Introduction

Ahmed and Ayres recently published encouraging results on the development of an expandable GRF [37]. Expandable GRFs made from naturally occurring carbohydrate polymers were prepared in various sizes in the shape of a rectangular prism. The GRFs were tested in fasted, healthy volunteers using riboflavin as a model compound. Deconvolution of riboflavin pharmacokinetics, a drug known to have saturable, site-specific absorption in the upper small intestine, was used to estimate the gastric residence time of the various formulations. The largest GRF tested, with dimensions of 7 cm x 1.5 cm x 1 cm before drying (these researchers estimated that the GRFs

Table 17.6 Composition of gastric retentive formulations tested in healthy volunteers

Grams per 100 g of water (water removed after forming the gel)

Formulation A

Formulation B

Formulation C

Ingredient

(used in Study 1)

(used in Study 2)

(used in Study 2)

Locust bean gum

0.75

1

0.75

Xanthan gum

0.75

1

0.75

Polyethylene glycol 400

3

3

3

Cellulose acetatea

0.3

0.15

0.15

Activated charcoala

0.05

0.02

0.02

Indium chloridea

Traceb

Trace15

Trace1

a Used to radiolabel the dosage form b Each GRF contained a maximum of 0.5 MBq of Indium-111 at time of dosing a Used to radiolabel the dosage form b Each GRF contained a maximum of 0.5 MBq of Indium-111 at time of dosing recovered approximately 75% of their original size in about 45 min based upon in vitro and in vivo data), was estimated to have a gastric residence time of approximately 15 h in fasted subjects. However, the authors noted that their results were preliminary, and further investigation was needed; with particular emphasis on studying the influence of the feeding regimen on the in vivo performance of the GRF.

The GRFs evaluated in this case study (previously unpublished clinical results) were of very similar composition to those studied by Ahmed and Ayres, but a variety of shapes were investigated. In addition, no drug was incorporated into the dosage forms as the initial goal was solely to determine whether the formulation was gastroretentive. Burke and coinvestigators [38] described how they developed a robust radiolabeling technique to allow scintigraphic evaluation of gastric residence time in healthy volunteers. The method consisted of adsorbing 111InCl2 onto activated charcoal, dispersing the radiolabeled charcoal into molten cellulose acetate, cooling this mixture and grinding it up into small particles, and then incorporating it into the GRF during its manufacture.

Table 17.6 describes the composition of the GRFs studied in two clinical trials. A large, nondisintegrating tablet was used as a reference product in all studies to account for differences between patients in regard to their typical gastrointestinal transit times. The GRFs were prepared as gels in molds, then dehydrated and packed into hard gelatin capsules. Figure 17.7 shows a GRF packed into a clear, 000 capsule and after 0.5, 1, 2 and 3 h in 0.1 N HCl at 37°C. Note that Formulations B and C were developed after Formulation A, and that an improvement in the radiolabel-ing procedure was made. This improvement enabled a reduction in the amount of cellulose acetate and activated charcoal that was needed. This reduction in nonhy-drating solids improved the gel strength and hydration rate of the proposed GRFs.

The first clinical study evaluated GRFs of the same size and shape (7 cm x 1.5 cm x 1 cm) as the best performing GRF reported by Ahmed and Ayres, while the second study evaluated a shorter/wider rectangular prism (5 cm x 3 cm x 1.5 cm), a sphere (3 cm in diameter), a ring (4.7 mm outer diameter, 1.5 cm inner diameter, 1.5 cm thick) and a "pillow" (4 cm x 4 cm in the longest dimension, 1.5 cm thick). All sizes reported for the GRFs are those for freshly prepared hydrated gels prior to drying. Gamma scintigraphy was used to determine the gastric residence time of the GRFs.

Fig. 17.7 Hydration of the gastric retentive formulation used in Study 1 as a function of time in 0.1 N HCl

Table 17.7 Overview of clinical studies and objectives Study Periods Primary objectives

1 1-4 A. To determine gastric residence time and in vivo performance of Formulation

A in the shape of rectangular prism when taken after a low calorie breakfast. B. To determine the effect of nighttime dosing on gastric residence time of Formulation A in the shape of rectangular prism when taken after a low calorie meal.

2 1-8 To determine effect of gel shape and composition on gastric residence time when taken after a low calorie breakfast. 2 9-12 To determine the effect of meal size and frequency on gastric residence time of Formulation B in the shape of rectangular prism.

Table 17.7 provides an overview of the clinical studies, and the primary objectives of each study. In all of these studies, a meal was consumed immediately prior to dosing. This enabled the proposed GRFs to hydrate in the stomach prior to the housekeeper wave (or Phase 3 contraction) of the migrating myoelectric complex (MMC) attempting to empty the dosage form out of the stomach.

Study 1 investigated the effect of morning and nighttime dosing after a low calorie meal, on the gastric residence time of Formulation A. This formulation was prepared in the shape of large, rectangular prism (7 cm x 1.5 cm x 1 cm), identical to the dimensions of the best performing GRF described by Ahmed and Ayres [37]. The results of Study 1 are fully described in Table 17.8. The median gastric emptying time for morning dosing of the GRF was 4 h (range 2.5-24 h), compared to 2.5 h (range 0.5-5 h) for the tablet. The median emptying time of the GRF and the tablet for evening dosing was 6 h (range for the GRF following evening dosing was 4-8 h, while the range for the tablet was from 4 to 7 h). The authors do not consider this small extension in gastric residence time for the GRF after morning dosing to be clinically relevant, but it was interesting to note a trend that the GRF generally provided a small increase in gastric residence time in most subjects.

A potential mechanism for this trend in increased gastric residence time is that the GRF reduced the rate of emptying of the meal, which would subsequently delay the onset of the housekeeper wave. Table 17.9 shows that the GRF delayed gastric emptying of the meal by approximately 1.5 h as estimated by the time for 50% (T50) and 90% (T90) of the meal to empty from the stomach.

As can be seen in Table 17.10, Study 2 explored a variety of gel shapes, to further understand the potential of these polysaccharide gels to enhance gastric residence time.

Table 17.8 Gastric emptying times of Formulation A, prepared in the shape of a rectangular prism (7 cm x 1.5 cm x 1 cm prior to dehydration) in Study 1

Gastric emptying times following Gastric emptying times morning dosing (h) following evening dosing (h)

Table 17.8 Gastric emptying times of Formulation A, prepared in the shape of a rectangular prism (7 cm x 1.5 cm x 1 cm prior to dehydration) in Study 1

Gastric emptying times following Gastric emptying times morning dosing (h) following evening dosing (h)

Subject no.

GRF

Tablet

GRF

Tablet

001

4.5

0.5

Drop out

Drop out

002

4.0

4.0

8.0

6.0

003

4.0

2.5

4.0

4.0

004

2.5

2.5

5.0

6.0

005

4.0

2.5

6.0 and 14.5a

6.0

006

24.0 and 25.0b

5.5

8.0

7.0

Median

4.0

2.5

6.0

6.0

Min

2.5

0.5

4.0

4.0

Max

24.0

5.5

8.0

7.0

aFor subject 005, the GRF broke up into two pieces on emptying. One piece emptying at 6 h the other piece was retained and emptied at 14.5 h postdose. Initial emptying was used for all calculations bFor subject 006, the GRF broke up into two pieces on emptying from the stomach. One piece emptying at 24 h ,the other piece was retained and emptied at 25 h postdose. Initial emptying was used for all calculations

Table 17.9 Effect of a gastroretentive dosage form (GRF) and night time dosing on the time for 50% (T50), and 90% (T90) of the meal to empty from the stomach in Study 1

Subject no.

Morning dosing (h)

Evening dosing (h)

GRF r50

GRF T90

Tablet T50

Tablet 7;0

GRF T50

GRF T90

Tablet T50

Tablet 7;0

001

2.9

4.4

1.0

1.7

Drop out

Drop out

002

2.6

3.7

1.3

3.6

3.3

6.9

2.3

5.4

003

2.8

3.9

0.7

2.0

3.2

3.9

1.3

3.3

004

2.0

2.4

0.7

1.8

2.2

4.6

1.1

3.5

005

1.8

2.9

1.5

2.3

1.1

4.9

0.5

2.0

006

1.3

5.4

1.3

4.7

5.0

7.1

1.3

2.5

Median

2.3

3.8

1.2

2.2

3.2

4.9

1.3

3.3

Min

1.3

2.4

0.7

1.7

1.1

3.9

0.5

2.0

Max

2.9

5.4

1.5

4.7

5.0

7.1

2.3

5.4

The rationale was to identify shapes that would still swell to a size larger than the pylorus, and also be more resistant to compression during a Phase 3 contraction. The shapes evaluated included a rectangular prism, a sphere, a pillow and a ring using a higher concentration of the polysaccharides (Formulation B). The rectangular prism and pillow shapes were further evaluated using a lower concentration of the polysac-charides (Formulation C) to provide a more fundamental understanding of the system. All dosage forms were administered after a low calorie breakfast.

The data in Tables 17.11 and 17.12 show that the modified GRF shapes and higher concentrations of locust bean gum and xanthan gum (Formulation B) did not significantly and consistently extend gastric residence time over the nondisintegrat-ing tablet. In addition, in Study 2 the GRFs had no effect on the rate of gastric

Table 17.10 Description and picture of gastric retentive shapes used in Study 2

Shape

Outer dimensions prior to removal of water Photograph

Ring (dehydrated)

4.7 mm outer diameter, 1.5 cm inner diameter, 1.5 cm thick

Sphere (Hydrated) Diameter = 3 cm

Pillow (Hydrated)

4 x 4 cm, tapered to 3 x 3 cm at edges, 1.5 cm thick

Table 17.11 Gastric emptying times (hours) in Study 2, periods 1-4. All dosage forms given after a low calorie (~180 kcal) breakfast

Formulation B

Table 17.11 Gastric emptying times (hours) in Study 2, periods 1-4. All dosage forms given after a low calorie (~180 kcal) breakfast

Formulation B

Subject no.

Reference tablet

Rectangular prism

Ring

Pillow

Gastric emptying time (hours)

001

2.8

24.4

24.5

3.5

002

3.3

4.8

4.8

3.7

003

2.7

3.3

3.3

2.8

004

Removed from study

Removed from study

Removed from study

62.7 a

005

2.3

3.3

3.3

2.8

006

2.3

3.2

2.3

2.8

Median

2.7

3.3

3.3

2.8

Min

2.3

3.2

2.3

2.8

Max

3.3

24.4

24.5

3.7

a Not used in calculation of mean, median, and maximum because subject removed from study after this dosing period emptying of the meal. Interestingly, in these first eight dosing periods of Study 2, whenever Formulation B was administered, there was always one subject who retained the GRF in the stomach for more than 20 h. In contrast, neither the reference tablet nor Formulation C provided a single observation of a gastric retention time of more than 5 h. This observation could simply be due to random chance, but

Table 17.12 Gastric emptying times (hours) in Study 2, periods 5-8. All dosage forms given after a low calorie (~180 kcal) breakfast

Formulation B Formulation C Reference tablet Sphere Pillow Rectangular prism

Table 17.12 Gastric emptying times (hours) in Study 2, periods 5-8. All dosage forms given after a low calorie (~180 kcal) breakfast

Formulation B Formulation C Reference tablet Sphere Pillow Rectangular prism

Subject no.

Gastric emptying time (hours)

007

2.8

21.0

3.8

3.8

008

1.8

2.8

3.3

2.8

009

3.2

3.8

3.3

2.8

010

2.7

2.8

3.3

3.3

011

4.7

2.8

2.3

3.3

012

2.3

3.3

2.3

4.3

Median

2.8

3.1

3.3

3.3

Min

1.8

2.8

2.3

2.8

Max

4.7

21.0

3.8

4.3

Table 17.13 Gastric emptying times (hours) in Study 2, periods 9-12

Low calorie breakfast followed by snack 2.5 h later High calorie breakfast

Table 17.13 Gastric emptying times (hours) in Study 2, periods 9-12

Low calorie breakfast followed by snack 2.5 h later High calorie breakfast

Subject no.

Reference tablet

Formulation B Rectangular prism

Reference tablet

Formulation B Rectangular prism

Gastric emptying time (hours)

013

21.0

21.0

9.8

9.8

014

2.3

25.5

21.0

16.0

015

2.3

2.4

16.0

21.0

016

21.0

16.0

26.2

16.0

017

-

-

-

21.0a

018

21.1

21.0

9.8

9.8

Median

21.0

21.0

16.0

16.0

Min

2.3

2.4

9.8

9.8

Max

21.0

25.5

26.2

21.0

Dosage forms were given either after a low calorie breakfast (~180 kcal) followed by a snack 2.5 h later; or after a high calorie breakfast (~800 kcal) followed by lunch 5 h later aNot used in calculation of mean, median, and maximum because subject removed from study after this dosing period it may suggest that these GRFs are nearing the physical attributes necessary for clinically relevant gastric retention. It should be pointed out, that in general, the GRFs left the stomach intact. This observation suggests that the formulations were either compressed to a small enough size to pass through the pylorus, or that there was inadequate rehydration of the gels in vivo.

The last four periods of Study 2 examined the effect of meal size and meal frequency on the gastric residence time of Formulation B, prepared in the shape of a rectangular prism. The results in Table 17.13 show that when either the tablet or GRF were given after a high calorie breakfast, and followed by lunch 5 h later, every subject retained the tablet and the GRF for more than 9 h. In addition, when the dosage forms were given after a low calorie meal, followed by a low calorie snack 2.5 h later, more than half the subjects had gastric emptying times of at least 16 h for both the tablet and the GRF.

These data in Tables 17.11-17.13 clearly demonstrate that meal composition and frequency of meals were the factors that most significantly influenced gastric residence time. As such, it is essential that meals be carefully controlled when evaluating the performance of GRFs in clinical trials. The strategy of dosing after a low calorie breakfast followed by lunch 5 h later appears to be a useful means of screening the potential of a dosage form to provide meaningful gastric retention. It has been shown that the Phase 3 contractions after breakfast are the strongest of the day, and thus likely represent the most challenging physiological environment for a GRF to overcome.

The proposed GRFs in this study were well tolerated by the volunteers, but failed to provide a clinically relevant increase in gastric residence time over a large, non-disintegrating tablet. The reason for this is most likely due to inadequate gel strength of the GRFs to resist compression to a size small enough to pass through the pylorus. However, there are insufficient data to rule out that this failure was due to inadequate swelling of the dehydrated gels.

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