2016 年 39 巻 4 号 p. 648-651
The present study examined the dissolution of magnesium oxide (MgO) from MgO tablets placed in a food thickening agent (food thickener) and its effects on laxative activity. We prepared mixtures of MgO tablets suspended in an aqueous suspension and food thickeners in order to evaluate the dissolution of MgO. The results of the dissolution tests revealed that agar-based food thickeners did not affect the MgO dissolution. In contrast, some xanthan gum-based food-thickener products show dissolution rates with certain mixtures containing disintegrated MgO tablets suspended in a food thickener that decrease over time. However, other xanthan gum-based food-thickener products show dissolution rates that decrease immediately after mixing, regardless of the time they were allowed to stand. In order to investigate the laxative activity of MgO, we orally administered a mixture of MgO suspension and food thickener to mice and observed their bowel movements. The animal experiments showed that when agar-based food thickeners were used, the laxative activity of MgO was not affected, but it decreased when xanthan gum-based food thickeners were used.
Thickening agents (food thickeners) are commonly used swallowing supplements in medical institutions and nursing care facilities to prevent aspiration in patients with dysphagia.1–3) Moreover, because deglutition aid jellies developed for oral administration of drugs are commercially available, patients with dysphagia often have the opportunity to use such jellies when taking medication. However, although the utility of such jellies as swallowing auxiliary products has been thoroughly examined,1–5) the effects of food thickeners on the pharmacokinetics of oral drugs has not been sufficiently investigated, which has prompted warnings against the indiscriminate use of thickening agents.6) In recent years, undisintegrated tablets have been observed in the stools of patients who have received magnesium oxide (MgO) tablets immersed in food thickeners.7) Moreover, disintegration tests of MgO tablets in food thickeners have shown that the disintegration time of the tablets is prolonged. Dissolution tests have shown that the dissolution rate of MgO decreases when MgO tablets are mixed in a food thickener, and by suspending and disintegrating the MgO tablets in an aqueous solution before mixing with the food thickener, the decrease in the dissolution rate of MgO can be avoided.8)
The effect of food thickener on the pharmacokinetics of oral drugs has not been sufficiently investigated. Importantly, none of the studies incorporated the optimized administration of the MgO which has been shown to influence the drug’s efficacy in a food thickener. The purpose of this study was to investigate the potential laxative activity of the mixtures of disintegrated MgO tablets suspended in a food thickener. First, we evaluated the optimized administration of the MgO by the dissolution tests, and finally evaluated the laxative activity of MgO with food thickener in mice. We performed dissolution tests using mixtures of disintegrated MgO tablets suspended in a food thickener, or disintegrated MgO tablets suspended in a deglutition-aid jelly, and examined the dissolution rate of MgO in the mixtures. Subsequently, we orally administered the mixtures of disintegrated MgO tablets suspended in a food thickener or disintegrated MgO tablets suspended in a deglutition aid jelly to mice and examined the laxative activities of the mixtures in mice.
We used Magmitt® 500 mg Tablets (M Tablets) made by Kyowa Chemical Industry Co., Ltd. (Japan). A deglutition aid jelly for oral administration (jelly-wafer) developed by Ryukakusan Co., Ltd. (Japan) was used. As food thickeners, we used the xanthan gum-based thickeners, Tsururinko Quickly (Tsuru-Q; Clinico Co., Ltd., Japan) and Neo-hightoromeal III (Neo Hi-toro III; Food-Care Inc., Japan), and an agar-based thickener, Ultra-agar (Ina Food Industry Co., Ltd., Japan), which has the same constituents as jelly-wafers.
Food Thickeners and Line Spread Test (LST)In accordance with the Classification of Modified Diet for Dysphagic Persons in 2013 of the Japanese Society of Dysphagia Rehabilitation (JSDR),9) we measured food thickeners prepared at various concentrations by using plastic measuring plates in a LST. That is, we injected a food thickener (20 mL) into a metal ring (30 mm in diameter), lifted the ring after 30 s, and measured the distance (mm) that the samples travelled after 60 s, a mean (n=3) in six directions were defined as the LST value.
Preparation of Food ThickenerThe food thickeners were each prepared in accordance with their respective indications in order to produce moderately thick concentrations (equivalent to an LST score of 32 to 36 mm). Moreover, moderate thickness refers to the amount of thickness that is first tried by patients with dysphagia. We prepared Tsuru-Q at 3.5% (w/v), Neo Hi-toroIII at 2.3% (w/v), Ultra-agar at 0.9% (w/v). Because the jelly-wafers were already in a jellied state, we used the products as they were. Then, 3 mL of food thickener that was prepared at various concentrations or 3 mL of jelly-wafer was mixed with suspending and disintegrating the MgO tablets in 2 mL of water.
Dissolution of Mixture Consisting of M Tablet Suspension and Food ThickenerAfter one M tablet was suspended and disintegrated in 2 mL of water at room temperature, 3 mL of a food thickener that was prepared at various concentrations or 3 mL of a jelly-wafer was mixed and allowed to stand for 30 min at room temperature. The entire mixtures were subsequently placed in dissolution vessels and dissolution testing was performed on the samples. The dissolution test solution was collected and measured using a micropipette. Moreover, untreated M tablets were used as a control. The dissolution tests were conducted in accordance with the dissolution testing procedures of the Japanese Pharmacopoeia; we performed dissolution using an 8-shaft dissolution tester (NTR-8000AC; Toyama Sangyo Co., Ltd., Japan) and performed dissolution using a first fluid (pH 1.2) as the dissolution test solution by paddle method at 50 rpm with 6 vessels. Sampling times were 30, 60, and 120 min.
The dissolution rate of MgO was calculated by quantifying and calculating the eluted magnesium using atomic absorption spectrophotometry (atomic absorption spectrophotometer AA-6300; Shimadzu Corporation, Japan).
Animal ExperimentsAnimals Used in the Present StudyWe bought 6-week-old male Crl:CD1(ICR) mice from Charles River Laboratories Japan Inc. and performed the experiments after a 1-week preliminary breeding period. One group comprised five mice, which were independently bred under the following conditions: room temperature of 22±3°C, humidity level of 50±20%, and light period from 7:00 a.m. to 7:00 p.m. In addition, during breeding, the mice had free access to food and water.
The animal experiments in the present study were conducted in accordance with the Guidelines for Proper Conduct of Animal Experiments of the Science Council of Japan and were approved by the animal experiment committee of Drug Safety Research Laboratories, Shin Nippon Biomedical Laboratories, Ltd. (approval No. IACUC335-009), where these experiments were conducted. This test facility is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International).
Drugs Used in the Present StudyThe M tablets were suspended and disintegrated in water for injection heated to 80°C or higher (150 mg/mL) and mixed in a ratio of 2 : 3 with food thickeners prepared at various thicknesses or a jelly-wafer, and after being allowed to stand for 30 min at room temperature, were orally administered to mice.
The dose of MgO used was 600 mg/kg. Laxative activity was confirmed in 90% of mice that received a single oral dose of MgO at 600 mg/kg; therefore, we selected this dose for use in the present study. Moreover, in a previous study, we disintegrated M tablets in a 0.5% carboxymethylcellulose sodium solution and administered this formulation (10 mL/kg) to mice. When MgO (0, 300, 400, 500, 600, 800, 1000 mg/kg, n=10) was orally administered to mice, the laxative activity was increased from 0 to 90% after 8 h of administration. Dose-dependent increases were seen (0, 0, 20, 70, 90, 80, 90% at 0, 300, 400, 500, 600, 800, 1000 mg/kg, respectively).
We performed hourly observations of the conditions of the stools specimens and noted the time when soft stools or diarrhea were observed following administration. We then calculated the number of mice that presented with soft stools or diarrhea.
The dissolution rates of MgO 120 min after the start of the dissolution test were as follows: jelly-wafer, 100.0%; ultra-agar, 85.9%; Tsuru-Q, 48.0%, and Neo Hi-toro III, 48.3% (Fig. 1).
◆: Tsururinko Quickly, □: Neo Hightoromeal, ×: Ultra agar, ▲: Jelly wafer, ●: Magmitt Tab. (500 mg).
In the group that received oral administration of samples containing Tsuru-Q as a food thickener, 2 out of 5 mice (40%) presented with soft stools or diarrhea, with peak expression occurring 4 h after administration. In contrast, in the group that received oral administration of samples containing Neo Hi-toro III, Ultra-agar, or jelly-wafers as food thickeners, 5 out of 5 mice (100%) presented with soft stools or diarrhea, with peak expression occurring 6 h after administration (Fig. 2).
◆: Tsururinko Quickly, □: Neo Hightoromeal, ×: Ultra agar, ▲: Jelly wafer, ●: Magmitt Tab. (500 mg).
In the present study, we prepared the food thickeners to have LST values of 36 mm, which represents the amount of thickness that is first tried by patients with dysphagia. Because even if food thickeners with different principal constituents are used, if the LST values are the same, it can be assumed that the viscosity values are approximately the same; therefore we attempted a relative evaluation of the food thickeners by using the thickeners having the same LST values. The results of the dissolution test of samples revealed that the dissolution of MgO was low (approximately 48%) 120 min after the start of the test when xanthan gum-based food thickeners (Tsuru-Q and Neo Hi-toro III) were mixed into the M tablet suspension (Fig. 1). In light of the current findings, although xanthan gum-based food thickeners are commonly used in medical institutions and nursing-care facilities, they should not be readily mixed with M tablet suspensions and administered to patients. In a previous study,8) we showed that when Tsuru-Q was mixed in an M tablet suspension, the dissolution rate of MgO was greater than 80% 120 min after the start of the test. The difference with the present study was the length of time that the samples were allowed to stand for. In the present study, we allowed all samples to stand for 30 min, whereas previous studies did not specifically set a standing time. Moreover, because interviews conducted with those working in clinical practice revealed that up to 30 min is needed to mix food thickeners in an M tablet suspension before administration to patients,8) we let the solutions used in the present study stand for 30 min. The results of the two studies, which had differing mixture standing times show that when Tsuru-Q is used, the effects on the dissolution rate of MgO is minimal, directly after mixing with the M tablet suspension, but the dissolution rate decreased when allowed to stand for a long period of time. However, when Tsuru-Q and Neo Hi-toro III, another xanthan gum-base thickener, were mixed into the M tablet suspension, the dissolution rate decreased regardless of the time the mixture was allowed to stand for.8) These results show that when a commonly available xanthan gum-based food thickener is used, the dissolution rate differs depending on the product used; therefore, it is necessary to consider changes in the dissolution rate during the standing time when selecting a food thickener.
The results of dissolution testing performed on the sample mixture of an agar-based food thickener and an M tablet suspension revealed that the dissolution rate of MgO was approximately 86% 120 min after the start of the test (Fig. 1). Similarly, results of dissolution testing performed on the sample mixture of the agar-based deglutition aid jelly for oral administration and M tablet suspension revealed that the dissolution rate of MgO was 100% 120 min after the start of the test (Fig. 1). These findings show that agar-based food thickeners are more suitable than xanthan gum-based thickeners for mixing M tablet suspensions.
Laxative activity is expressed by the antacid action created through the neutralization reaction between MgO and gastric acid, and through the formation of magnesium bicarbonate, after the oral administration of MgO. In the present study, we examined the relationship between the dissolution rates of MgO revealed by dissolution testing and laxative activity (efficacy) in mice; laxative activity was observed in all mice that received an agar-based food thickener or deglutition aid jelly for oral administration (Fig. 2), both of which had high dissolution rates (Fig. 1). Laxative activity was confirmed in only 40% of the mice that received administration of the xanthan gum-based Tsuru-Q (Fig. 2), which had a low dissolution rate (Fig. 1). However, laxative activity was observed in all mice that received the xanthan gum-based Neo Hi-toro III (Fig. 2), which had a low dissolution rate (Fig. 1). The results of dissolution testing showed that the dissolution rate of MgO and the individual expression of laxative activity are not always consistent. There is difference in composition between the two xanthan gum-based thickeners. Calcium lactate and trisodium citrate are contained in Tsuru-Q as additives, whereas these additives are not added to Neo Hi-toro III. Moreover, the producing companies of these thickeners disclose the amount of xanthan gum in two thickeners. Treatment with carboxymethylcellulose and thickening agents, but not Tsuru-Q, increased the laxative activity at the same level. Laxative activity was lowered when treatment with Tsuru-Q. Because the effect of additive is unknown, these results suggest that effects of additives must be considered when selecting a food thickener.
In conclusion, the agar-based food thickeners did not affect the dissolution of MgO. The animal experiments showed that when agar-based food thickeners were used, the laxative activity of MgO was not affected, but it decreased when xanthan gum-based food thickeners were used. The results of dissolution testing showed that the dissolution rate of MgO and the individual expression of laxative activity are not always consistent. These results suggested that commercially most available food thickeners are associated with changes in pharmacodynamics profiles of clinically useful drug. Food thickeners need to be carefully used in clinical situations.
The present study was planned by health care practitioners, and was not contracted by Kyowa Chemical Industry Co., Ltd. Yuya Yoshimura and Kazushige Kato are employees of Kyowa Chemical Industry Co., Ltd. There are no other potential conflict of interest to be disclosed.
