Hydrophilic gel-forming matrix systems are widely used in oral controlled-release dosage forms. Hydrophilic polymer hydrates
form a viscous gel layer around the tablet surface, and drug release is controlled in a sustained manner by diffusion through
a gel layer and the erosion of the gel (1). Drug solubility, however, greatly affects the rate of diffusion and erosion. It
is especially difficult to control the release rate of highly water-soluble and insoluble drugs (2–4). Moreover, various gastrointestinal
factors such as ionic strength and mechanical destructive force also affect the drug-release rate (5–8). To solve these problems
or predict these influences, many studies have examined factors affecting drug release.
In this study, a highly functional pregelatinized starch (HS) was investigated as the potential basis for developing a hydrophilic
matrix system for sustained release (9). The influence of drug solubility and external factors such as ionic strength, mechanical
force, and accelerated storage conditions on the drug-release rate was evaluated. In addition, the effect of polyethylene
glycol (PEG) on drug-release profiles was investigated to obtain zero-order release profiles.
Figure 1 (All figures are courtesy of the authors.)
HS was prepared by controlled thermal pregelatinization of potato starch and a spray-drying technique. It is compatible with
the National Formulary, European Pharmacopoeia, and Japanese Pharmaceutical Excipients. The properties of HS are shown in Table I. HS has different properties from conventional pregelatinized starches and conventional
hydrophilic gel-matrix excipients because of its high viscosity and insoluble element in dissolution media (see Figure 1).
Materials. Model drugs. Ethenzamide (ETZ), acetaminophen (APAP), and sodium salicylic acid (SSA) were used as model drugs and may be characterized
as water-insoluble, moderately water-soluble, and highly water-soluble drugs, respectively. All drugs were purchased from
Yoshitomi Pharmaceutical (Tokyo).
Matrix excipients. HS was prepared by Asahi Kasei Chemicals (Tokyo). Hydroxypropyl methylcellulose [(HPMC) Metolose 90SH-100SR, Metolose 90SH-4000SR,
Metolose 10000SR] was purchased from Shin-Etsu Chemical (Tokyo).
Other excipients. Partially pregelatinized corn starch (Starch 1500) was purchased from Colorcon (West Point, PA). Fully pregelatinized corn
starch (Amycol C) and fully pregelatinized potato starch (Amycol HF) were purchased from Nippon Starch Chemical (Osaka, Japan).
Microcrystalline cellulose (MCC), Ceolus KG-802, was manufactured by Asahi Kasei Chemicals. PEG (Macrogol 6000) was supplied
by Sanyo Chemical (Kyoto, Japan). Sorbitol (Sorbitol SP) was purchased from Kowa Pharmaceutical (Nagoya, Japan).
Evaluation of properties of modified starches and HPMC. Average particle diameter. Measurement samples of 5 g were sieved for 5 min using an air-jet JIS sieve of 20, 38, 75, and 150 µm-mesh. The weight percent
remaining on each sieve after sieving was calculated, and the particle diameter was calculated as the cumulative weight percent
Water-soluble content. Sample dispersions of 1% were prepared at 20 °C and were centrifuged for 15 min at 5000 G. The supernatant was dried at 105
°C until a constant weight was reached. The dry weight was defined as the amount of soluble content and was expressed as a
percentage of the initial weight of the samples.
Viscosity. The viscosity of 2% sample dispersions was determined at 25 °C with a rotary viscometer (TVB-10, Toki Sangyo, Tokyo) using
an M1 body.
Preparation of matrix tabletsA model drug, a matrix excipient, and other excipients were physically admixed. The mixtures of 180 mg were compressed using
an 8.0-mm diameter round-faced punch at compression pressure of 60 MPa.
Drug-release study. The dissolution tests were carried out at 37 °C ± 0.5 °C using a USP Type 1 apparatus or a USP Type 2 apparatus rotating from
50 to 200 rpm. The test media consisted of 900 mL of second fluid of the Japanese Pharmacopoeia (14th edition) (JP-2, pH 6.8, and ionic strength 0.14 M) and McIlvaine buffer (pH 7.2 and ionic strength 0.39 M).
Stability test under accelerated conditions. Dissolution profiles and the yellowness index (YI) of HS and HPMC matrix tablets were evaluated after storage at 40 °C and
75% relative humidity (RH) in sealed glass bottles, and at 60 °C in polyamine–polyethylene bags. The YI was measured by a
spectrophotometer (SE200, Nippon Denshoku, Tokyo).