Capsules for Drug Delivery 1431 InVivo Release from Capsules

In vivo disintegration and release of drug from capsules has been investigated using gamma scintigraphy and Magnetic Marker Imaging (MMI). Disintegration of a fastrelease sumatriptan tablet that was over-encapsulated in a gelatin capsule shell was comparable to that observed with nonencapsulated tablets in fasted subjects, both in terms of shell dissolution and tablet disintegration. Individual values are shown in Fig. 14.7 [6].

Brown et al. [7] confirmed such fast in vivo disintegration in the fasted state, even when the gelatin was cross-linked and capsules failed to meet pharmacopoeial standards for disintegration time.

Digenis et al. [8] used gamma scintigraphy to study the effect of formaldehyde-induced cross-linking on disintegration time and shell rupture in fasted and fed volunteers. The bioavailability of the contained drug, amoxicillin, was also determined in a conventional bioavailability study. Findings are summarized in Table 14.4.

In vivo disintegration time (onset of capsule rupture) was prolonged in both fasted and fed subjects with cross-linked capsules. It was significantly longer with severely cross-linked capsules in fed subjects. Onset of absorption was also prolonged by

Initial Complete Initial Complete

Disintegration Disintegration Disintegration Disintegration

Nonencapsulated Encapsulated

Initial Complete Initial Complete

Disintegration Disintegration Disintegration Disintegration

Nonencapsulated Encapsulated

Fig. 14.7 Disintegration profiles of nonencapsulated and encapsulated sumatriptan 100 mg tablets [6]

Table 14.4 Effect of cross-linking on in vivo performance of gelatin capsules In vivo disintegration (min) Bioavailability*

Table 14.4 Effect of cross-linking on in vivo performance of gelatin capsules In vivo disintegration (min) Bioavailability*

Degree of cross-linking

Fasted

Fed

Fasted

Fed

AUC

max

max

AUC

max

max

None (Control)

7

11

18.03

7.78

1.17

18.86

7.02

1.5

Moderate

22

23

18.08

6.42

1.62

18.32

6.35

1.6

Severe

31

71

15.93

5.77

1.85

18.56

6.42

2.55

PK parameters are the usual ones viz. AUC (0-inf) =

(mg h ml-

max

= hours

about 1 h in the same group. Numeric differences were also evident for the other PK parameters but were less striking and not statistically significant. Hence, for the usually more clinically relevant values of peak plasma concentration and area under the curve the impact of cross-linking, even with a compound-like amoxicillin, whose absorption window is in the upper small intestine, was hardly significant.

Cole et al. [9] also used scintigraphy and pharmacokinetic determinations (using ibuprofen) to characterize behavior of gelatin and 1st generation hypromel-lose capsules. Hypromellose capsule opening was hindered in acid conditions and in vivo disintegration (onset and complete) was significantly longer with hypromel-lose capsules. However, there were no numerical nor statistical differences in the pharmacokinetics of the ibuprofen, suggesting that the differences in disintegration were not biopharmaceutically relevant. Esophageal transit times were also comparable with both types of capsule.

MMI is also used to characterize dosage form behavior in vivo by means of magnetically marked dosage forms. The technique affords continuous measurement of location and trafficking of a dosage form in the GI tract. Hard gelatin capsules marked with iron oxide as a magnetic marker were evaluated in eight healthy volunteers for in vivo disintegration. In vitro disintegration corresponded well with in vivo performance, capsule rupture time being between 1.5 and 2.5 min [10].

These studies allay putative concerns suggested by in vitro studies that delayed shell disintegration might compromise in vivo performance.

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