablet binding properties to these non-compressed tablets, which gives the desired hardness and friability, and in controlling the drug release characteristics. In another study, these authors developed a similar formulation without using an oil [100]. Gupta [75]
developed oating ampicillin tablets using a formula and procedure similar to those of Desai [4]. However, the former formula included a buffer system that was expected to improve the stability of ampicillin in the acidic medium, especially in the slow release tablets. In this study, sodium citrate was used as a buffering agent, which maintained a pH of about 6.0 in the microenvironment of the ampicillin molecules in the tablets; the drug was most stable at pH 6.5 in non-buffered solution. Moreover, the buffering agent did not affect the dissolution rate of ampicillin. The results of this study also demonstrated that calcium gluconate increased the hardness of tablets reasonably. Dennis et al. [63] described a buoyant CR powder formulation, which may be either lled into capsules or compressed into tablets. The formulation consisted of a drug of basic character, a pH-dependent polymer, which was a water-soluble salt of alginic acid (such as sodium or potassium alginate), and a pH-independent hydrocolloid gelling agent (such as HPMC, methyl cellulose, HPC, or a mixture of two or more), and binder. The formulation was considered unique in the sense that it released the drug at a controlled rate regardless of the pH of the environment, being free of calcium ion and CO 2 producing material, and had drug release properties similar to a tablet of identical composition. Other authors have also prepared tablets with alginate and HPMC that were able to oat on gastric contents and provided SR characteristics [22,34,64]. Sheth and Tossounian [73,101] developed SR oating tablets that were hydrodynamically balanced in the stomach for an extended period of time until all the drug-loading dose was released. Tablets were comprised of an active ingredient, 080% by weight of inert materials, and 2075% by weight of one or more hydrocolloids such as methylcellulose, HPC, HPMC, hydroxyethylcellulose, and sodium carboxymethylcellulose, which upon contact with gastric uid provided a water impermeable colloid gel barrier on the surface of tablets (Figs. 2 and 3). Mitra [62] described a multilayered, exible, sheet-like medicament device that was buoyant in the gastric juice of the stomach and had SR characteristics. The device consisted of at least one dry, selfsupporting carrier lm made up of a water-insoluble polymer matrix having a drug dispersed or dissolved
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Fig. 2. Intragastric oating tablet (US Patent [4, 167, 558, September 11, 1979). Reproduced with permission from Chien [102].
therein, and a barrier lm overlaying the carrier lm. The barrier lm consisted of one water-insoluble and a water- and drug-permeable polymer or copolymer. Both barrier and carrier lms were sealed together along their periphery and in such a way as to entrap a plurality of small air pockets, which brought about the buoyancy of laminated lms. Both the desired time period for buoyancy and the
rate of drug release can be modulated by the appropriate selection of a polymer matrix. Polymers such as polycarbonate has been used to develop hollow microspheres that were capable of oating on the gastric uid and released their drug contents for prolonged period of time. Thanoo et al. [55] developed drug-loaded polycarbonate microspheres using a solvent evaporation technique. A high drug loading ( .50%) was achieved by this process. Further, increasing the drug to polymer ratio in the microspheres increased their mean particle size and the release rate of the drugs. Kawashima and coworkers [53,56] prepared hollow microspheres (microballoons) with a drug loaded in their outer shells by an emulsion-solvent diffusion method. The ethanol / dichloromethane solution of a drug and an enteric acrylic polymer was poured into an aqueous solution of polyvinyl alcohol (PVA) that was maintained at 408C. The latter solution was constantly stirred while adding the former solution to form emulsion droplets. The gas phase generated in the dispersed polymer droplet by the evaporation of dichloromethane formed an internal cavity in the microsphere of the polymer with the drug. During in vitro testing, the microballoons oated continuously over the surface of an aqueous or an acidic dissolution medium containing surfactant for more than 12
Fig. 3. Intragastric oating bilayer tablet (US Patent [4, 140, 755, February 20, 1979). Adapted from Desai [4].
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h. Further, the drug release proles from the microballoons exhibited enteric behavior, and drug release rates were controlled by changing the ratio of polymer to drug in the balloon. A patent assigned to Eisai Co. Ltd. of Japan described a oatable coated shell, which consisted essentially of a hollow globular shell made from polystyrene. The external surface of the shell was coated with an under-coating and a nal coating. While the former was a layer of a cellulose acetate phthalate, the latter consisted of a layer of ethyl cellulose and HPMC in combination with an effective amount of a pharmaceutically active ingredient selected from the group consisting of a gastric acid secretion inhibitor, a gastric acid neutralizer and an anti-pepsin inhibitor. Although these capsules were buoyant, because of the air present in the empty capsule shell, and were able to achieve prolonged residence in the stomach, it was difcult to incorporate drugs into such a system [103]. Harrigan [104] described a oating system, known as an intragastric oating drug delivery device. The device comprised of a drug reservoir encapsulated in a microporous compartment having pores along its top and bottom surfaces. The peripheral walls of the drug reservoir compartment were completely sealed to prevent any physical contact of the undissolved drug with the stomach walls (Fig. 4). The oatation chamber caused the system to oat in the gastric uid. Yuasa et al. [58] developed intragastric oating and SR granules of diclofenac sodium using a polymer solution of hydroxypropylcellulose L grade (HPC-L) and ethylcellulose, and calcium silicate as a oating carrier, which has a characteristically porous structure with numerous pores and a large individual pore volume. The coated granules acquired oating
ability from the air trapped in the pores of calcium silicate when they were coated with a polymer. Whitehead et al. [105] developed a multiple-unit oating dosage form from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm in diameter were produced by dropping a sodium alginate solution into aqueous calcium chloride. After the internal gelation was complete, beads were separated from the solution and snap-frozen in liquid nitrogen before being freeze-dried at 2408C for 24 h. The results of resultant-weight measurements suggested that these beads maintained a positive oating force for over 12 h. In their subsequent study [39], the gastroretentive properties of F beads were investigated in fed healthy male subjects, using the technique of g-scintigraphy, and compared with that of NF beads made from identical material. A prolonged GRT of over 5.5 h was achieved in all subjects for the F formulations, whereas the NF beads displayed short GRTs, with a mean onset emptying time of 1 h. Iannuccelli and co-workers [38,106] described a multiple-unit system that contained an air compartment. The units forming the system were composed of a calcium alginate core separated by an air compartment from a membrane of calcium alginate or calcium alginate / PVA. The porous structure generated by leaching of the PVA, which was employed as a water-soluble additive in the coating composition, was found to increase the membrane permeability, preventing the collapse of the air compartment. The in vitro results suggested that the oating ability increased with an increase in PVA concentration and molecular weight. A synergism between a bioadhesive system and a oating system has also been explored. Chitnis et al.
Fig. 4. Intragastric oating drug delivery device (US Patent [ 4, 055, 178, October 25, 1977). Reproduced with permission from Chien [102].
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[80] synthesized a series of bioadhesive polymers that were cross-linked polymers of methacrylic acid (PMA) and acrylic acid (PAA). Floating tablets of isosorbide mononitrate were prepared and then dipcoated with Carbopol suspensions or 0.5% suspension of these bioadhesive polymers in 0.5% Carbopol gel, and nally air-dried. The results showed that tablets coated with bioadhesive polymers had better adhesive properties at pH 1.0 as compared to those coated with suspensions of Carbopol . Further, the coated tablets had lower densities, indicating that the polymer coat might confer buoyancy to these tablets. Such studies provide a rational basis to further improve gastroretentive systems.
release pills as seeds surrounded by double layers (Fig. 5a). The inner layer was an effervescent layer containing both sodium bicarbonate and tartaric acid. The outer layer was a swellable membrane layer containing mainly polyvinyl acetate and puried shellac. Moreover, the effervescent layer was divided into two sublayers to avoid direct contact between sodium bicarbonate and tartaric acid. Sodium bicarbonate was contained in the inner sublayer and tartaric acid was in the outer layer. When the system was immersed in a buffer solution at 378C, it sank at once in the solution and formed swollen pills, like balloons, with a density much lower than 1 g / ml. The reaction was due to carbon dioxide generated by neutralization in the inner effervescent layers with the diffusion of water through the outer swellable membrane layers (Fig. 5b). The system was found to
Fig. 5. (a) A multiple-unit oral oating dosage system. Reproduced with permission from Ichikawa et al. [82]. (b) Stages of oating mechanism: (A) penetration of water; (B) generation of CO 2 and oating; (C) dissolution of drug. Key: (a) conventional SR pills; (b) effervescent layer; (c) swellable layer; (d) expanded swellable membrane layer; (e) surface of water in the beaker (378C). Reproduced with permission from Ichikawa et al. [82].
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oat completely within 10 min and approximately 80% remained oating over a period of 5 h irrespective of pH and viscosity of the test medium. While the system was oating, a drug ( p -aminobenzoic acid) was released. A variant of this approach utilizing citric acid (anhydrous) and sodium bicarbonate as effervescing agents and HPC-H grade as a release controlling agent has also been reported [79]. In vitro results indicated a linear decrease in the FT of the tablets with an increase in the amount of effervescing agents in the range of 1020%. Attempts have also been made to develop SR oating tablets using a mixture of sodium bicarbonate, citric acid and chitosan. Inouye et al. [83] used two types of chitosan with different degrees of deacetylation (chitosan H and L) and prednisolone as a model drug. Although both chitosans provided SR of drug in acidic dissolution medium, and imparted quick buoyancy to the preparations, the drug release from the preparation using chitosan L was slower than that from the preparation of chitosan H. In a follow up study by the same group, the release properties were controlled by regulating the chitosan content of the granules, or the chitosan L membrane thickness of the laminated preparations [60]. Chitosan based SR oating granules for indomethacin have also been developed [59]. Umezawa [94] developed oating minicapsules having a diameter in the range of 0.12.0 mm. The core (center) of minicapsules was comprised of a granule of sodium bicarbonate admixed with lactose and polyvinylpyrrolidone, coated by repeated spraying with a 2% methanol solution of HPMC in a coating pan. The center was then outer coated with pepstatin. The CO 2 that was liberated on contact with gastric acid caused the minicapsules to oat and permitted pepstatin to stay longer in the stomach. It was claimed that oral administration of an amount containing 50200 mg pepstatin per dose could release enough pepstatin to suppress the pepsin activity in patients being treated for gastric and duodenal ulcers. Ichikawa et al. [112] described a similar capsule, which contained a plurality of granules having different residence times in the stomach. The granules were comprised of a core containing the drug, coated by double layers. The inner coat was a foamable layer, and the outer layer was an expansive
lm layer comprising a polymer, which allowed gastric juice to pass therethrough and expand by foam produced by the reaction between the gastric juice and the foamable layer. Moreover, the foamable layer was divided into two sublayers: an inner layer containing bicarbonate and an outer layer containing an organic acid. It is worth mentioning here that carbonates, in addition to imparting buoyancy to these formulations, provide the initial alkaline microenvironment for polymers to gel [8]. Moreover, the release of CO 2 helps to accelerate the hydration of the oating tablets, which is essential for the formation of a bioadhesive hydrogel [87]. This provides an additional mechanism (bioadhesion) for retaining the dosage form in the stomach, apart from oatation. Based on this approach, Asrani [87] developed a novel oating bioadhesive DDS using verapamil HCl as the model drug. In the study, tablet buoyancy was found to be affected by the amount of sodium bicarbonate added and the type of polymer used in the formulations. Further, these formulations were capable of sustaining release up to 24 h. As a matter of fact, there are several factors that inuence the buoyancy of oating tablets. These include nature of excipients, viscosity grades of the polymers, tablet weight, tablet density, tablet diameter and pH of the dissolution medium [71,72,113]. Similar formulation variables are known to affect the in vitro performance of oating capsules. These variables include polymer excipients, contents of the polymer, weight of the lled powdered mixture (i.e., density of the capsules), and the amount of the effervescent added [89]. Atyabi and co-workers [114116] developed a oating system utilizing ion exchange resins. The system consisted of resin beads, which were loaded with bicarbonate and a negatively charged drug that was bound to the resin. The resultant beads were then encapsulated in a semipermeable membrane to overcome rapid loss of CO 2 . Upon arrival in the acidic environment of stomach, an exchange of chloride and bicarbonate ions took place, as was expected. As a result of this reaction, CO 2 was released and trapped in the membrane, thereby carrying beads toward the top of gastric contents and producing a oating layer of resin beads. In contrast, the uncoated beads sank quickly. Radioactivity mea-
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surement by scintigraphy showed that gastric residence was substantially prolonged, compared with a control, when the system was given after a light, mainly liquid meal. Furthermore, the system was capable of slow release of drug, a property which widens the scope of such oating system for SR preparation of drugs possessing negative charge since they can be easily bound to the resin in combination with bicarbonate ions. Todd and Fryers [117] described a similar formulation, which contained anhydrous cholestyramine (an anionic exchange resin), low viscosity grade alginic acid / sodium alginate, citric acid, and sufcient sodium carbonate or bicarbonate mixtures thereof to neutralize the acid groups of the alginic and citric acids. Two patents on FDDS issued to the Alza Corporation disclosed drug delivery devices for the controlled and continuous administration of medicinal agents [108,109]. As an osmotically controlled oating system, the device comprised of a hollow deformable unit that was convertible from a collapsed to an expanded position and returnable to a collapsed position after an extended period of time. A housing was attached to the deformable unit and it was internally divided into a rst and second chamber with the chambers separated by an impermeable, pressure responsive movable bladder. The rst chamber contained an active drug, while the
second contained a volatile liquid, such as cyclopentane or ether that vaporizes at physiological temperature to produce a gas, enabling the drug reservoir to oat. To enable the unit to exit from the stomach, the device contained a bioerodible plug that allowed the vapor to escape (Figs. 6 and 7). Although this type of sophisticated dosage form might be used to administer a drug at a controlled rate for a prolonged period of time, it could not be recommended for smokers because of safety reasons [6]. Floating dosage forms with an in situ gas generating mechanism are expected to have greater buoyancy and improved drug release characteristics. However, the optimization of the drug release may alter the buoyancy and, therefore, it is sometimes necessary to separate the control of buoyancy from that of drug release kinetics during formulation optimization [1]. Mitchell and Phadke (Drug release modulation in a press-coated hydrophilic polymer matrix containing an effervescent core, Marion Merrell Dow Inc., Kansas City, MO, unpublished data) investigated the release of pseudoephedrine HCl from press-coated tablets where the core was composed of an effervescent mixture (anhydrous citric acid and sodium bicarbonate) and HPMC formed the outer coat. Their results demonstrated that by press coating the hydrophilic polymer and drug matrix onto an effervescent core, it was possible to modify
Fig. 6. Intragastric osmotic controlled drug delivery system (US Patent [ 3, 786, 813, January 22, 1974). Reproduced with permission from Chien [102].
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Fig. 7. Gastro-inatable drug delivery device (US Patent [3, 901, 232, August 26, 1975). Reproduced with permission from Chien [102].
the dissolution rate of pseudoephedrine HCl from the matrix, allowing slower initial release and more complete release than could be obtained with a single layer polymer matrix tablet. It is noteworthy here that release kinetics for effervescent oating systems signicantly deviate from the classical Higuchi model and approach zero-order kinetics systems [82,89,110]. This deviation in drug release behavior has been attributed to the air entrapped in the matrix [118], which is considered a barrier to diffusion, and matrix relaxation [89]. In contrast, noneffervescent oating systems obey the Higuchi model, indicating that drug release occurs via a diffusion mechanism [7,69,89,95].
where it is practically insoluble and is poorly absorbed. The HBS system maximizes the dissolution of the drug by prolonging the GRT. Moreover, pharmacokinetic data have demonstrated the blood level equivalence of once per day dosing with the HBS capsule to three times daily dosing from conventional, 5-mg Valium tablets [64]. Floating liquid alginate preparations, e.g., Liquid Gaviscon, are used to suppress gastroesophageal reux and alleviate the symptoms of heart burn. The formulation consists of a mixture of alginate, which forms a gel of alginic acid, and a carbonate or bicarbonate component (e.g., sodium bicarbonate), which reacts with gastric acid and evolve CO 2 bubbles. The gel becomes buoyant by entrapping the gas bubbles, and oats on the gastric contents as a viscous layer, which has a higher pH than the gastric contents [119]. Topalkan is a third-generation aluminummagnesium antacid that involves not only its antacid properties but an even greater degree the availability of alginic acid in its formula. It has antipeptic and protective effects with respect of the mucous membrane of the stomach and esophagus, and provides, together with the magnesium salts, a oating layer of the preparation in the stomach [120]. Almagate FlotCoat is another novel antacid formulation that confers a higher antacid potency together with a prolonged GRT and a safe as well as extended delivery of antacid drug [121]. It is obvious that these newer formulations differ from the standard antacid products, which are either rapidly neutralized to water-soluble ions or sediment to the fundus of the stomach, and are evacuated into the duodenum by normal peristalsis [121].
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ments of various excipients, these authors concluded that higher molecular weight polymers and slower rates of polymer hydration are usually associated with enhanced oating behavior. Therefore, the selection of high molecular weight and less hydrophilic grades of polymers seems to improve oating characteristics [29]. However, there are certain undesirable properties associated with hydrophilic polymers. For instance, a capsule containing hydrophilic minimatrices (minitablets) has a stronger tendency to quickly form a single cohesive mass in vivo, due to the imbibed gastric uids, which would be emptied from the stomach as such [127]. In fact, such capsules exhibit a tendency to adhere to one another before being administered orally, which is due to the inherent nature of gelatin capsule shells and the hydration of the minitablets on storage. Rouge et al. [54] have described two different approaches to circumvent this problem: (1) addition of a protective ller excipient into the capsule, and (2) coating the minitablets with Eudragit NE30D (ethyl acrylate / methylmethacrylate), which is insoluble in gastric juice but permeable and swellable. Thus, prevention of aggregation improves the dispersion of minitablets, thereby increasing the contact surface area of tablets with the medium, which may increase the drug release.
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integration apparatus containing 900 ml of 0.1 N HCl as a testing medium maintained at 378C. The time required to oat the HBS dosage form is noted as oating (or oatation) time. Dissolution tests are performed using the USP dissolution apparatus. Samples are withdrawn periodically from the dissolution medium, replenished with the same volume of fresh medium each time, and then analyzed for their drug contents after an appropriate dilution. Recent methodology as described in USP XXIII states The dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started. A small, loose piece of nonreactive material such as not more than a few turns of a wire helix may be attached to the dosage units that would otherwise oat. However, standard dissolution methods based on the USP or British Pharmacopoeia (BP) have been shown to be poor predictors of in vitro performance for oating dosage forms [128,129]. Pillay and Fassihi [128] investigated the application of the helical wire sinker to the swellable oating system containing theophylline (a sparingly water-soluble drug). They observed that the procedure tends to inhibit the three-dimensional swelling process of the dosage form and consequently drug release from the formulation was suppressed. Based on their observations, the authors proposed an alternative method in which the oatable delivery system was fully submerged under a ring / mesh assembly. The results showed signicant increase in drug release ( .20%). In addition, the proposed method was found to provide reproducible hydrodynamic conditions and consistent release proles. However, in the case of a swellable oating system, which contained diltiazem (a highly watersoluble drug), the authors did not nd any difference in release between the proposed method and the USP method. These nding led to the conclusion that drug release from swellable oating systems depends on full surface exposure, unhindered swelling and the drug solubility in water. Another attempt to modify ofcial dissolution methods was made by Burns et al. [130] who developed and validated an in vitro dissolution method for a oating dosage form which had both rapid release and SR properties. The method, although based on the standard BP (1993) / USP (1990) apparatus 2 method, was modied such that paddle
blades were positioned at the surface of the dissolution medium. The results obtained with this modied paddle method showed reproducible biphasic-release dissolution proles when paddle speeds were increased from 70 to 100 rpm and the dissolution medium pH was varied from 6.0 to 8.0. The dissolution prole was also unaltered when the bile acid concentration in the dissolution medium was increased from 7 to 14 mM. In contrast, the standard paddle or basket methods as described in the BP (1993) were unable to provide either sufcient mixing of the dissolution medium to disperse oily rapid release material or sufcient mechanical erosion of the SR component of the formulation. In additional studies [129], the authors modied a standard dissolution vessel for more reliable assessment of the performance of oating dosage forms, particularly those which rely on an erosion mechanism for drug release. The results showed a more reproducible dissolution prole while eliminating the need for the positioning of the paddle blades at the surface of the dissolution medium, thereby simplifying sampling procedures and preventing adhesion of dosage forms to the paddle blades. Nevertheless, the method retained its ability to differentiate between acceptable and unacceptable dissolution performance. The specic gravity of FDDS can be determined by the displacement method using analytical grade benzene as a displacing medium [33]. Timmermans [30] recommended that the initial (dry and Moes state) bulk density of the dosage form and changes in the oating strength with time should be characterized prior to in vivo comparison between F and NF units. Further, the optimization of oating formulations should be realized in terms of stability and durability of the oating forces produced, thereby avoiding unforeseeable variations in oating capability that might occur during in vivo studies. These investigators have also described a method for determining the buoyant capabilities of the F forms and the sinking characteristics of the NF forms [131,132]. The method involves the use of a specially designed apparatus for measuring the total force acting vertically on an object immersed in a liquid. The technical details of the apparatus used in this method have been described elsewhere [131,133]. The in vivo gastric retentivity of a oating dosage
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form is usually determined by g-scintigraphy [42] or roentgenography [53,81,95]. Studies are done both under fasted and fed conditions using F and NF (control) dosage forms. It is also important that both dosage forms are nondisintegrating units, and human subjects are young and healthy.
Madopar formulation is essentially complete in less than 30 min [67]. Pharmacokinetic (PK) studies in Parkinsonian patients and healthy volunteers have also revealed that Madopar HBS behaves as a controlled / slow-release formulation of L-dopa and benserazide [43,134]. In comparison with standard Madopar , the rate of absorption was reduced, providing lower peak concentrations of L-dopa. Further, the drug was released and absorbed over a period of 45 h, thus maintaining substantial plasma concentrations for 68 h after dosing [43]. Desai and Bolton [7] compared the dissolution proles of oating theophylline CR tablet (300 mg) and a commercial SR tablet (Theo-Dur ; 300 mg). They found that oating tablets showed a more gradual release of the drug. The initial release rate was found to be comparatively faster, with a slower rate after 8 h. On the other hand, the release rate of Theo-Dur was slower initially but increased later. However, these differences were not statistically signicant, and two formulations were regarded as bioequivalent.
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(uterotonic activity), or a combination of intestinal and systemic exposure (diarrhea), while maintaining its antiulcer efcacy. In addition, the prolonged gastric availability of the misoprostol from a sitedirected delivery system may also reduce the dosing frequency [135]. Floating tablets containing 2050 mg of 5-uorouracil have been successfully evaluated in four patients with stomach neoplasms in which tablets remained oating in the stomach for a period of 2 h after administration [79].
Pharmacokinetic studies by Miyazaki et al. [59] demonstrated that oating granules of indomethacin prepared with chitosan were superior to the conventional commercial capsules in terms of the decrease in the peak plasma concentration and maintenance of indomethacin concentration in plasma. The values of various bioavailability parameters are shown in Table 4. There are only few instances in which the relative bioavailability of a oating dosage form is reduced compared to the conventional dosage form. An illustrative example is that of SR oating tablets of amoxycillin trihydrate the in vivo evaluation of which in healthy fasted males indicated that the relative bioavailability was reduced to 80.5% when compared with the conventional capsules; other pharmacokinetic parameters indicated no improved efcacy even though the tablets remained buoyant for 6 h and had a satisfactory release pattern in vitro [74]. However, the lower bioavailability of drugs could be balanced in part by potential clinical advantages of FDDS, and may be compensated by taking a higher daily dose. For instance, in patients with advanced Parkinsons disease, who experienced pronounced uctuations in symptoms while on standard L-dopa treatment, a HBS dosage form provided a better control of motor uctuations [136,137] (for review, see Ref. [138]), although its bioavailability had been found to be 50 to 60% of the standard formulation [134,139]. There were signicant improvements with regard to both akinetic and dyskinetic phenomena. The reduced uctuations in the plasma levels of drugs result from delayed gastric emptying. After oral dosing the bioavailability of standard Madopar has been found to be 6070%; the difference in bioavailabilities of standard and HBS formulations seems to be due to incomplete absorption rather than an altered disposition of the drug [43]. Cook et al. [140] demonstrated that a HBS capsule containing iron salts has an increased efcacy and reduced side effects. Floating dosage forms with SR characteristics can also be expected to reduce the variability in transit performance [50] and various pharmacokinetic parameters [134]. It might be expected that developing HBS dosage form for tacrine might provide a better delivery system and reduce its GI side effects in Alzeihmers patients. In addition, buoyant delivery systems might provide a benecial
B.N. Singh, K.H. Kim / Journal of Controlled Release 63 (2000) 235 259 Table 4 Comparative pharmacokinetic parameters for oating (F) and non-oating (NF) dosage forms a
Drugs Numbers of subjects Oral dose (mg) Cmax ( mg/ml) F Acetaminophen b [72] 6 500 2.027 (0.692.787) NF 10.399 c (7.73614.086) 1.467 d (0.5601.944) 6.833 c (1.989) 0.167 c (0.053) 0.068 d (0.023) 0.127 f (0.026) 0.431 c (0.071) 5.76 c (2.11) 2.59 f (0.35) 0.0132 g (0.003870.0182) 24.5 m (15.6105) 3.69 f (1.28) 5.53 c (1.16) 8.67 d,f (2.07) AUC u ` ( mg?h/ml) F 27.025 (8.72544.267) NF 32.348 c (11.25945.872) 20.283 d (3.76241.103) 18.967 c (4.167) 1.228 c (0.354) 0.876 d (0.174) 0.66 f (0.121) 1.02 c (0.051) 9.39 c (2.51) 9.37 f (1.56) 0.0283 g (0.01390.0357) 21.7 m (7.3566.2) 92.19 f (46.45) 30.5 c (4.9) 39.5 d,f (8.5) t max (h) F 3.00 (0.55.0) NF 0.67 c (0.51.0) 3.50 d (2.05.0) 1.917 c (1.068) 2.6 c (0.9) 3.7 d (1.2) 2.01 f (0.43) 0.53 c (0.12) 0.51.5 c 12 f 1.5 g (11.5) 1.0 m (0.51.25) 8.0 f (0.0) 3.0 c (0.86) 4.17 d,f (1.35) t 1 / 2 (h) F NR
253
NF NR
500
NR
25
11.3 (8.1)
Furosemide h [66]
30 F,f 40 c
0.323 (0.102)
0.982 (0.186)
1.05 (0.22)
2.05 (0.44)
Indomethacin i [59]
25
3.62 j (1.75) 2.23 k (0.33) 0.00082 g (0.000660.00107) 0.64 m (0.3824.6) 3.04 (0.77) 5.65 f (0.65)
11.63 j (3.12) 10.65 k (2.30) 0.0114 g (0.01060.015) 0.42 m (0.168.59) 105.77 (54.48) 29.3 f (3.4)
NR NR 13.5 g (7.726.5)
Isradipine l [31]
10
NR
Theophylline b [7]
300
NR
NR
12
450
NR
NR
Values represented as mean ( 6S.D. or range) except for isradipine in which median value is listed for each parameter; NR, not reported. Data obtained from saliva of healthy human volunteers (fasted). c Immediate release formulations. d High density formulations. e AUC 0 12 h f Sustained-release formulations. g Data obtained from plasma of healthy human volunteers (fasted). h Data obtained from plasma of beagle dogs. i Data obtained from plasma of rabbits and AUC represented as AUC 0 8 h. . j Drugchitosan ratio51:0.5 k Drugchitosan ratio51:2 l AUC 0 24 h m Data obtained from gastric juice of healthy human volunteers (fasted), Cmax as mg / g and AUC 0 24 h as mg?h / g). n Cmax as mmol / l and AUC 0 8 h as mmol?h / l.
b
strategy for the treatment of gastric and duodenal cancers. The concept of FDDS has also been utilized in the
development of various anti-reux formulations. Washington et al. [141] investigated the gastric distribution and residence time of a pectin-containing
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formulation. They observed that the formulation was able to oat and form a discrete phase on top of the stomach contents. Indeed, the product emptied from the stomach more slowly than the food (P ,0.05), and more than 50% of the formulation remained in the fundal region for 3 h. Atyabi et al. [114] reported a oating system prepared from anionic exchange resins that could also be used as a protective barrier (oating seal) against gastroesophageal reux. Todd and Fryers [117] have described a similar pharmaceutical composition that could be used in the treatment of biliary gastritis, which results from duodeno-gastric reux of bile into the stomach. Apart from aforementioned advantages, oating systems are particularly useful for acid-soluble drugs [6], drugs which are poorly soluble or unstable in intestinal uids [142], and those which may undergo abrupt changes in their pH-dependent solubility due to factors such as food, age and pathophysiological conditions of the GI tract. Developing controlled release systems for such drugs as bromocriptine might lead to potential treatment of Parkinsons disease. After oral administration, approximately 30% of the dose is absorbed from the GI tract [143]. However, its low absorption potential, which often results from low dose usage, might be improved by a HBS dosage form, which could signicantly enhance its therapeutic efcacy. Furthermore, the co-delivery of bromocriptine and metoclopramide based on a dual delivery concept similar to that of the Madopar HBS might further improve the therapeutic efcacy of the HBS dosage form. The use of metoclopramide, a standard antiemetic agent, is justiable since it can prevent the side effects caused especially by high doses of bromocriptine [144]. Another therapeutic area in which FDDS can be explored is the eradication of Helicobacter pylori, which is now believed to be the causative bacterium for chronic gastritis and peptic ulcers. Although the bacterium is highly sensitive to most antibiotics, its eradication from patients requires high concentrations of drug be maintained within the gastric mucosa for a long duration [145]. Recently Katayama et al. [146] developed a SR liquid preparation of ampicillin using sodium alginate that spreads out and adheres to the gastric mucosal surface whereby the drug is continuously released. Thus, it
can be expected that topical delivery of a narrowspectrum antibiotic through a FDDS may result in complete removal of the organisms in the fundal area of the gastric mucosa due to bactericidal drug levels being reached in this area, and might lead to better treatment of peptic ulcer disease.
5.4. Limitations
One of the disadvantages of oating systems is that they require a sufciently high level of uids in the stomach for the drug delivery buoy to oat therein and to work efciently. However, this limitation can be overcome by coating the dosage form with bioadhesive polymers, thereby enabling them to adhere to the mucous lining of the stomach wall [80]. Alternatively, the dosage form may be administered with a glass full of water (200250 ml). Floating systems are not feasible for those drugs that have solubility or stability problems in gastric uids. Drugs such as nifedipine, which is well absorbed along the entire GI tract and which undergoes signicant rst-pass metabolism, may not be desirable candidates for FDDS since the slow gastric emptying may lead to reduced systemic bioavailablity [1]. Also there are limitations to the applicability of FDDS for drugs that are irritant to gastric mucosa.
6. Conclusions The currently available polymer-mediated noneffervescent and effervescent FDDS, designed on the basis of delayed gastric emptying and buoyancy principles, appear to be an effective and rational approach to the modulation of controlled oral drug delivery. This is evident from the number of commercial products and a myriad of patents issued in this eld. The FDDS become an additional advantage for drugs that are absorbed primarily in the upper segments of GI tract, i.e., the stomach, duodenum, and jejunum. Some of the unresolved, critical issues related to the rational development of FDDS include (1) the quantitative efciency of oating delivery systems in the fasted and fed states; (2) the role of buoyancy in enhancing GRT of FDDS; and (3) the correlation between prolonged
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GRT and SR / PK characteristics. Finally, with an increasing understanding of polymer behavior and the role of the biological factors mentioned above, it is suggested that future research work in the oating drug delivery systems should be aimed at discovering means to accurately control the drug input rate into the GI tract for the optimization of the pharmacokinetic and toxicological proles of medicinal agents.
Acknowledgements Brahma Singh gratefully acknowledges St. Johns University, the College of Pharmacy and Allied Health Professions for the support he received as a doctoral fellow.
References
[1] N. Rouge, P. Buri, E. Doelker, Drug absorption sites in the gastrointestinal tract and dosage forms for site-specic delivery, Int. J. Pharm. 136 (1996) 117139. [2] M.A. Longer, H.S. Chng, J.R. Robinson, Bioadhesive polymers as platforms for oral controlled drug delivery III: Oral delivery of chlorothiazide using a bioadhesive polymer, J. Pharm. Sci. 74 (1985) 406411. [3] V. Alvisi, A. Gasparetto, A. Dentale, H. Heras, A. FellettiSpadazzi, A. DAmbrosi, Bioavailability of a controlled release formulation of ursodeoxycholic acid in man, Drugs Exp. Clin. Res. 22 (1996) 2933. [4] S. Desai, A novel oating controlled release drug delivery system based on a dried gel matrix, M.S. thesis, St. Johns University, Jamaica, NY, 1984. [5] J.T. Fell, Targeting of drugs and delivery systems to specic sites in the gastrointestinal tract, J. Anat. 189 (1996) 517 519. [6] C.G. Wilson, N. Washington, The stomach: its role in oral drug delivery, in: M.H. Rubinstein (Ed.), Physiological Pharmaceutics: Biological Barriers to Drug Absorption, Ellis Horwood, Chichester, 1989, pp. 4770. [7] S. Desai, S. Bolton, A oating controlled-release drug delivery systems: in vitroin vivo evaluation, Pharm. Res. 10 (1993) 13211325. [8] A.A. Deshpande, N.H. Shah, C.T. Rhodes, W. Malick, Development of a novel controlled-release system for gastric retention, Pharm. Res. 14 (1997) 815819. [9] J. Urquhart, F. Theeuwes, Drug delivery system comprising a reservoir containing a plurality of tiny pills, US Patent 4, 434, 153, February 28, 1984. [10] R.C. Mamajek, E.S. Moyer, Drug-dispensing device and method, US Patent 4, 207, 890, June 17, 1980.
[11] V.M. Lenaerts, R. Gurny, in: Bioadhesive Drug Delivery Systems, CRC Press, Boca Raton, FL, 1990. [12] C.M. Lehr, Bioadhesion technologies for the delivery of peptide and protein drugs to the gastrointestinal tract, Crit. Rev. Ther. Drug Carrier Syst. 11 (1994) 119160. [13] G. Ponchel, J.M. Irache, Specic and non-specic bioadhesive particulate systems for oral delivery to the gastrointestinal tract, Adv. Drug Del. Rev. 34 (1998) 191219. [14] R. Cargill, L.J. Caldwell, K. Engle, J.A. Fix, P.A. Porter, C.R. Gardner, Controlled gastric emptying. I. Effects of physical properties on gastric residence times of nondisintegrating geometric shapes in beagle dogs, Pharm. Res. 5 (1988) 533536. [15] L.J. Caldwell, C.R. Gardner, R.C. Cargill, Drug delivery device which can be retained in the stomach for a controlled period of time, US Patent 4, 735, 804, April 5, 1988. [16] L.J. Caldwell, C.R. Gardner, R.C. Cargill, T. Higuchi, Drug delivery device which can be retained in the stomach for a controlled period of time, US Patent 4, 758, 436, July 19, 1988. [17] L.J. Caldwell, C.R. Gardner, R.C. Cargill, Drug delivery device which can be retained in the stomach for a controlled period of time, US Patent 4, 767, 627, August 30, 1988. [18] J.A. Fix, R. Cargill, K. Engle, Controlled gastric emptying. III. Gastric residence time of a nondisintegrating geometric shape in human volunteers, Pharm. Res. 10 (1993) 1087 1089. [19] F. Kedzierewicz, P. Thouvenot, J. Lemut, A. Etienne, M. Hoffman, P. Maincent, Evaluation of peroral silicone dosage forms in humans by gamma-scintigraphy, J. Control. Release 58 (1999) 195205. [20] A.B. Rednick, S.J. Tucker, Sustained release bolus for animal husbandry, US Patent 3, 507, 952, April 21, 1970. [21] H. Bechgaard, K. Ladefoged, Distribution of pellets in the gastrointestinal tract. The inuence on transit time exerted by the density or diameter of pellets, J. Pharm. Pharmacol. 30 (1978) 690692. [22] S.S. Davis, A.F. Stockwell, M.J. Taylor, J.G. Hardy, D.R. Whalley, C.G. Wilson, H. Bechgaard, F.N. Christensen, The effect of density on the gastric emptying of single- and multiple-unit dosage forms, Pharm. Res. 3 (1986) 208213. [23] R. Groning, G. Heun, Oral dosage forms with controlled gastrointestinal transit, Drug Dev. Ind. Pharm. 10 (1984) 527539. [24] R. Groning, G. Heun, Dosage forms with controlled gastrointestinal passage-studies on the absorption of nitrofurantoin, Int. J. Pharm. 56 (1989) 111116. [25] J. Russell, P. Bass, Canine gastric emptying of polycarbophil: an indigestible, particulate substance, Gastroenterology 89 (1985) 307312. [26] J. Russell, P. Bass, Canine gastric emptying of ber meals: inuence of meal viscosity and antroduodenal motility, Am. J. Physiol. 249 (1985) G662G667. [27] S.H. Leung, B.K. Irons, J.R. Robinson, Polyanionic hydrogel as a gastric retention system, J. Biomater. Sci. Polym. Ed. 4 (1993) 483492. [28] G.E. Heun, Entwicklung von peroral applizierbaren Ar-
256
B.N. Singh, K.H. Kim / Journal of Controlled Release 63 (2000) 235 259 zneiformen mit aktiv gesteuerter Gastrointestinalpassage, Dissertation Braunschweig, 1987. V.S. Gerogiannis, D.M. Rekkas, P.P. Dallas, N.H. Choulis, Floating and swelling characteristics of various excipients used in controlled release technology, Drug Dev. Ind. Pharm. 19 (1993) 10611081. J. Timmermans, A.J. Moes, How well do oating dosage forms oat?, Int. J. Pharm. 62 (1990) 207216. N. Mazer, E. Abisch, J.C. Gfeller, R. Laplanche, P. Bauerfeind, M. Cucala, M. Lukachich, A. Blum, Intragastric behavior and absorption kinetics of a normal and oating modied-release capsule of isradipine under fasted and fed conditions, J. Pharm. Sci. 8 (1988) 647657. G.A. Agyilirah, M. Green, R. DuCret, G.S. Banker, Evaluation of the gastric retention properties of a cross-linked polymer coated tablet versus those of a non-disintegrating tablet, Int. J. Pharm. 75 (1991) 241247. S. Sangekar, W.A. Vadino, I. Chaudry, A. Parr, R. Beihn, G. Digenis, Evaluation of the effect of food and specic gravity of tablets on gastric retention time, Int. J. Pharm. 35 (1987) 187191. S.A. Muller-Lissner, N. Will, W. Muller-Duysing, F. Heinzel, A.L. Blum, A oating capsule with slow release of drugs: a new method of oral drug medication, Dtsch. Med. Wochenschr. 106 (1981) 11431147, Article in German. M. Oth, M. Franz, J. Timmermans, A. Moes, The bilayer oating capsule: a stomach-directed drug delivery system for misoprostol, Pharm. Res. 9 (1992) 298302. J.G. Moore, P.E. Christian, J.A. Brown, C. Brophy, F. Datz, A. Taylor, N. Alazraki, Inuence of meal weight and caloric content on gastric emptying of meals in man, Dig. Dis. Sci. 29 (1984) 513519. P. Mojaverian, R.K. Ferguson, P.H. Vlasses, M.L. Rocci, A. Oren, J.A. Fix, L.J. Caldwell, C. Gardner, Estimation of gastric residence time of the Heidelberg capsule in humans: effect of varying food composition, Gastroenterology 89 (1985) 392397. V. Iannuccelli, G. Coppi, R. Sansone, G. Ferolla, Air compartment multiple-unit system for prolonged gastric residence. Part II. In vivo evaluation, Int. J. Pharm. 174 (1998) 5562. L. Whitehead, J.T. Fell, J.H. Collett, H.L. Sharma, A.-M. Smith, Floating dosage forms: an in vivo study demonstrating prolonged gastric retention, J. Control. Release 55 (1998) 312. S.A. Muller-Lissner, A.L. Blum, The effect of specic gravity and eating on gastric emptying of slow-release capsules, New Engl. J. Med. 304 (1981) 13651366. A. Rubinstein, D.R. Friend, Specic delivery to the gastrointestinal tract, in: A.J. Domb (Ed.), Polymeric Site-Specic Pharmacotherapy, Wiley, Chichester, 1994, pp. 282283. J. Timmermans, B. Van Gansbeke, A.J. Moes, Assessing by gamma scintigraphy the in vivo buoyancy of dosage forms having known size and oating force proles as a function of time, Proc. 5th Int. Conf. Pharm. Technol., vol. I, APGI, Paris, 1989, 4251. S.L. Malcolm, J.G. Allen, H. Bird, N.P. Quinn, M.H. Marion, C.D. Marsden, C.G. OLeary, Single-dose pharmacokinetics of Madopar HBS in patients and effect of food and antacid on the absorption of Madopar HBS in volunteers, Eur. Neurol. 27 (1987) 28S35S. B.N. Singh, Effects of food on clinical pharmacokinetics, Clin. Pharmacokinet. 37 (1999) 213255. P. Mojaverian, P.H. Vlasses, P.E. Kellner, M.L. Rocci Jr., Effects of gender, posture, and age on gastric residence time of an indigestible solid: pharmaceutical considerations, Pharm. Res. 10 (1988) 639644. A.J. Coupe, S.S. Davis, I.R. Wilding, Variation in gastrointestinal transit of pharmaceutical dosage forms in healthy subjects, Pharm. Res. 8 (1991) 360364. J. Timmermans, Comparative evaluation of the gastric transit of oating and non-oating matrix dosage forms, Bull. Mem. Acad. R. Med. Belg. 145 (1990) 365375, Abstract in English. Article in French. B. Van Gansbeke, J. Timmermans, A. Schoutens, A.J. Moes, Intragastric positioning of two concurrently ingested pharmaceutical matrix dosage forms, Nucl. Med. Biol. 18 (1991) 711718. A.J. Moes, Gastroretentive dosage forms, Crit, Rev. Ther. Drug Carrier Syst. 10 (1993) 143195. Factors controlling the buoyancy J. Timmermans, A.J. Moes, and gastric retention capabilities of oating matrix capsules: new data for reconsidering the controversy, J. Pharm. Sci. 83 (1994) 1824. C.E. Bennett, J.G. Hardy, C.G. Wilson, The inuence of posture on the gastric emptying of antacid, Int. J. Pharm. 21 (1984) 341347. D.W. Davis, Method of swallowing a pill, US Patent 3, 418, 999, December 31, 1968. Y. Kawashima, T. Niwa, H. Takeuchi, T. Hino, Y. Ito, Preparation of multiple unit hollow microspheres (microballoons) with acrylic resin containing tranilast and their drug release characteristics (in vitro) and oating behavior (in vivo), J. Control. Release 16 (1991) 279290. N. Rouge, J.C. Leroux, E.T. Cole, E. Doelker, P. Buri, Prevention of the sticking tendency of oating minitablets lled into hard gelatin capsules, Eur. J. Pharm. Biopharm. 43 (1997) 165171. B.C. Thanoo, M.C. Sunny, A. Jayakrishnan, Oral sustainedrelease drug delivery systems using polycarbonate microspheres capable of oating on the gastric uid, J. Pharm. Pharmacol. 45 (1993) 2124. Y. Kawashima, T. Niwa, H. Takeuchi, T. Hino, Y. Itoh, Hollow microspheres for use as a oating controlled drug delivery system in the stomach, J. Pharm. Sci. 81 (1992) 135140. G. Jayanthi, S.B. Jayaswal, A.K. Srivastava, Formulation and evaluation of terfenadine microballoons for oral controlled release, Pharmazie 50 (1995) 769770. H. Yuasa, Y. Takashima, Y. Kanaya, Studies on the development of intragastric oating and sustained release preparation. I. Application of calcium silicate as a oating carrier, Chem. Pharm. Bull. 44 (1996) 13611366. S. Miyazaki, H. Yamaguchi, C. Yokouchi, M. Takada, W.M. Hou, Sustained-release and intragastric-oating granules of
[29]
[44] [45]
[30] [31]
[46]
[32]
[47]
[33]
[48]
[34]
[49] [50]
[35]
[51]
[36]
[52] [53]
[37]
[38]
[54]
[39]
[55]
[40]
[56]
[41]
[57]
[42]
[58]
[43]
[59]
B.N. Singh, K.H. Kim / Journal of Controlled Release 63 (2000) 235 259 indomethacin using chitosan in rabbits, Chem. Pharm. Bull. 36 (1988) 40334038. K. Inouye, Y. Machida, T. Sannan, T. Nagai, Buoyant sustained release granules based on chitosan, Drug Des. Del. 4 (1989) 5567. Y. Machida, K. Inouye, T. Tokumura, M. Iwata, T. Nagai, Preparation and evaluation of intragastric buoyant preparations, Drug Des. Del. 4 (1989) 155161. S.B. Mitra, Sustained release oral medicinal delivery device, US Patent 4, 451, 260, May 29, 1984. A. Dennis, P. Timmins, K. Lee, Buoyant controlled release powder formulation, US Patent 5, 169, 638, December 8, 1992. P.R. Sheth, J. Tossounian, The hydrodynamically balanced system (HBSE ): a novel drug delivery system for oral use, Drug Dev. Ind. Pharm. 10 (1984) 313339. J.H. Gustafson, L. Weissman, R.E. Weinfeld, A.A. Holazo, K.-C. Khoo, S.A. Kaplan, Clinical bioavailability evaluation of a controlled release formulation of diazepam, J. Pharmacokinet. Biopharm. 9 (1981) 679691. A. Menon, W.A. Ritschel, A. Sakr, Development and evaluation of a monolithic oating dosage form for furosemide, J. Pharm. Sci. 83 (1994) 239245. W. Erni, K. Held, The hydrodynamically balanced system: a novel principle of controlled drug release, Eur. Neurol. 27 (1987) 21S27S. M.R. Franz, M.P. Oth, Sustained release, bilayer buoyant dosage form, US Patent 5, 232, 704, August 3, 1993. D. Khattar, A. Ahuja, R.K. Khar, Hydrodynamically balanced systems as sustained release dosage forms for propranolol hydrochloride, Pharmazie 45 (1990) 356358. P. Simoni, C. Cerre, A. Cipolla, C. Polimeni, A. Pistillo, G. Ceschel, E. Roda, A. Roda, Bioavailability study of a new, sinking, enteric-coated ursodeoxycholic acid formulation, Pharmacol. Res. 31 (1995) 115119. W. Phuapradit, Inuence of tablet buoyancy on the human oral absorption of sustained release acetaminophen tablets, Doctoral thesis, St. Johns University, Jamaica, NY, 1989. W. Phuapradit, S. Bolton, The inuence of tablet density on the human oral absorption of sustained release acetaminophen matrix tablets, Drug Dev. Ind. Pharm. 17 (1991) 10971107. P.R. Sheth, J.L. Tossounian, Novel sustained release tablet formulations, US Patent 4, 167, 558, September 11, 1979. A.K. Hilton, P.B. Deasy, In vitro and in vivo evaluation of an oral sustained-release oating dosage form of amoxycillin trihydrate, Int. J. Pharm. 86 (1992) 7988. S.K. Gupta, Stability studies of ampicillin oating tablets (Ampiot) and buffered Ampiot, M.S. thesis, St. Johns University, Jamaica, NY, 1987. N. Rouge, E. Allemann, M. Gex-Fabry, L. Balant, E.T. Cole, P. Buri, E. Doelker, Comparative pharmacokinetic study of a oating multiple-unit capsule, a high-density multiple-unit capsule and an intermediate-release tablet containing 25 mg atenolol, Pharm. Acta Helv. 73 (1998) 8187. N. Rouge, E.T. Cole, E. Doelker, P. Buri, Buoyancy and drug release patterns of oating minitablets containing piretanide
257
[60]
[78]
[61]
[79]
[62] [63]
[80]
[64]
[81]
[65]
[82]
[66]
[83]
[67]
[84]
[68] [69]
[85]
[70]
[86]
[87]
[71]
[72]
[88]
[89]
[73] [74]
[90]
[75]
[91]
[76]
[92]
[77]
[93]
and atenolol as model drugs, Pharm. Dev. Technol. 3 (1998) 7384. T.H. Gu, S.X. Chen, J.B. Zhu, D.J. Song, J.Z. Guo, H.M. Hou, Pharmacokinetics and pharmacodynamics of diltiazem oating tablets, Chung Kuo Yao Li Hsueh Pao 13 (1992) 527531, Abstract in English, Article in Chinese. K. Watanabe, Y. Machida, K. Takayama, M. Iwata, T. Nagai et al., Preparation and evaluation of intragastric oating tablet having pH independent buoyancy and sustained release property, Arch. Pract. Pharm. Yakuzaigaku 53 (1993) 17. V.S. Chitnis, V.S. Malshe, J.K. Lalla, Bioadhesive polymerssynthesis, evaluation and application in controlled release tablets, Drug Dev. Ind. Pharm. 17 (1991) 879892. M. Ichikawa, T. Kato, M. Kawahara, S. Watanabe, M. Kayano, A new multiple-unit oral oating dosage system. II: In vivo evaluation of oating and sustained-release characteristics with p-aminobenzoic acid and isosorbide dinitrate as model drugs, J. Pharm. Sci. 80 (1991) 11531156. M. Ichikawa, S. Watanabe, Y. Miyake, A new multiple-unit oral oating dosage systems. I: Preparation and in vitro evaluation of oating and sustained-release characteristics, J. Pharm. Sci. 80 (1991) 10621066. K. Inouye, Y. Machida, T. Sannan, T. Nagai, Buoyant sustained release tablets based on chitosan, Drug Des. Del. 2 (1988) 165175. H.M. Ingani, J. Timmermans, A.J. Moes, Conception and in vivo investigation of peroral sustained release oating dosage forms with enhanced gastrointestinal transit, Int. J. Pharm. 35 (1987) 157164. H.R. Chueh, H. Zia, C.T. Rhodes, Optimization of sotalol oating and bioadhesive extended release tablet formulations, Drug Dev. Ind. Pharm. 21 (1995) 17251747. L. Yang, R. Fassihi, Zero-order release kinetics from a self-correcting oatable asymmetric conguration drug delivery system, J. Pharm. Sci. 85 (1996) 170173. K. Asrani, Evaluation of bioadhesive properties of poly (acrylic acid) polymers and design of a novel oating bioadhesive drug delivery system, Doctoral thesis, St. Johns University, Jamaica, NY, 1994. W. Sawicki, S. Janicki, P. Pietkiewicz, Method of obtaining oating tablets with verapamil hydrochloride, Farm. Pol. 53 (1997) 698701, Article in Polish. G.L. Chen, W.H. Hao, In vitro performance of oating sustained-release capsule of verapamil, Drug Dev. Ind. Pharm. 24 (1998) 10671072. B.M. Regmi, J.P. Liu, X.D. Tu, Studies on ethmozine (EMZ) sustained release tablets, remaining-oating in stomach, Yao Hsueh Hsueh Pao 31 (1996) 5458, Abstract in English, Article in Chinese. W.L. Xu, X.D. Tu, Z.D. Lu, Development of gentamicin sulfate sustained-release tablets remaining-oating in stomach, Yao Hsueh Hsueh Pao 26 (1991) 541545, Abstract in English, Article in Chinese. S.L. Li, X.D. Tu, F.F. Mao, Development and pharmacokinetic study of metoprolol tartrate controlled-release tablet remaining-oating in stomach, Yao Hsueh Hsueh Pao 24 (1989) 381386, Abstract in English, Article in Chinese. Y. Diao, X.D. Tu, Development and pharmacokinetic study
258
B.N. Singh, K.H. Kim / Journal of Controlled Release 63 (2000) 235 259 characteristics of tablets. Use of experimental design techniques, Proc. Int. Symp. Control. Release Bioact. Mater. 21 (1994) 808809. F. Atyabi, H.L. Sharma, H.A.H. Mohammad, J.T. Fell, A novel oating system using ion exchange resins, Proc. Int. Symp. Control. Release Bioact. Mater. 21 (1994) 806807. F. Atyabi, H.L. Sharma, H.A.H. Mohammad, J.T. Fell, Controlled drug release from coated oating ion exchange resin beads, J. Control. Release 42 (1996) 2528. F. Atyabi, H.L. Sharma, H.A.H. Mohammad, J.T. Fell, In vivo evaluation of a novel gastric retentive formulation based on ion exchange resins, J. Control. Release 42 (1996) 105113. R.S. Todd, G.R. Fryers, Cholestyramine compositions and method for treating biliary gastritis, US Patent 4,172,120, October 23, 1979. R.W. Korsmeyer, R. Gurny, E. Doelker, P. Buri, N.A. Peppas, Mechanisms of potassium chloride from compressed, hydrophilic, polymeric matrices: effect of entrapped air, J. Pharm. Sci. 72 (1983) 11891191. N. Washington, C. Washington, C.G. Wilson, S.S. Davis, What is Liquid Gaviscon? A comparison of four international formulations, Int. J. Pharm. 34 (1986) 105109. I.I. Degtiareva, A. Bogdanov, Z. Khatib, N.V. Kharchenko, E.V. Lodianaia, O.L. Palladina, N.D. Opanasiuk, The use of 3rd-generation antacid preparations for the treatment of patients with nonulcerous dyspepsia and peptic ulcer complicated by reux esophagitis, Likars Ka Sprava 56 (1994) 119122, Abstract in English, Article in Russian. J.L. Fabregas, J. Claramunt, J. Cucala, R. Pous, A. Siles, In vitro testing of an antacid formulation with prolonged gastric residence time (Almagate Flot-Coat ), Drug Dev. Ind. Pharm. 20 (1994) 11991212. N.W. Read, K. Sugden, Gastrointestinal dynamics and pharmacology for the optimum design of controlled-release oral dosage forms, Crit. Rev. Ther. Drug Carrier Syst. 4 (1988) 221263. W.A. Ritschel, A. Menon, A. Sakr, Biopharmaceutic evaluation of furosemide as a potential candidate for a modied release peroral dosage form, Methods Find. Exp. Clin. Pharmacol. 13 (1991) 629636. N. Kohri, I. Naasani, K. Iseki, K. Miyazaki, Improving the oral bioavailability of sulpiride by a gastric-retained form in rabbits, J. Pharm. Pharmacol. 48 (1996) 371374. I.R. Wilding, A.J. Coupe, S.S. Davis, The role of gamma scintigraphy in oral drug delivery, Adv. Drug. Del. Rev. 7 (1991) 87117. Pharmaceutical Proles and Presence Ltd., Technical literature: The InteliSiteE Capsule-a simple solution to a difcult problem, 1996. Recherche et developpement ` A.J. Moes, de formes orales a J. Pharm. Belg. 44 (1989) 6070. liberation controlee, V. Pillay, R. Fassihi, Evaluation and comparison of dissolution data derived from different modied release dosage forms: an alternative method, J. Control. Release 55 (1998) 4555. S.J. Burns, D. Attwood, S.G. Barnwell, Assessment of a
of miocamycin sustained-release tablets remaining-oating in stomach, Yao Hsueh Hsueh Pao 26 (1991) 695700, Abstract in English, Article in Chinese. [94] H. Umezawa, Pepstatin oating minicapsules, US Patent 4, 101, 650, July 18, 1978. [95] V.B.M. Babu, R.K. Khar, In vitro and in vivo studies of sustained-release oating dosage forms containing salbutamol sulfate, Pharmazie 45 (1990) 268270. [96] C. Bogentoft, Oral controlled-release dosage forms in perspective, Pharm. Int. 3 (1982) 366369. [97] P.R. Sheth, J.L. Tossounian, Sustained release pharmaceutical capsules, US Patent 4, 126, 672, November 21, 1978. [98] K. Ushimaru, K. Nakamichi, H. Saito, Pharmaceutical preparations and a method of manufacturing them, US Patent 4, 702, 918, October 27, 1987. [99] S. Bolton, S. Desai, Floating sustained release therapeutic compositions, US Patent 4, 814, 179, March 21, 1989. [100] S. Bolton, P.H. Izevbehai, S. Desai, Floating sustained release therapeutic compositions, US Patent 4, 814, 178, March 21, 1989. [101] P.R. Sheth, J.L. Tossounian, Sustained release tablet formulations, US Patent 4, 140, 755, February 20, 1979. [102] Y.W. Chien, Oral drug delivery and delivery systems, in: Y.W. Chien (Ed.), Novel Drug Delivery Systems, Marcel Dekker, New York, NY, 1992, pp. 139196. [103] S. Watanabe, M. Kayano, Y. Ishino, K. Miyao, Solid therapeutic preparation remaining in stomach, US Patent 3, 976, 764, August 24, 1976. [104] R.M. Harrigan, Drug delivery device for preventing contact of undissolved drug with the stomach lining, US Patent 4, 055, 178, October 25, 1977. [105] L. Whitehead, J.T. Fell, J.H. Collett, Development of a gastroretentive dosage form, Eur. J. Pharm. Sci. 4 (Suppl.) (1996) S182. [106] V. Iannuccelli, G. Coppi, M.T. Bernabei, R. Cameroni, Air compartment multiple-unit system for prolonged gastric residence. Part I. Formulation study, Int. J. Pharm. 174 (1998) 4754. [107] W.A. Ritschel, Targeting in the gastrointestinal tract: new approaches, Methods Find. Exp. Clin. Pharmacol. 13 (1991) 313336. [108] A.S. Michaels, J.D. Bashwa, A. Zaffaroni, Integrated device for administering benecial drug at programmed rate, US Patent 3, 901, 232, August 26, 1975. [109] A.S. Michaels, Drug delivery device with self actuated mechanism for retaining device in selected area, US Patent 3, 786, 813, January 22, 1974. [110] H. Hashim, A. Li Wan Po, Improving the release characteristics of water-soluble drugs from hydrophilic sustained release matrices by in situ gas-generation, Int. J. Pharm. 35 (1987) 201209. [111] A.F. Stockwell, S.S. Davis, S.E. Walker, In vitro evaluation of alginate gel systems as sustained release drug delivery systems, J. Control. Release 3 (1986) 167175. [112] M. Ichikawa, S. Watanabe, Y. Miyake, Granule remaining in stomach, US Patent 4, 844, 905, July 4, 1989. [113] V.S. Gerogiannis, D.M. Rekkas, P.P. Dallas, N.H. Choulis, Effect of several factors on the oating and swelling
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123]
[124]
[125]
[126]
[127] [128]
[129]
B.N. Singh, K.H. Kim / Journal of Controlled Release 63 (2000) 235 259 dissolution vessel designed for use with oating and erodible dosage forms, Int. J. Pharm. 160 (1998) 213218. S.J. Burns, D. Corness, G. Hay, S. Higginbottom, I. Whelan, D. Attwood, S.G. Barnwell, Development and validation of an in vitro dissolution method for a oating dosage form with biphasic release characteristics, Int. J. Pharm. 121 (1995) 3744. J. Timmermans, A.J. Moes, Measuring the resultant-weight of an immersed test material, I. Validation of an apparatus and a method dedicated to pharmaceutical applications, Acta Pharm. Technol. 36 (1990) 171175. J. Timmermans, A.J. Moes, Measuring the resultant-weight of an immersed test material, II. Examples of kinetic determinations applied to monolithic dosage forms, Acta Pharm. Technol. 36 (1990) 176180. J. Timmermans, A.J. Moes, Apparatus and method for resultant-weight measuring system, US Patent 5, 076, 107, December 31, 1991. C. Crevoisier, B. Hoevels, G. Zurcher, M. Da Prada, Bioavailability of L-dopa after Madopar HBS administration in healthy volunteers, Eur. Neurol. 27 (1987) 36S46S. P.W. Collins, S.J. Tremont, W.E. Perkins, R.L. Fenton, M.P. McGrath, G.M. Wagner, A.F. Gasiecki, R.G. Bianchi, J.J. Casler, C.M. Ponte, J.C. Stolzenbach, P.H. Jones, D. Forster, Polymeric site-directed delivery of misoprostol to the stomach, in: R.M. Ottenbrite (Ed.), Polymeric Drugs and Drug Administration, American Chemical Society, Washington, DC, 1994, pp. 196203. N.O. Jensen, E. Dupont, E. Hansen, B. Mikkelsen, B.O. Mikkelsen, Madopar HBS: slow-release levodopa and benserazide in parkinsonian patients presenting marked uctuations in symptoms on standard L-dopa treatment, Eur. Neurol. 27 (1987) 68S72S. T.E. Eichhorn, A. Schrag, C. Trenkwalder, R. Selzer, R. Kohnen, W.H. Oertel, W. Poewe, Effectiveness of slow release L-DOPA / benserazide in treatment of end-of-dose
259
[130]
[138]
[139]
[131]
[140]
[132]
[141]
[133]
[142]
[134]
[135]
[143]
[144]
[136]
[145]
[146]
[137]
akinesia in Parkinson disease, Nervenarzt 66 (1995) 933 941, Abstract in English, Article in German. W.C. Koller, R. Pahua, Treating motor uctuations with controlled-release levodopa preparations, Neurology 44 (1994) S23S28. M.H. Marion, F. Stocchi, S.L. Malcolm, N.P. Quinn, P. Jenner, C.D. Marsden, Single-dose studies of a slow-release preparation of levodopa and benserazide (Madopar HBS) in Parkinsons disease, Eur. Neurol. 27 (1987) 54S58S. J.D. Cook, M. Carriaga, S.G. Kahn, W. Schalch, B.S. Skikne, Gastric delivery system for iron supplementation, Lancet 335 (1990) 11361139. N. Washington, C.G. Wilson, J.L. Greaves, P. DanneskioldSamsoe, An investigation into the oating behaviour of a pectin-containing anti-reux formulation (FF5005) by means of gamma scintigraphy, Scand. J. Gastroenterol. 23 (1988) 920924. A.A. Deshpande, C.T. Rhodes, N.H. Shah, A.W. Malick, Controlled-release drug delivery systems for prolonged gastric residence: an overview, Drug Dev. Ind. Pharm. 22 (1996) 531539. N. Haring, Z. Salama, H. Jaeger, Triple stage quadropole mass spectrometric determination of bromocriptine in human plasma with negative ion chemical ionization, Arzneim. Forsch. 38 (1988) 15291532. F. Plavsic, I. Francetic, J. Z. Kopitar, B. Vrhovac, L. Povsic, Urbancic, The effect of food and metoclopramide and side effects of bromocriptine, Eur. J. Drug Metab. Pharmacokinet. 16 (1991) 177181. M.J. Blaser, Hypotheses on the pathogenesis and natural history of Helicobacter pylori -induced inammation, Gastroenterology 102 (1992) 720727. H. Katayama, T. Nishimura, S. Ochi, Y. Tsuruta, Y. Yamazaki, Sustained release liquid preparation using sodium alginate for eradication of Helicobacter pylori, Biol. Pharm. Bull. 22 (1999) 5560.