4 site-specific drug delivery: polymers for gastroretention€¦ · 59 site-specific drug delivery:...

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4.1 Gastroretention: The Challenges and Benefits

Gastroretention is the mechanism by which a dosage form is retained in the stomach, generally for the purposes of improving drug delivery. It has been proposed as a mechanism through which drug absorption in the upper gastrointestinal tract can be maximised. Gastroretentive approaches to drug delivery aim to counteract the physiological mechanisms that cause the stomach to empty by providing a modified dosage form which can be retained.

Achieving gastroretention is very difficult, however, and the physiological challenges are summarised below. Polymers, with their adaptable properties, are materials which can potentially help to overcome these difficulties, and the responses they provide are indicated:

• The stomach is not meant to retain objects such as a large tablet: The function of the stomach is temporarily to store food, mix and triturate it, and then initiate the process of digestion. Materials of suitable consistency are emptied into the small intestine to permit the digestion and absorption of nutrients.

• The motility of the stomach will break down non-resilient dosage forms: A gastric destructive force of 1.5–1.9 N has been measured in man for breaking down tablets [1]. Polymeric dosage forms can be engineered to resist this degree of force.

• The housekeeper wave will clear ‘indigestible’ material from the stomach: Gastric motility and gastric emptying represent two different states, the fasted state and the fed state. In the fasted state, there are four phases: Phase 1 is a quiescent phase and has only rare contractions, whereas Phase 2 has contractions of increasing intensity. Phase 3 has maximum amplitude and frequency of contractions, and it is during this phase that the complex ‘housekeeper wave’ occurs. This has the function of removing large fragments of undigested food or dosage forms into the duodenum. Phase 4 is a short transitional period between Phase 3 and Phase 1. Harnessing the mucoadhesive or bioadhesive properties of polymers could avoid a dosage form being subject to the clearing mechanism.

4 Site-specific Drug Delivery: Polymers for Gastroretention

56

Update on Polymers for Oral Drug Delivery

• The pylorus can stretch, allowing the dosage form to pass: The human pylorus is 12-13 mm wide in its open resting state but the sphincter muscle can relax further to allow larger objects to pass [2]. Size-increasing mechanisms such as polymer swelling can be employed to reduce the possibility of a dosage form passing too quickly through the pylorus.

• Gastric emptying is variable, both between subjects and in an individual person: As Olsson and Holmgren indicate, ‘Almost everything affects gastric emptying’ [3]. For example, fatty and high calorie meals delay gastric emptying, and high calorie levels also result in a larger number of forwards and backwards movements in the stomach, resulting in greater shear being applied to the contents [4]. Even age, build and posture, and external triggers related to food, such as smells, sights and sounds, can affect gastric behaviour.

• Physiological variability: The volume of the stomach can lie between 50 and 1500 ml, but actual fluid volume measured post mortem has been found to be 118 ± 82 ml [5], or 45 ± 18 ml fasted [6].

Drugs with a narrow absorption window, for example ciprofloxacin or gabapentin, may benefit by being retained in the stomach using a device which gives sustained release into the stomach and upper small intestine. The risk of rapid transit through the stomach and small intestine to the colon, at which point absorption may be poor, can lead to inadequate bioavailability. Examples of drugs likely to benefit from this technique are listed in Table 4.1.

4.2 How can Gastroretention be Achieved?

A number of methods have been investigated to assist the gastric retention of drugs. These include:

• Size-increasing systems, where the large size of the device inhibits immediategastric emptying.

• Floatingsystems,inwhichadevicecontainingthedrugfloatsontopofthestomachcontents and is thus less subject to gastric emptying.

• Mucoadhesiveapproaches,whicharediscussedinalaterchapter.

Size-increasing and floating concepts are discussed at this point, with particular emphasis on the use of polymers.

57

Site-specific Drug Delivery: Polymers for Gastroretention

Tab

le 4

.1 D

rugs

whi

ch m

ay b

enefi

t fr

om g

astr

o-re

tent

ive

deliv

ery

Typ

es o

f dr

ug c

ompo

unds

whi

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t fr

om

gast

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del

iver

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ecifi

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ampl

es

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hat

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the

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Ant

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tics

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hat

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on p

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he

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Alb

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ave

poor

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n

58


4.2.1 Size-increasing Systems

The simplest size-increasing approach to gastroretention involves swelling hydrogel matrices. Swelling and the rate of drug release can be controlled by the choice of polymer, and examples of swellable polymers include hydroxypropylmethyl cellulose (HPMC) and polyethylene oxide. A number of in vitro studies have been conducted to examine the extent and rate of swelling, together with the mechanism of drug release and erosion, and these have been discussed in Chapter 3. In vivo proof-of-concept studies are, however, relatively scarce.

Examples of size-increasing matrix tablets have been marketed by Depomed under the names Glumetza and Proquin (metformin and ciprofloxacin, respectively). These are large matrix tablets containing a combination of HPMC and polyethylene oxide, which swells in contact with fluid to a predetermined size, nominally larger than the dimensions of the pylorus. Over time the drug dissolves and the residue of the dosage form erodes, eventually emptying from the stomach.

A range of clinical studies have been carried out. In 2003, for example, Gusler and co-workers [8] administered an extended release (ER) form of metformin to healthy volunteers (n = 13) in a three-way crossover study, after either a high- or a moderate-fat meal (50% or £30% fat, respectively). A third leg of the study was the administration of immediate release (IR) metformin after a high-fat breakfast. Transit was followed using gamma-scintigraphy. After a high-fat breakfast ER metformin remained in the stomach an average of 13 hours, compared to an average of 8 hours after a moderate-fat breakfast. Bioavailability was similar for both ER and IR metformin after a high-fat breakfast but slightly lower after a moderate-fat meal, attributable to more rapid gastric emptying. Although the study did suggest some degree of gastric retention, this might have been caused by the delaying effect of a high calorie diet on gastric emptying.

A study by Louie-Helm and co-workers, also in 2003, involved furosemide gastro-retentive (GR) tablets given to another group of healthy volunteers (n = 15). This study demonstrated 88 ± 15% bioavailability of the GR formulation compared with the IR formulation. Gamma-scintigraphy showed that the GR tablets remained in the stomach for between 3.9 and 16.8 hours, demonstrating some degree of gastroretention. Despite these initially encouraging results, Phase III clinical trials were later discontinued due to disappointing results. Although comparable fluid outputs were achieved with the IR formulation, there was an inherent variability in outcome.

More recently a study of the pharmacokinetics of gabapentin showed comparable results with the GR (Acuform) and IR dosage forms [9]. Again, these results were highly dependent on whether the dosage form was taken with food and the fat content of the meal. The AcuForm hydrophilic swelling matrix system is conceptually simple and uses standard pharmaceutical technology.

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Another approach to size-increasing systems, the Intec Accordion Pill, is more complex. In this system, flexible drug-loaded polymer sheets carried on a rigid polymer frame are loaded into a capsule, and upon reaching the stomach the device unfolds and is retained in the stomach. The concept is illustrated in Figure 4.1.

The polymers in these studies included Eudragit (methacrylic acid copolymers) and ethyl cellulose. The polymer is cast as a flexible film, which must withstand tearing in the stomach but not be so rigid as to cause damage. A number of clinical studies have been carried out using the Accordion Pill device. Klausner and co-workers used Furosemide as a model compound [11]. The dimensions of the unfolded device were 5.5 × 2.1 × 0.07 cm. Gastroretention was assessed using X-rays at predetermined intervals, and in 9 out of 14 volunteers the device remained in the stomach after five hours. Diuresis and naturesis were higher with a GR device compared to an IR system, although comparison with non-GR controlled release systems was not included.

Phase 1 studies of Zalepon as an Accordion Pill have ‘demonstrated statistically significant superiority over the marked Zalepon (Sonata)’. The Accordion Pill aims to prolong the absorption phase in the duodenum, maintaining stable drug levels overnight. Another study, using Carbidopa (levodopa), showed improvement in bioavailability using the gastroretentive Accordion Pill [12]. One benefit of this system is the achievement of gastroretention during low-calorie diets. Research into this unfolding device has demonstrated the practicality of the polymer film concept with rigid supports in terms of its gastroretentive ability. Its size is also important.

Intec Accordion Pill showinglayered film structure (units

in mm)

The film is folded into astandard capsule

The film unfolds in the stomach,as seen in this gastroscopy of a

healthy volunteer 15 minutes afterswallowing the Intec Accordion

Pill.

Drug Reservoir

0.8

45

24

Figure 4.1 The Intec Accordion Pill, comprising a drug reservoir between polymeric sheets – the folded sheet in a capsule and the unfolded sheet in the

stomach of a volunteer. Reproduced with permission from M. Afargan and N. Lapidot, Drug Delivery Technology, 2006, 6, 8. ©2006, Drug Delivery Technology

& Specialty Pharma [10]

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A similar expanding system using cast polymer sheets has been studied by Ahmed and Ayres [13]. The polymers in this case were locust bean gum, xanthan gum, polyvinyl pyrrolidine and polyethylene glycol. Cast gels of riboflavin were contained in capsules and tested in the fasted state (n = 6). The pharmacokinetics was studied in humans and the gastroretentive properties in dogs. To examine gastroretention, riboflavin gels were cast into a variety of shapes (cubic, 1.5 × 1.5 × 1.5 cm; rectangular 3.0 × 1.5 × 1.5 cm; cylindrical 2.2 × 1.7 cm; cylindrical, 5.5 × 1.0 cm), dried (causing shrinkage) and then filled into capsules. In vitro these shapes returned to 75-80% of their original size within 30 minutes. Of these, the only one showing significant gastroretention in dogs was the cubic form, which remained in the stomach for nine hours. The other shapes emptied in less than two hours.

To examine bioavailability in humans, Ahmed and Ayres prepared three gastroretentive devices, with dimensions before drying of 7 × 1.5 × 1 cm, 5 × 1.5 × 1 cm and 3 × 1.5 × 1 cm for large, intermediate and small dosage forms, respectively. Each was loaded with 100 mg riboflavin and total riboflavin recovery calculated from urinary excretion. Recovery of riboflavin over 24 hours using an IR formulation was 5.3 mg. In the small device this fell to 4.1 mg, but in the intermediate and large devices it increased to 9.3 and 17.4 mg, respectively. The devices gave an increasing mean residence time, from 4.7 hours IR, to 7.0 hours with the large GR device. The improved bioavailability demonstrated by the GR system in the fasted state is of particular interest. However, food was administered two hours after the dose, and the authors acknowledge that increasing the fasting period will be required to confirm these results. The authors attribute the improvement in bioavailability to retention of the device in the stomach, although this was not confirmed by concurrent imaging data.

A further example of size-increasing systems is the use of superporous hydrogels. As the name implies, superporous hydrogels have pores of one to several hundred microns in size. Superporous hydrogels swell very rapidly, in less than a minute [14]. Their use has been demonstrated in a human study in which Dorkoosh and co-workers used gamma-scintigraphy to assess the retention of radio-labelled superporous hydrogels in the intestine [15]. However, this study did not directly examine gastroretention. The polymers were placed in enteric-coated capsules, which had a fasted post-dose gastric emptying time of 75-105 minutes, and followed their transit into the small intestine by gamma-scintigraphy. The authors stated that the polymers were attached to the upper part of the intestine for 45-60 minutes, but they did not continue the study to examine the complete intestinal transit time, nor was there a control study, so it was not possible to conclude if there was any increase in intestinal transit due to these polymers. There were no reports of intestinal blockage in this study, but it is not known how the system would behave with repeated doses.

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The gastric retention of hydrogels has also been studied in beagle dogs, both fed and fasted. Gastric retention was 2-3 hours in the fasted state and 24 hours in the fed state [16], although dog numbers were low (n = 2 in the fasted state using two different hydrogels, and n = 1 in the fed state). A further study using pigs showed gastric retention of over 6 hours in both fed and fasted states [17, 18] – but gastric emptying in pigs is not necessarily comparable to that in humans.

4.2.2 Floating Systems

The principle of the floating gastroretention approach is that the dosage form floats on the stomach contents, retarding its transit to the pylorus. This concept is in use for antacid formulations, in which a liquid is designed to float on the stomach contents and prevents gastric reflux. To achieve floating the dosage form needs to be less dense than the stomach contents, and this can be achieved by the use of either gas-generating or oil-based systems.

Hydrodynamically balanced systems (HBS) comprise a mixture of the drug, gel-forming hydrophilic polymers such as HPMC, and hydrophobic fatty materials. The density of the device is lower than that of water and it therefore floats on the gastric fluid. The hydrophilic/drug layer swells, releasing the drug by diffusion, and the dry centre (density <1) and the presence of fatty stearates inhibit water penetration to the inside. This is a passive mechanism, depending on the air captured within the dry mass and the presence of fatty material. In one study on fed subjects for a double-layered HBS system, gamma-scintigraphy demonstrated gastric retention of up to 10 hours. However, as with size-increasing systems, this may not be entirely due to the floating mechanism since food can retain ‘normal’ enteric-coated or controlled release dosage forms in the stomach for more than 12 hours. No investigation of gastric retention in the fasted state was carried out.

Madopar HBS (levodopa and benserazide) has been marketed by Roche for the treatment of Parkinson’s disease. The product information indicates that the system ‘provides prolonged release of the active in the stomach where the capsule remains for several hours’. The bioavailability of Madopar HBS is only 60% of the IR formulation [19]. It appears to have greater utility in achieving sustained drug release, rather than improving the bioavailability of the drug of narrow therapeutic window, levodopa. Bioavailability is not affected by food, but since no studies are reported confirming that gastroretention is achieved in the fasted state it is difficult to establish whether true gastroretention is achieved.

An example of a gas-generating system is illustrated in Figure 4.2 [20]. In this study, Strubing and co-workers prepared floating matrix tablets containing Kollidon SR (polyvinyl acetate and povidone). Flotation was found to continue in vitro over

62


24 hours, and ‘floating strength’ was improved by using a high polymer/drug ratio. Figure 4.2 shows the gas generation in the system. The concept was illustrated using MRI scanning (Figure 4.3). Such a dosage form should be coated with a polymer that allows the dosage form to become hydrated, and gas generated, e.g., using sodium bicarbonate and water, the polymer facilitating drug egress but preventing gas being liberated.

Figure 4.2 Photograph of a polymeric tablet slice showing gas generation over time. Reproduced with permission from S. Strubing, H. Metz and K. Mader,

Journal of Controlled Release, 2008, 126, 2, 149. ©2008, Elsevier [20]

Figure 4.3 MRI images of gas-generating floating tablets over time. Reproduced with permission from S. Strubing, H. Metz and K. Mader, Journal of Controlled

Release, 2008, 126, 2, 149. ©2008, Elsevier [20]

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An in vivo study of gastroretention by floating has been carried out by Tadros [21]. The formulation was a large HPMC-based tablet, giving >12 hours flotation in vitro following a one-minute time lag. However, there was difficulty in assessing flotation in vivo. Although the gastric emptying time could be measured, it was difficult to confirm from the images whether flotation was actually occurring, or whether gastroretention was a consequence of the dosage form size (700 mg) and the fed state. Gastric emptying was demonstrated to be 5.5 ± 0.77 hours. Figure 4.4 shows the X-ray tracking of transit.

A separate in vivo study has investigated a freeze-dried calcium alginate multiple-unit system floating on the stomach contents (Figure 4.5) [22]. Alginates are non-toxic, biodegradable, linear copolymers comprising l-glucoronic acid and d-mannuronic acid residues. This formulation gave good in vitro flotation. Prolonged gastroretention

Figure 4.4 Tracking a floating dosage form in a human volunteer. Reproduced with permission from M.I. Tadros, European Journal of Pharmaceutics and

Biopharmaceutics, 2010, 74, 2, 332. ©2010 Elsevier [21]

Floating beadsFloating beads Floating beads

Non-Floating beads

Stom

ach

t = 0 t = 50 mins t = 540 mins

Figure 4.5 Gamma-scintigraphs showing transit of floating and non-floating bead formulations in the stomach after 0, 50 and 540 min (non-floating beads emptied

at 50 min). Reproduced with permission from L. Whitehead, J.T. Fell, J.H. Collett, H.L. Sharma and A. Smith, Journal of Controlled Release, 1998, 55, 1, 3.

©1998, Elsevier [22]

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times, amounting to over 5.5 hours, were achieved in all subjects for the floating formulation, which remained high in the stomach over the entire test period. In contrast, non-floating beads gave brief gastroretention, with a mean onset emptying time of only one hour.

Another approach to floating systems is the use of microballoons, comprising a polymer shell enclosing a spherical cavity. A study has examined the use of these hollow microballoons in humans [23]. Riboflavin was encapsulated in Eudragit S and HPMC polymers, and the resulting floating spheres showed sustained release. The residence time in the stomach was related to the ability of the spheres to float on ingested water, and also to the ingestion of food, which in the fed state helped to retain material in the stomach. A gamma-scintigraphic study showed that in the fed state the microballoons were concentrated in the upper part of the stomach and were retained for up to 300 minutes, longer than for a non-floating formulation. In the fasted state the microballons were able to remain afloat for only around 60 minutes before being removed by the migrating myoelectric complex.

The final floating system to be discussed involves the modular DomeMatrix technology. This consists of dosing modules ‘clipped together’ to allow different dosing regimes. The system incorporates a void space, giving it an effective density less than that of water. The modules are tablets prepared from HPMC (K100M) mixed with calcium phosphate and the modular facet is introduced using customised punches with complementary interlocking faces. The void space is prepared using two interlocking concave faces (Figure 4.6), and flotation has been obtained in vitro for over five hours. 2.5-5 hours’ retention was demonstrated in the fed state in the stomach of human volunteers [24].

Figure 4.6 Dome matrix modules with concave interlocking modules. A + B give C, which has a void space. Reproduced with permission from O.L. Strusi, F. Sonvico, R. Bettini, P. Santi, G. Colombo, P. Barata, A. Oliveira, D. Santos

and P. Colombo, Journal of Controlled Release, 2008, 129, 2, 88. ©2008, Elsevier [24]

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4.2.3 Mucoadhesive Systems

Mucoadhesion is discussed in Chapter 7. However, the application of the concept to achieving gastroretention will be referred to here, namely the gastrointestinal patch system [25-30].

The GI mucoadhesive patch comprises four layers:

• AsurfacelayersensitivetopH,e.g.,HPMC(HP-55)orEudragitL100orS100.

• Anadhesivelayer(carbopolandpolyethyleneglycol400).

• Acentralcelluloselayercontainingthedrug.

• Abackbonelayerofwater-insolublepolymer(ethylcellulose)toprotectproteindrugs from degradation by enzymes in the lumen.

This dosage form has been assessed in rats, dogs and humans. Rat studies showed that the site of adhesion was dependent on the polymer used, the site of drug release depending on the pH threshold of the polymer and the corresponding pH of the intestine, for example Eudragit S dosage forms tended to release more distally in the small intestine, where the pH was higher. Retention time was around two hours at each site. Testing in dogs showed similar trends, where the delivery of proteins gave improved pharmacological activity compared with colonic and enteric delivery systems. Human studies suggested that compared with IR, an increased residence time of caffeine in the blood could be achieved using these systems. It is not clear whether they offer advantages over normal controlled release systems.

4.3 Conclusions

A number of approaches continue to dominate the field of gastroretention, each using polymer properties to control drug release. Size-increasing systems use the swelling properties of hydrophilic gel networks. Floating systems exploit the ability of polymers to form a gas-impermeable layer. An ideal approach does not yet exist, however, all the current systems relying on exploitation of the physiological response to food in the stomach, rather than on the formulation itself.

References

1. M. Kamba, Y. Seta, A. Kusai and K. Nishimura, International Journal of Pharmaceutics, 2002, 237, 1/2, 139.


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2. J.F. Munk, R.M. Gannaway, M. Hoare and A.G. Johnson in Gastrointestinal Motility in Health and Disease, Ed., H.L. Duthie, MTP Press Ltd, Lancaster, UK, 1978, p.349.

3. C. Olsson and S. Holmgren, Comparative Biochemistry and Physiology, Part A: Molecular and Integrative Physiology, 2001, 128, 3, 481.

4. P. Boulby, R. Moore, P. Gowland and R.C. Spiller, Neurogastroenterol Motility, 1997, 11, 1, 27.

5. F. Gotch, J. Nadell and I.S. Edelman, Journal of Clinical Investigations, 1957, 36, 289.

6. C. Schiller, C.P. Frohlich, T. Geissman, W. Siegmund, H. Monnikes, N. Hosten and W. Weitschies, Alimentary Pharmacology and Therapeutics, 2005, 22, 971.

7. T. Sousa, R. Paterson, V. Moore, A. Carlsson, B. Abrahamsson and A.W. Basit, International Journal of Pharmaceutics, 2008, 363, 1/2, 1.

8. G.M. Gusler, S.E. Hou, A.L. Connor, I.R. Wilding and B. Berner, AAPS Journal, 2003, 5, S1.

9. T. Gordi, E. Hou, S. Kasichayanula and B. Berner, Clinical Therapeutics, 2008, 30, 5, 909.

10. M. Afargan and N. Lapidot, Drug Delivery Technology, 2006, 6, 8.

11. E.A. Klausner, E. Lavy, D. Stepensky, E. Cserepes, M. Barta, M. Friedman and A. Hoffman, Journal of Clinical Pharmacology, 2003, 43, 7, 711.

12. E.A. Klausner, E. Lavy, M. Barta, E. Cserepes, M. Friedman and A. Hoffman, Pharmaceutical Research, 2003, 20, 9, 1466.

13. I.S. Ahmed and J.W. Ayres, International Journal of Pharmaceutics, 2007, 330, 1/2, 146.

14. H. Omidian, K. Park and J.G. Rocca, Journal of Pharmaceutical Sciences, 2007, 59, 3, 317.

15. F.A. Dorkoosh, M.P. Stokkel, D. Blok, G. Borchard, M. Rafiee-Tehrani, J.C. Verhoef and H.E. Junginger, Journal of Controlled Release, 2004, 99, 2, 199.

16. J. Chen, W.E. Blevins, H. Park and K. Park, Journal of Controlled Release, 2000, 64, 1-3, 39.

67


17. W. Han, H. Omidian and J.G. Rocca, AAPS PharmSci, 2003, 5, W4119.

18. W. Han, H. Omidian and J.G. Rocca in the Proceedings of 31st Annual Meeting of the Controlled Release Society, Hawaii, USA, 2004.

19. C. Crevoisier, B. Hoevels, G. Zürcher and M. Da Prada, European Neurology, 1987, 27, Supplement 1, 36.

20. S. Strubing, H. Metz and K. Mader, Journal of Controlled Release, 2008, 126, 2, 149.

21. M.I. Tadros, European Journal of Pharmaceutics and Biopharmaceutics, 2010, 74, 2, 332.

22. L. Whitehead, J.T. Fell, J.H. Collett, H.L. Sharma and A. Smith, Journal of Controlled Release, 1998, 55, 1, 3.

23. Y. Sato, Y. Kawashima, H. Takeuchi and H. Yamamoto, International Journal of Pharmaceutics, 2004, 275, 1/2, 97.

24. O.L. Strusi, F. Sonvico, R. Bettini, P. Santi, G. Colombo, P. Barata, A. Oliveira, D. Santos and P. Colombo, Journal of Controlled Release, 2008, 129, 2, 88.

25. S. Eaimtrakarn, Y. Itoh, J.I. Kishimoto, Y. Yoshikawa, N. Shibata and K. Takada, International Journal of Pharmaceutics, 2001, 224, 1/2, 61.

26. S. Eaimtrakarn, Y.V. Prasad, S.P. Puthli, Y. Yoshikawa, N. Shibata and K. Takada, Drug Metabolism and Pharmacokinetics, 2002, 17, 4, 284.

27. S. Eaimtrakarn, Y.V. Rama Prasad, T. Ohno, T. Konishi, Y. Yoshikawa, N. Shibata and K. Takada, Journal of Drug Targeting, 2002, 10, 3, 255.

28. S. Eaimtrakarn, Y.V. Rama Prasad, S.P. Puthli, Y. Yoshikawa, N. Shibata and K. Takada, International Journal of Pharmaceutics, 2003, 250, 1, 111.

29. Y.V. Rama Prasad, S.P. Puthli, S. Eaimtrakarn, M. Ishida, Y. Yoshikawa, N. Shibata and K. Takada, International Journal of Pharmaceutics, 2003, 250, 1, 181.

30. Y.V. Rama Prasad, S. Eaimtrakarn, M. Ishida, Y. Kusawake, R. Tawa, Y. Yoshikawa, N. Shibata and K. Takada, International Journal of Pharmaceutics, 2003, 268, 1/2, 13.

4 site-specific drug delivery: polymers for gastroretention€¦ · 59 site-specific drug delivery:...

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