A unique dosage form to evaluate the mechanical destructive force in the gastrointestinal tract

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Abstract

The purpose of this study was to prepare tablets that could evaluate the destructive force in the gastrointestinal (GI) tract. Many factors are known to affect in vivo drug release from oral dosage forms. There is still relatively little information on the mechanical destructive force in the GI tract. Press-coated tablets with an extremely brittle outer layer were developed using a unique, highly hydrophobic Teflon powder that could be shaped with weak compression force. A marker drug contained in the tablets was released only when the tablets received a force larger than its predetermined crushing strength. We referred to this type of tablet as a ‘destructive force dependent release system’ (DDRS). A total of nine healthy, male subjects were orally administered the tablets under fed and/or fasting conditions. Tablets with a predetermined crushing strength of 1.50 N were crushed by all of the four subjects who took them under fed conditions and two of the five subjects under fasting conditions. Tablets with a crushing strength of 1.89 N were crushed by two of the six subjects who took them under fed conditions and none of the five subjects under fasting conditions. The range of mechanical destructive force in the human stomach was obtained.

Introduction

In order to establish a rational dissolution test that can predict in vivo drug release, we need to understand the physiological conditions in the gastrointestinal (GI) tract. Although much data has been collected on pH conditions (Lui et al., 1986, Chan et al., 1990, Mojaverian et al., 1991) and transit rates of dosage forms in the GI tract (Meyer et al., 1979, Davis et al., 1986, Davis et al., 1988, Kenyon et al., 1994), we still have relatively limited information on the mechanical destructive force there. This information is necessary to design oral dosage forms, especially sustained-release and colonic delivery formulations (Steffensen and Pedersen, 1986). Dose dumping, or the crushing of dosage forms at an unexpected site in the GI tract, impairs the reliability of the formulation's effectiveness.

A manometer (Stanghellini and Malagelada, 1983) and pressure-sensitive radio telemetry capsules (Coupe et al., 1991) have been used to monitor the GI contraction waves, but the sizes and forms of the sensors used in these studies were much larger than those of actually marketed tablets or capsules. Thus, in those studies, it was difficult to estimate the mechanical destructive force applied to the dosage forms within the GI tract. Several recent studies have investigated the effect of the mechanical destructive force in the GI tract on in vivo drug dissolution (Katori et al., 1995, Shameem et al., 1995). However, the tablets used in these studies were made from hydrophilic materials. So the crushing strength of the dosage forms decreased with an increase in soaking time in the GI fluid, making it impossible to determine the exact destructive force applied when the dosage forms were crushed in the GI tract. When tablets are used as a standard to measure the destructive force in the GI tracts, the tablets must meet the following requirements: (1) the crushing strength of the tablets can be well controlled; (2) soaking in GI fluid does not affect the crushing strength; (3) the crushing in the GI tract can easily be detected; and (4) the shape and size of the tablets are similar to ordinary tablets.

This study presents a new method to evaluate the destructive force in the GI tract using a unique material, Teflon powder with ideal characteristics. It is very hydrophobic and it does not dissolve in any media. Further, it can be easily shaped into brittle mass with only a small compression force. Based on these characteristics, it was possible to design a dosage form which releases a marker drug only when the tablet received a force larger than its predetermined crushing strength.

Section snippets

Materials

Teflon® powder (TE-820-J, TE-914-J) was purchased from DuPont-Mitsui Fluorochemicals (Japan). AEA® (polyvinylacetal diethylaminoacetate) was obtained from Sankyo (Japan). Riboflavin was purchased from Tokyo Tanabe (Japan). Carboxymethylcellulose was purchased from Gotoku (Japan). Magnesium stearate was purchased from Nippon Oil and Fat (Japan). Polysorbate 80 was purchased from Kao (Japan). Gelatin capsules (size #00) were purchased from Matsuya (Japan).

Hydrophobicity of compressed Teflon powder

The apparent contact angle between the

Hydrophobicity of compressed Teflon powder

The apparent contact angle between the surface of the compressed Teflon powder bed and water was much larger than 90° in both Teflon grades (Table 1). The hydrophobicity of Teflon is so great that a water droplet placed on its compressed powder bed surface forms almost a sphere in both Teflon grades.

Physical characteristics of the DDRS

Fig. 4 and Table 2 show the relationship between the compression force and crushing strength of the DDRS. The crushing strength of the DDRS was proportional to the compression force in both Teflon

Discussion

Onset time of urinary riboflavin excretion is considered to represent the time to riboflavin release from dosage forms. After administration of DDRSs, a significant increase of riboflavin excretion was detected in 1–2 h or longer sampling period in all subjects (Fig. 7, Fed CS-1.50 N). When all subjects were administered only the core tablets with AEA coating, they excreted riboflavin in urine in 1 h after administration (data not shown). Consequently, even in the DDRS with lowest mechanical

Conclusions

We prepared a dosage form which can evaluate the mechanical destructive force in the human stomach. The in vivo study showed that the human stomach potentially imparts a mechanical destructive force of 1.89 N to all dosage forms under fed conditions. This value can be used not only to recognize differences between in vitro and in vivo dissolution properties of dosage forms, but also as criteria for dose dumping in developing controlled-release dosage forms.

Acknowledgements

This study was supported by the Japan Health Sciences Foundation.

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    In vivo gastric forces are dependent on several factors, such as gender, age, health, and metabolic state (fasted state or fed state) (Kamba, Seta, Kusai, Ikeda, & Nishimura, 2000; Shani-Levi et al., 2017). In a reference study performed by Kamba et al. (2000), nine healthy volunteers (male, age 28–46 years old, weight 50–71 kg) ingested distinct destructive force-dependent release systems (DDRS) to assess the intensity of the grinding forces in the stomach. DDRS consisted of a riboflavin-loaded tablet coated with a Teflon layer.

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