Results and discussion
Preliminary screening of matrix excipients: influence of α-amylase in dissolution media. Several thermally modified starches were investigated as matrix-forming excipients for sustained-release tablets (10–14).
These studies pointed out that only fully pregelatinized starches functioned for the purpose of forming matrices because of
their high gelling capacities (11, 13, 14). However, it was reported that matrix tablets with fully pregelatinized starch
could not provide stable drug-release profiles when α-amylase was added in test media to mimic the gastrointestinal environment
(11).
The influence of α-amylase on drug release from HS matrix tablets was investigated and compared with commercially available
partially and fully pregelatinized starches. Four different tablets, composed of APAP, MCC, and modified starch (HS, Starch
1500, Amycol C, and Amycol HF) were tested.
Figure 2
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Figure 2 shows the dissolution profiles of APAP from various starch matrix tablets (starch/APAP/MCC = 60%/10%/30%) in different
two buffers, JP-2 buffer without α-amylase (see Figure 2a) and JP-2 buffer with α-amylase in a 5-g/L concentration (see Figure
2b). The activity of α-amylase was adjusted to 1700 IU/L, which is close to the median α-amylase activity in pancreatic juice
(11).
Matrix tablets made of conventional partially pregelatinized corn starch disintegrated completely within 0.5 h, and sudden
APAP release occurred. For both fully pregelatinized starches, sustained- release profiles were obtained in media without
α-amylase. However, the drug-release rate from the fully pregelatinized starch matrix changed faster in media containing α-amylase.
These results were the same phenomenon as described in previous work (11). On the other hand, matrix tablets made of HS were
well controlled in the same way, with or without α-amylase. This situation can be explained by the high gel-forming ability
of HS with high viscosity to prevent the dissolution and by the high resistance to α-amylase based on its degree of pregelatinization.
HS has the same viscosity as HPMC and the moderate degree of pregelatinization between conventional partially pregelatinized
starches and fully gelatinized starches (see Table I) contributes to its good balance of resistance to α-amylase and the gel-forming
ability.
Based on this prescreening test, the following evaluations were done with HS and HPMC as matrix excipients: a dissolution
study under high ionic-strength conditions, a dissolution study under high mechanical-force conditions, a zero-order release,
and a storage stability of dissolution profiles and of tablet color.
Dissolution study under high ionic-strength conditions. The influence of ionic strength of dissolution media on APAP release rate was investigated. HS or HPMC matrix tablets containing
APAP and MCC were prepared (HS or HPMC/APAP/MCC = 60%/ 10%/30%) and tested for dissolution using two media of different ionic
strength: JP-2 buffer (ionic strength 0.20 M) and McIlvaine buffer (ionic strength 0.39 M).
Figure 3
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Figure 3 shows the release profiles of APAP from HS and HPMC matrix tables. The release profiles of APAP from HS matrix tablets
hardly changed between the JP-2 buffer and the McIlvaine buffer, but the profiles of HPMC were largely influenced by ionic
strength. The HPMC matrix tablet couldn't maintain its matrix structure at high ionic-strength conditions, and burst release
of APAP occurred. These results were caused by the difference in swelling ability in high-ionic-strength conditions. In the
case of HPMC, as the ionic strength increases, the degree of swelling attributable to hydration decreases because the amount
of water available to hydrate HPMC was reduced when more water is required to keep the ions in solution (5). In contrast,
HS has a lot of hydroxyl groups on its backbone, so HS could hydrate in high ionic-strength conditions without competing with
electrolytes.
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