Effects of yogurt as a deglutition aid on disintegration and dissolution of oral tablets

Abstract Patients with dysphagia have difficulty swallowing oral medications. Swallowing aid foods, such as deglutition aid jellies and food thickeners, are often used to help such patients take oral medications. Yogurt is occasionally used to help swallow medications. It is also advantageous as it is nutritious and easy to swallow. However, the influence of yogurt on the pharmacokinetics of oral medications is poorly understood. In this study, we aimed to evaluate yogurt as a potential swallowing aid for the intake of oral tablets, by comparing the physical properties and effects of yogurt on disintegration and dissolution profiles of various oral tablets with deglutition aid jelly and xanthan gum‐based food thickener. Yogurt and the food thickener were found to extend the disintegration time of several tablets; however, this increase was unremarkable. Although dissolution of magnesium oxide tablets decreased by 6%, 14%, and 25% after immersion in deglutition aid jelly, food thickener, and yogurt, respectively, at 15 min, this impact on dissolution reduced over time (dissolution rates of all samples at 120 min were over 90%). Rheological measurements showed that yogurt and food thickeners have a weak gel structure and therefore have better fluidity than deglutition aid jelly. The adhesiveness and dynamic viscosity of yogurt were higher than those of the food thickener, which delayed tablet disintegration and reduced the dissolution rate. However, these effects were not substantial. We can thus conclude that yogurt may be a useful swallowing aid for patients with deglutition disorders who take oral medications.

many patients, which increases the risk of accidental aspiration of food and drinks (Feng et al., 2013;Fujitani, 2000;Iida et al., 2013;Oad et al., 2019), and also makes it difficult for patients to take oral medications (Kelly et al., 2009;Oad et al., 2019). To aid medication intake, patients with dysphagia use food thickeners to increase the viscosity of liquids, and deglutition aid jellies to convert solids into a gelatinous form (Ookoshi, 2004). However, these swallowing aids can interfere with the disintegration of dosage forms and the dissolution of the drugs within these dosage forms (Cichero, 2013;Morita et al., 2011;Matsuo et al., 2020;Obara et al., 2020;Tomita, Goto, et al., 2019). Immersing tablets in food thickeners for a long time can delay or inhibit tablet disintegration . Therefore, it is important to minimize immersion time (≤1 min) to avoid problems with disintegration . The immersion of voglibose orally disintegrating (OD) tablets in deglutition aid jelly for 10 min has been reported to reduce the pharmacological activity of voglibose (Tomita, Goto, et al., 2019). Research on the effects of food thickeners and deglutition aid jellies on oral medications has increased our understanding of this subject.
Yogurt is rich in nutrients, such as proteins, minerals, and vitamins, and it has been reported to lower the risk of sarcopenia (Cuesta-Triana, et al., 2019;Hashemi Gahruie et al., 2015). Yogurt has moderate viscosity and hardness, making it a suitable training meal for patients with dysphagia. The use of yogurt to facilitate swallowing of medications was recommended by the Japanese Society of Dysphagia Rehabilitation Dysphagia Diet Committee (DDC) in the Japanese Dysphagia Diet 2013 (Fujitani et al., 2013). In clinical practice, yogurt is used to help patients with dysphagia take medications (Fujitani, 2000). It is also used as an index of hardness for foods (Ookoshi, 2004). However, the effects of yogurt on the disintegration and dissolution of oral medications are poorly understood.
The properties of yogurts vary depending on the lactic acid bacteria used in manufacture, and these properties affect the degree of swallowing required. Some lactic acid bacteria synthesize exopolysaccharides, which affect the viscosity, hardness, and adhesiveness of yogurt. Lactococcus lactis subsp. cremoris FC (L. cremoris FC) is a strain of lactic acid bacteria isolated from fermented milk from the Caucasus region (Ishida et al., 2005). The strain L. cremoris FC produces exopolysaccharides that affect the texture and stability of the yogurt (De Vuyst & Degeest, 1999;Ishida et al., 2005;Ruas-Madiedo & de los Reyes-Gavilán, 2005). It has been reported that yogurt manufactured using L. cremoris FC decreases the rate of laryngeal invasion and aspiration in patients with dysphagia, compared with yogurt manufactured using other strains of lactic acid bacteria (Gotoh et al., 2019). In this study, we aimed to assess yogurt as a potential swallowing aid for oral tablets. This was achieved by comparing the effects of yogurt on the disintegration and dissolution of magnesium oxide tablets with those of the xanthan-based food thickener and deglutition aid jelly. We chose magnesium oxide tablets as these are commonly used by patients in care facilities. In addition, we evaluated the effects of these swallowing aids on other oral medications, including film-coated tablets, sugar-coated tablets, enteric-coated tablets, and OD tablets. The physical properties, adhesiveness, dynamic viscosity, and rheology of the swallowing aids were also compared. We hypothesized that yogurt manufactured using L. cremoris FC could be used as an aid for the administration of oral medication.

| Materials
The choice of medications for use in this study was based on the results of a questionnaire survey conducted in care facilities and a previous study on the effects of food thickeners on disintegration and dissolution of medications (Matsuo et al., , 2021Tomita, Sakai, et al., 2019).
Details of the medications used in this study are shown in Table 1.
Deglutition aid jelly, xanthan gum-based food thickener, and yogurt made with L. cremoris FC were purchased from Ryukakusan Co. Ltd. Hyogo, Japan), respectively. The appearances of these and their ingredients are shown in Figure 1 and Table 2, respectively.

| Preparation of food thickener
The method for the preparation of the xanthan gum-based food thickener has been previously described . In brief, xanthan gum-based food thickener (3.0 g) was added to 100 ml of soft water (Suntory Tennensui; Suntory Beverage & Food Limited, Japan) and mixed. The prepared food thickener was used 2 min after mixing.

| Disintegration test
The disintegration test was performed as described in the Japanese Pharmacopeia 17th Edition (The Ministry of Health, Labour and Welfare of Japan, 2016a). This method has previously been described in the literature (Matsuo et al., , 2021. The tablets were immersed in each deglutition aid for 1 min, and then transferred to a basket of the disintegration testing apparatus (NT-40HS, Toyama Sangyo Co., Ltd., Japan).
Approximately 0.5-1.0 g of each of the swallowing aids was left attached to the tablets. The test was carried out using the first fluid (sodium chloride (2.0 g) and hydrochloric acid (7.0 ml) in 1000 ml of water, pH 1.2) and the second fluid (0.2 mol/L potassium dihydrogen phosphate (250 ml) and 0.2 mol/L sodium hydroxide (118 ml) in 1000 ml of water, pH 6.8). The enteric-coated tablets were tested in both fluids, while the other tablets were tested only at pH 1.2. The disintegration time was defined as the time taken for the contents of the tablets to be completely released from the baskets. The maximum test time was 2 h. Each experiment was performed using nine tablets.

| Dissolution test for magnesium oxide tablets
The dissolution test was performed using the paddle apparatus, as described in the Japanese Pharmacopeia 17th Edition (The Ministry of Health, Labour and Welfare of Japan, 2016b). This method has previously been described in the literature (Matsuo et al., 2021). Magnesium oxide tablets were pre-treated with the swallowing aid foods, as described in Section 2.3. Magnesium oxide content in the dissolution medium was measured by chelate titration using ethylenediaminetetraacetic acid (EDTA): 1mlof0:05mol=LEDTA ¼ 2:015mgof magnesium oxide:

| Adhesiveness
The evaluation of adhesiveness has previously been described in the literature . In brief, the deglutition aids (10.0 g) were added to 100 ml polyvinylpyrrolidone (PVP) or glass beakers.
Each beaker was reversed for 1 min and adhesiveness was defined as the residue rate in the beaker.

| Rheological measurements
The yogurt was tested at 10 and 20 C, while the other samples were tested at 20 C. Measurements were obtained using a controlled stress rheometer (MCR-102, Anton Paar, Austria) equipped with cone plates (50 mm diameter, angle 1 ). The temperature of the measuring cell was maintained with a Peltier system (P-PTD200, Anton Paar, Austria To determine the linear viscoelastic region, strain-dependent measurements were made from 0.01% to 10% strain, at a frequency of 1 Hz. As a result, 0.1% strain was adopted as the measurement condition. To evaluate the viscoelastic properties of the samples, frequency-dependent measurements were made between 0.1 and 10 Hz at 0.1% strain, and the storage modulus (G'), loss modulus (G") were determined.

| Statistical analysis
Data are presented as mean ± standard deviation. Statistical analyses were performed using Student's t-test or one-way analysis of variance with post hoc test (Dunnett's test or Tukey-Kramer method). Differences were considered statistically significant at p < 0.05.

| Effects of yogurt on disintegration and dissolution of magnesium oxide tablets
The disintegration times of magnesium oxide tablets immersed in yogurt were compared with the disintegration times in deglutition aid jelly and food thickener ( Figure 2). Magmitt ® tablets, and the magnesium oxide tablets, "MOCHIDA," "KENEI," and "Yoshida," were immersed in swallowing aids for 1 min. All experiments were performed in an aqueous medium of pH 1.2 (n = 9). Jel, immersed in deglutition aid jelly; Non, not immersed; Thi, immersed in food thickener; Yog, immersed in yogurt. *p < 0.05; **p < 0.01, and ***p < 0.001, which represent significant differences (compared with non-immersed tablets, Dunnett's test) F I G U R E 3 Dissolution rate of Magmitt ® tablets after immersion in swallowing aid foods. The dissolution rates of Magmitt ® tablets were measured at 15, 30, 60, and 120 min by chelate titration (n = 3). The symbols in the figure indicate: Â not immersed, • yogurt, and ▲ deglutition aid jelly, 〇 food thickener. a p < 0.05; a' p < 0.01; and a" p < 0.001 (for immersed tablets vs. non-immersed tablets). b p < 0.05 and b' p < 0.01 (for tablets immersed in yogurt vs. tablets immersed in deglutition aid jelly) which represent significant differences (compared with all samples tested at the same time points, Turkey Kramer test) jelly at 15 min were 60%, 70%, and 78%, respectively. However, dissolution rates of all the samples at 120 min were over 90%, and were similar to the dissolution rates of the non-immersed tablets.

| Effects of yogurt on the disintegration of other oral tablets
Three furosemide tablets (two uncoated and one film-coated tablet), four amlodipine tablets (one film-coated and three OD tablets), an aspirin tablet (enteric-coated), and a sodium valproate tablet (sugarcoated) were evaluated (Figures 4 and 5). Immersion of these tablets in deglutition aid jelly did not prolong the disintegration time of any of the tablets, compared with non-immersed tablets. Yogurt and food thickener delayed the disintegration of Lasix ® (furosemide) tablets and three amlodipine OD tablets (Figure 4). In contrast, the filmcoated amlodipine tablets showed rapid disintegration after immersion in all the deglutition aids ( Figure 4). The enteric-coated aspirin tablets did not disintegrate in the first test medium (pH 1.2) in any of the cases, but disintegrated in approximately 10 min in the second amlodine ® OD, (f) amlodipine OD "SAWAI," and (g) amlodipine 2.5 mg "SAWAI," tablets were immersed in swallowing aid foods for 1 min before disintegration time experiments were conducted. All experiments were performed in aqueous medium of pH 1.2 (n = 9). Jel, immersed in deglutition aid jelly; Non, not immersed; Thi, immersed in food thickener; Yog, immersed in yogurt. **p < 0.01 and ***p < 0.001, which represent significant differences (compared with non-immersed tablets, Dunnett's test) test medium (pH 6.8) ( Figure 5). The disintegration of the sugarcoated Valerin ® (sodium valproate) tablets was not affected by immersion in any of the deglutition aids.

| Comparison of physical properties of the deglutition aids
The adhesiveness of the yogurt, deglutition aid jelly, and food thickener were 81%, 31%, and 54%, respectively, in the glass beaker, and 91%, 11%, and 49%, respectively, in the PVP beaker ( Figure 6). Adhesiveness of the deglutition aid jelly, which demonstrated lower effects on disintegration and dissolution of tablets than the other foods did, was low. To further examine physical properties, rheological measurements were performed (Figure 7). The viscosities of all the samples were inversely proportional to the shear rate. (Figure 7a). Therefore, it indicated that all samples had a shear-thinning characteristic that is fluid at high shear rates. Besides, the viscosities of yogurt were higher than the viscosities of the other samples at all shear rates. The storage modulus (G') of yogurt and jelly ranged approximately from 100 to 400 Pa and was higher than that of the food thickener (Figure 7b). In addition, their values were slightly increased as frequency increased,

| DISCUSSION
Yogurt is considered an easy-to-eat food for patients with dysphagia because of its appropriate viscosity and hardness. If yogurt can be used as an aid in taking oral medications, adherence would be expected to improve in patients who usually consume yogurt. It has been reported that yogurt prepared using the L. cremoris FC strain is better at preventing aspiration compared with yogurt made using other strains of lactic acid bacteria (Gotoh et al., 2019). In this study, we aimed to assess L. cremoris FC-containing yogurt as a potential yogurt-immersed tablets was found to be lower, at 15 min, than that of non-immersed tablets, but was similar to drug release of nonimmersed tablets or of those immersed in jelly and food thickener, at 120 min. The gastric retention times of medicines are generally within 120 min (Aulton & Taylor, 2013). Yogurt was found to delay the disintegration of some rapidly disintegrating tablets (certain magnesium oxide tablets and OD tablets). This tendency was similar to that of food thickeners, but the disintegration times tended to be slightly longer with yogurt than with the food thickener. Deglutition aid jelly, on the other hand, did not cause a delay in disintegration.
The adhesiveness of swallowing aid foods was in this order: yogurt > food thickener > deglutition aid jelly ( Figure 6). We previously reported that the high adhesiveness of food thickener caused an elongation of the disintegration time of the tablets compared to low adhesiveness in food thickener . The results could demonstrate that deglutition aid jelly had a minimal effect on the tablets. Dynamic viscosity of the deglutition aid jelly was also lower than that of yogurt, but it was similar to that of the food thickener ( Figure 7a). Deglutition aid jelly consists of solids and liquid ( Figure 1). The solids exist as small boluses ( Figure 1) and have stronger gel-like behavior than yogurt and the food thickener (Figure 7b,c, tanδ). When the solids of the jelly attached to the tablets, voids of jelly solids around the tablets were formed, allowing water to easily invade the voids. It is thought that the minimal effects of deglutition aid jelly on disintegration and dissolution of tablets might be related to the solid and liquid nature of the deglutition aid jelly, not dynamic viscosity. In yogurt, the adhesiveness, dynamic viscosity, G', and G" were the highest out of all the swallowing aid foods. Attachment of yogurt to the tablets might have occurred more easily, while detachment from the tablets might have been more difficult than those of the deglutition aid jelly and food thickener. Moreover, casein, which is found in yogurt, aggregates under acidic conditions (Niki, 2002). This might have caused the delay in disintegration and the reduction in dissolution rate in the acidic medium. However, our physical assessments of swallowing aid foods were performed at 10 and 20 C to obtain fundamental data for taking medications. After taking medications with swallowing aid foods, they move through the gastric duct, where they are sheared at a higher temperature of approximately 37 C. To further elucidate whether swallowing aid foods easily detach from tablets, further experiments at 37 C are warranted.
It is important to establish the safety of oral medications when taken with yogurt and to verify the effects of yogurts on various medications, both in vitro and in vivo. The pharmacological activities of bisphosphonates, tetracyclines, and quinolones are reduced by the calcium found in milk. Therefore, these medications cannot be administered with yogurt. Furthermore, the effects of yogurt on the taste of medications were not evaluated in this study. It is important to assess these factors to ensure medication adherence; this is an aspect which should be investigated in future studies. It is also crucial for pharmacists to confirm dietary habits and methods for taking medications in patients with dysphagia so that optimal swallowing aids can be recommended. Subsequent studies should investigate swallowing aids based on pharmacists' input on patient habits.
In conclusion, this study demonstrated that yogurt manufactured using L. cremoris FC did not remarkably affect the disintegration or dissolution profiles of magnesium oxide tablets or those of the other oral tablets evaluated. Similar to deglutition aid jelly and food • yogurt tested at 10 C, 〇 yogurt tested at 20 C, ■ food thickener tested at 20 C, and Â deglutition aid jelly tested at 20 C