Effect of magnesium stearate or calcium stearate as additives on dissolution profiles of diltiazem hydrochloride from press-coated tablets with hydroxypropylmethylcellulose acetate succinate in the outer shell

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Abstract

Effect of magnesium stearate (MgSt) or calcium stearate (CaSt) on the dissolution profiles of diltiazem hydrochloride in the core of press-coated (PC) tablets with an outer shell composed of hydroxypropylmethylcellulose acetate succinate (HPMCAS) was evaluated by porosity and changes in IR spectra of tablets. In JP first fluid (pH 1.2), the lag time increased with decreasing porosity and was greatest by the addition of MgSt to HPMCAS. While, in JP second fluid (pH 6.8), it increased with decreasing porosity by the addition of CaSt, but hardly changed by the addition of MgSt. Thus, using tablets prepared with the same composition as the outer shell, the changes in IR spectra and uptake amount of the dissolution media after immersion in first fluid and second fluid were determined. The results suggested that some physicochemical interaction occur between MgSt and HPMCAS in tablets with HPMCAS and MgSt and the uptake increased markedly in each dissolution medium. These phenomena seem to cause a prolongation of lag time in first fluid but a shortening of it in second fluid in PC tablets with HPMCAS and MgSt. In contrast, CaSt and HPMCAS did not show such interactions and increased the hydrophobic properties of the outer shell. Consequently, the lag time was only slightly prolonged in first fluid, however, markedly prolonged in second fluid due to suppression of second fluid penetration into micro pores in the outer shell and HPMCAS gel formation on the surface in PC tablets with HPMCAS and CaSt.

Introduction

Recently, oral drug delivery systems for colon targeting have attracted a great deal of interest for the local treatment of a variety of bowel diseases (Hardy et al., 1987, Stolk et al., 1990) and for improving systemic absorption of drugs susceptible to enzymatic digestion in the upper gastrointestinal tract (Saffran et al., 1986). Various approaches have been reported to develop new methodologies for site-specific drug release (Stolk et al., 1990, Mooter et al., 1993, Gazzaniga et al., 1993).

Enteric coated formulations could be a simple and practical means for colon-specific drug delivery. However, such methods do not have sufficient site specificity because, with this type of formulation, most of the drug is released in the upper small intestine after gastric emptying even though drug release is effectively prevented in the stomach. Rate-controlled release systems such as sustained-release formulations are very promising. However, due to the potentially large variation of gastric emptying time of formulations in humans (Davis et al., 1986, Davis et al., 1988), in this approach the colon arrival time of formulations can not be accurately predicted, resulting in poor colonical availability.

Based on the physiological characteristics of the human gastrointestinal tract and the movement of formulations, (Davis et al., 1986, Davis et al., 1988, Khosla et al., 1990, Adkin et al., 1993), an appropriate integration of acid resistance and timed-release functions into a single unit formulation seems desirable to improve the site-specificity of drug release in the colon. That is, since the transit time of formulations in the small intestine is less variable, i.e. 3±1 h, the timed-release function could work more effectively in the small intestine as compared with the stomach. The drug carrier will be delivered to the terminal ileum or colon through the small intestine due to a predetermined time after gastric emptying and drug release will begin. On the other hand, in the stomach, the drug release should be suppressed completely by acid resistance function in the formulations.

Previously, we developed press-coated tablets prepared with a powder mixture of hydroxypropylmethylcellulose acetate succinate (HPMCAS), magnesium stearate (MgSt) and calcium stearate (CaSt) in the outer shell for colon targeting formulations on the basis of the above concept (Fukui et al., 2001). In the process of this screening, we found that in MgSt, the lag time in second fluid was less than 2 h although drug release in first fluid was suppressed completely for 12 h. By contrast, in CaSt, the lag time was little suppressed in first fluid but could be prolonged as long as 9 h in second fluid. This was interesting since these two compounds are generally used as lubricants for tableting and seemed to have similar physicochemical properties (Butcher and Jones, 1972, Baichwal and Augsburger, 1988, Miller and York 1988, Phadke and Sack, 1996).

Drug release from formulations using water insoluble polymer as a controlled-release membrane has been thought to involve a simple diffusion mechanism (Benita and Donbrow, 1982, Vidmar et al., 1982, Sakr et al., 1987, Ozturk et al., 1990). On the other hand, the drug release mechanisms for press-coated tablets using an enteric polymer as the main material in the outer shell seemed different in first fluid and in second fluid. Therefore, clarification of the dissolution behavior of drug could afford useful information for developing new colon targeting formulations or other drug delivery systems.

Thus, in the present study, press-coated tablets were prepared using a powder mixture of MgSt and HPMCAS or CaSt and HPMCAS in the outer shell under various conditions. Effects of MgSt or CaSt on the dissolution behavior (lag time and release rate) of diltiazem hydrochloride (DIL) as a model drug in first fluid and second fluid were investigated on the basis of porosity or the change of IR spectra of tablets.

Section snippets

Materials

Diltiazem hydrochloride (DIL) (Tanabe Seiyaku Co., Ltd. Osaka, Japan) was used as a high solubility drug. Cornstarch (CS) (Nihon Shokuhin Kako Co., Ltd. Tokyo, Japan), calcium citrate (CC) (Satsuma Kako Co., Ltd. Japan), polyvinylpyrrolidone (PVP) (BASF, Germany), carboxymethylcellulose-calcium (CMC-Ca) (Gotoku Chemical Co., Ltd. Tokyo, Japan) and magnesium stearate (Sakai Chemical Industry Co., Ltd. Osaka, Japan) were used for the preparation of core tablets. Hydroxypropylmethylcellulose

Dissolution behavior of DIL from press-coated tablets in first fluid

Three kinds of press-coated (PC) tablets with HPMCAS (H-PC tablets), 20% MgSt and 80% HPMCAS (MH-PC tablets) or 20% CaSt and 80% HPMCAS (CH-PC tablets) in the outer shell were prepared at various compression forces. The dissolution profiles of DIL from PC tablets were determined in first fluid (pH 1.2) and typical dissolution profiles are shown in Fig. 1.

The results showed that the times, at which DIL was first detected (lag times), were prolonged and the release rates of DIL after the lag

Conclusions

Effect of MgSt or CaSt as additives on dissolution profiles of DIL from PC tablets with HPMCAS in the outer shell was evaluated mainly by the porosity and change in IR spectra. MH-PC tablets led to the prolongation of lag time and delay of release rate in first fluid and shortening of lag time in second fluid. From the results of the effect of porosity on lag time, change in IR spectra and uptake of dissolution media after immersion in first fluid and second fluid, some physicochemical

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