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Evaluation of the ease of taking mini-tablets compared with other tablet formulations in healthy volunteers
European Journal of Pharmaceutical Sciences 84 (2016) 157–161
Contents lists available at ScienceDirect
European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps
Evaluation of the ease of taking mini-tablets compared with other tablet formulations in healthy volunteers Yoshiyuki Hayakawa a,b, Shinya Uchida a, Noriyuki Namiki a,⁎ a b
Department of Pharmacy Practice and Science, School of Pharmaceutical Sciences University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan
a r t i c l e
i n f o
Article history: Received 29 July 2015 Received in revised form 26 October 2015 Accepted 26 December 2015 Available online 29 December 2015 Keywords: Mini-tablet Orally disintegrating tablet Water intake VAS score
a b s t r a c t “Mini-tablets” (MTs) are tablets of diameter ≤ 3 mm and have been widely studied and developed. However, reports comparing MTs with other tablet formulations are few. We wished to evaluate the ease of taking a MT quantitatively in comparison with an orally disintegrating mini-tablet (ODMT), conventional tablet (CT) and conventional orally disintegrating tablet (ODT). Four types of tablets were prepared. We prepared tablets of two diameters (3 mm for MTs and ODMTs vs. 8 mm for CTs and ODTs) and two formulations (MTs and CTs vs. ODMTs and ODTs). Our randomized crossover trial in 18 healthy volunteers (8 men and 10 women; mean age, 22.5 years) indicated that the visual analog scale (VAS) score for the ease and amount of water required for intake of MTs was significantly lower than those of CTs. An ODMT required the least amount of water and smallest VAS score for the ease of taking a tablet. Our results showed that the advantage of MTs with regard to the ease of taking and decreased amount of water required was exerted for a unit of dosing comprising b 5 tablets. These data suggested the usefulness of MTs and the importance of the number of MTs for comfortable consumption by patients. © 2015 Published by Elsevier B.V.
1. Introduction Tablets are the most widely used drug formulation among various types of formulation (e.g., tablets, capsules, granules). They are easy to handle and convenient to carry and store. However, problems may arise in pediatric or elderly patients whose swallowing functions are inferior to those of adult patients. Orally disintegrating tablets (ODTs) are a user-friendly formulation (Hirani et al., 2009). ODTs could be beneficial for patients who have difficulty swallowing conventional tablets (CTs). Furthermore, ingestion of ODTs with little water or without water may be beneficial for patients with disorders for which water intake must be restricted (e.g., overactive bladder). Several commercial types of ODTs have become popular in the last decade. However, taste-masking is required for ODTs if the drug substance has an unpleasant taste (Mizumoto et al., 2008). In this case, any other formulation without taste masking is needed. Mini-tablets (MTs) have a diameter ≤3 mm. They have been studied widely and developed (Lennartz and Mielck, 1998). MTs are considered to be easier to swallow than CTs, whose diameter is N3 mm. This decrease in tablet diameter could improve patient adherence to
⁎ Corresponding author. E-mail address: [email protected] (N. Namiki).
http://dx.doi.org/10.1016/j.ejps.2015.12.029 0928-0987/© 2015 Published by Elsevier B.V.
medication and decrease the risk of aspiration. Many studies on different types of MTs, such as orally disintegrating mini-tablets (ODMTs), sustained-release MTs, “floating” MTs, and bioadhesive MTs, have been carried out (Stoltenberg and Breitkreutz, 2011; Mohamed et al., 2013; Goole et al., 2008; Schmitz et al., 2005). Several clinical trials of MTs in preschool-aged children have been reported (Thomson et al., 2009; Spomer et al., 2012; Klingmann et al., 2013; van Riet-Nales et al., 2013). These reports suggest that MTs are the most acceptable and preferred oral formulation compared with powder or syrup formulations. Kluk et al. (2015) reported recently that ≤ 10 MTs mixed with jelly were acceptable to children aged 2–3 years. However, reports of clinical trials comparing MTs and other tablet formulations (e.g., CTs, ODTs) are lacking. In many cases, MTs are administered as a unit of several tablets, but quantitative data for evaluation of the ease of intake of such units are lacking. We aimed to evaluate the ease of taking MTs quantitatively in comparison with other tablet formulations, as well as the intake of different numbers of MTs. First, one tablet of each formulation was evaluated. We compared 1 MT with 1 ODMT, 1 CT and 1 ODT by measuring the volume of water required for ingestion and the ease of intake using a visual analog scale (VAS), methods that have been employed by our research team previously (Uchida et al., 2013; Sugiura et al., 2012). Next, we evaluated the volume of water required for the intake and ease of taking tablets when units of 1, 2, 5 and 10 MTs were administered.
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2. Materials and methods 2.1. Materials D-Mannitol (Mannit Q™) was kindly provided by the Mitsubishi Shoji Foodtech Co., Ltd. (Tokyo, Japan). All other samples were obtained commercially. α-Lactose monohydrate (Dilactose®S) was from the Freund Corporation (Tokyo, Japan). Microcrystalline cellulose (CEOLUS™ UF-702) was from the Asahi Kasei Chemicals Corporation (Tokyo, Japan). Low-substituted hydroxypropyl cellulose (L-HPC LH21) was from the Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). Crospovidone (Kollidone® CL) wasfrom the BASF (Rhineland-Palatinate, Germany). Magnesium stearate (Parteck® LUB MST (magnesium stearate vegetable grade)) was from the Merck KGaA (Darmstadt, Germany).
2.2. Preparation of tablets Compositions of each formulation are shown in Table 1. Shapes of a CT and MTs are depicted in Fig. 1. All excipients were mixed together and compacted. MTs and ODMTs were prepared on a Single-punch Tablet Machine (HANDTAB; Ichihashiseiki, Kyoto, Japan) with a 3-mm, six-tip mini-tableting tool. Six MTs were compacted together, and the force was 6 kN. One MT weighed 20 mg, and average compaction was 1 kN. CTs and ODTs were prepared on the same tablet machine with an 8-mm tableting tool with compaction forces of 8 kN and weight of 200 mg per tablet. Hardness of tablets was measured using a Tablet Hardness Tester (PC-30; Okada Seiko Co. Ltd., Tokyo, Japan). Hardness, weight and thickness were measured on 10 tablets of each type and the mean value was calculated. 2.3. Clinical trial All volunteers provided written informed consent to participate in this study. The study was conducted in accordance with the Declaration of Helsinki and its amendments. The study protocol was approved by the Ethics Committee of the University of Shizuoka (protocol number 25–41; Shizuoka, Japan). 2.3.1. Measurement of the clinical disintegration time of tablets The clinical disintegration time was measured for four types of tablet (MT, ODMT, CT, ODT) as described previously (Yoshita et al., 2013). Ten healthy volunteers (3 men and 7 women; age (mean ± SD), 22.0 ± 1.2 years) participated in this randomized crossover study. Before the test, the oral cavity of the participants was rinsed with a cup of water (120 mL). Each tablet was placed on the tongue and disintegrated in the oral cavity. The clinical disintegration time of each tablet was measured by an investigator using a stopwatch. Remnants of each tablet were removed and rinsed from the mouth with water after each test.
2.3.2. Measurement of the amount of water required for the ingestion and ease of taking tablets Eighteen healthy volunteers (8 men and 10 women; age, 22.5 ± 1.0 years) participated in this randomized crossover trial. Measurement of the amount of water required for ingestion of CTs and ODTs was conducted as described previously (Uchida et al., 2013). Subjects were asked to consume 1 MT and 1 CT with drinking water. In the case of 1 ODMT and 1 ODT, they were asked to drink water after these tablets had disintegrated in the oral cavity. Subjects freely filled the cup with water from a 500-mL bottle and then drank the minimum volume of water required to consume each tablet smoothly. The amount of water was measured using the weight of the cup and bottle. After drinking water, they were asked to evaluate the ease of taking a tablet using a VAS with the most difficult sensation for taking a tablet marked at 100 mm (Fig. 2). In the second trial, all volunteers randomly took 1 CT or one unit containing 1, 2, 5 or 10 MTs (Fig. 1) with water. Ten MTs and 1 CT are the same weight. One unit of MTs or 1 CT was placed into the mouth simultaneously. After drinking water, the amount of water required and VAS score for the ease of intake of each unit of tablets were measured by the same methods as the first trial. 2.4. Statistical analyses Data for tablet characteristics are the mean ± standard deviation (S.D.), whereas data from the clinical study (VAS and amount of water) are the median value. Statistical analyses were undertaken using a Graphpad Prism v5.02 (Graphpad Software, San Diego, CA, USA). Each pair of samples was analyzed separately and compared using the non-parametric Wilcoxon signed rank test with the Bonferroni correction to detect differences among the amount of water required for ingestion of tablets and the ease of taking tablets. p b 0.017 was considered significant for the first trial, and p b 0.0125 for the second trial. 3. Results 3.1. Characteristics of each tablet Weight, thickness, hardness and clinical disintegration time of each tablet are shown in Table 2. One ODMT disintegrated in b10 s. One MT and one ODT disintegrated in ≈20 s. One CT disintegrated in ≈1 min. 3.2. VAS score for ease and amount of the water required for the ingestion of each tablet in the first trial The VAS score for the ease and amount of water required for ingestion of a single tablet is shown in Fig. 3. VAS score for 1 CT was the
Table 1 Composition of a mini-tablet, orally disintegrating mini-tablet, conventional tablet and orally disintegrating tablet. Ingredients (mg)
MT (3 mm)
ODMT (3 mm)
CT (8 mm)
ODT (8 mm)
Dilactose® S L-HPC LH-21 Kollidone® CL Mannit Q™ CEOLUS™ UF-702 Parteck® LUB MST Total
13.8 2 – – 4 0.2 20
– – 2 13.8 4 0.2 20
138 20 – – 40 2 200
– – 20 138 40 2 200
MT, mini-tablet; ODMT, orally disintegrating mini-tablet; CT, conventional tablet; ODT, orally disintegrating mini-tablet.
Fig. 1. Conventional tablet and mini-tablet used in this study. The diameters of a conventional tablet (CT) and mini-tablet (MT) were 8.0 and 3.0 mm, respectively. The total weight of tablets between 1 CT and 10 MTs was equal. Volunteers took 1 CT or 1, 2, 5, and 10 MTs in the second trial. Scale is in mm.
Y. Hayakawa et al. / European Journal of Pharmaceutical Sciences 84 (2016) 157–161
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Fig. 2. Visual analog scale to evaluate the ease of taking a tablet.
largest value (54.5) of all the tablets tested, and the difference from the value of 1 MT (9.0) was significant (p = 0.0013). VAS score for 1 ODT (32.0) was significantly higher than that for 1 MT (p = 0.0060), but it was not significant for 1 ODMT (2.0; p = 0.0735). Median amount of water required for taking 1 ODMT (6.6 mL) and 1 CT (29.9 mL) was significantly lower and higher than that of 1 MT (12.1 mL), respectively (p = 0.0069 and p = 0.0004, Fig. 3(B)). There was no significant difference between 1 ODT (19.1 mL) and 1 MT (p = 0.0894). Only one volunteer took 1 MT and 1 ODMT with 60 mL of water. Other volunteers took 1 MT and 1 ODMT with b 30 mL of water. 3.3. VAS score for the ease and amount of water required for ingestion of each unit of tablets in the second trial The VAS score for the ease and amount of water required for ingestion of 1 CT or 1 unit of 1, 2, 5, and 10 MTs in the second trial is shown in Fig. 4. VAS scores of the ease of intake for 1 MT (4.0) and 2 MTs (21.0) were significantly lower than that of 1 CT (49.0; p = 0.0006 and 0.0028, respectively). VAS scores for 5 MTs (36.0) were similar to that of 1 CT, and that of 10 MTs (62.5) was slightly higher than that of 1 CT, but the difference was not significant (p = 0.0935). Median amounts of water required for ingestion of 1 MT (11.4 mL) and 2 MTs (15.9 mL) were significantly smaller than that of 1 CT (23.9 mL; p = 0.0004 and 0.0013, respectively, Fig. 4(B)). No significant differences in the amounts of water required between 1 CT and 5 MTs (24.7 mL) or 10 MTs (26.5 mL) were observed (p = 0.4431 and 0.1169, respectively). 4. Discussion We prepared four types of tablets in the present study. We prepared tablets of two diameters (3 mm for MTs and ODMTs vs. 8 mm for CTs and ODTs); we prepared two types of formulation (conventional formulation for MTs and CTs vs. orally disintegrating formulation for ODMTs and ODTs). An ODMT disintegrated the fastest because of its small diameter and formulation type (orally disintegrating). Disintegrating times of MTs and ODTs were similar to each other and shorter (≈20 s) compared with the disintegrating times of CTs (≈1 min). A MT and CT were
of the same formulation (same ingredients and same ratio). Hence, the ratio of surface area:volume of a MT was higher than that of a CT, and this higher surface area could affect the disintegrating time of a MT. The fast disintegration in the mouth and higher surface area of uncoated MTs could impact on taste-masking and storage (especially in high humidity). In the first trial, we compared four types of tablets to reveal the acceptability of each tablet to volunteers in terms of the ease of taking tablets and amount of water required for intake. A VAS is known to be more sensitive to small changes compared with a simple descriptive scale, and can be used to evaluate the feeling of ease of taking tablets by volunteers. The amount of water required for tablet intake is also thought to reflect their characteristics because patients need a larger amount of water if they feel that the medicine will be difficult to take. Compared with 1 MT, VAS scores for the ease of intake of 1 CT and 1 ODT were significantly higher, suggesting that subjects could take 1 MT than 1 CT and 1 ODT more readily. MTs have been reported to be more acceptable and preferred oral formulation compared with powder and syrup formulations in young children (Spomer et al., 2012; Klingmann et al., 2013; van Riet-Nales et al., 2013). Results from the present study are in accordance with those reports in children, and are the first evidence that MTs could be taken readily by adult patients (especially the elderly). The amount of water required to take 1 CT was significantly larger than that to take 1 MT, but a significant difference between 1 ODT and 1 MT was not observed. Thus, it is likely to result in no significant difference in the amount of water required between taking 1 MT and 1 ODT. Other features of an ODT (e.g., less feeling or fewer remnants in the mouth) could make the VAS score for the ease of taking an ODT worse. Interestingly, a larger inter-individual variability for the amount of water required for taking 1 ODT was detected in comparison with that for taking 1 MT. For instance, most people needed 10–20 mL water to take 1 MT. In contrast, 4 subjects (22%) took 1 ODT without water, whereas 7 subjects (39%) needed N 30 mL water. One ODMT required the least amount of water and smallest VAS score for ease of taking tablets. If issues such as the taste of the drug contained in the tablet or stability for storage were not problems, an ODMT could be the most acceptable type of tablet.
Table 2 Diameter, weight, thickness, hardness, and clinical disintegration time of a mini-tablet, orally disintegrating mini-tablet, conventional tablet and orally disintegrating tablet.
Diameter (mm) Weight (mg) Thickness (mm) Hardness (N) Clinical disintegration time (s)
MT
ODMT
CT
ODT
3.0 20.1 ± 0.6 2.44 ± 0.04 21.4 ± 3.8 23.2 ± 5.1
3.0 20.2 ± 0.5 2.64 ± 0.02 15.2 ± 6.2 8.1 ± 1.2
8.0 202.6 ± 1.2 3.55 ± 0.03 97.1 ± 4.4 63.5 ± 9.0
8.0 200.6 ± 1.8 4.09 ± 0.08 112.3 ± 9.5 23.5 ± 8.2
Data are the mean ± standard deviation (S.D.) for 10 determinations. MT, mini-tablet; ODMT, orally disintegrating mini-tablet; CT, conventional tablet; ODT, orally disintegrating tablet.
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Fig. 3. Visual analog scale (VAS) score for ease (A) and amount of the water required (B) for ingestion of each tablet in the first trial. Volunteers randomly took a mini-tablet (MT), an orally disintegrating mini-tablet (ODMT), a conventional tablet (CT) and an orally disintegrating tablet (ODT) with water. Then, the amounts of water intake and VAS score for ease of intake were measured. Each point represents a value for the volunteers. The horizontal line in each column indicates the median value for 18 volunteers.
MTs are usually not taken as single tablets but as a unit of several tablets. Next, we investigated the influence of the number of MTs in one unit of dosing on the acceptability of tablets in the second trial. Our preparations ensured that the weight of 10 MTs was equal to that of 1 CT. For the intake of MTs, VAS scores for the ease of intake and amount of water required increased with increasing numbers of tablets. Also, significant differences in these parameters against that of 1 CT were not observed if taken with a unit of 5 MTs or 10 MTs. Therefore, the advantage of MTs for the ease of taking and reduced amount of water required shown in the first trial was exerted for a unit of dosing comprising b5 tablets. Conversely, ingestion of a unit of 10 MTs, which was equal to the weight of 1 CT, needed slightly more water with a higher VAS score for ease of taking compared with that of 1 CT. Indeed, some volunteers commented that they could not take 10 MTs with a sip of water, and that a few MTs remained in their mouth. These results suggest that the effect of the number of tablets is as important as the diameter of tablets. Our study revealed the usefulness and risk of MTs. A MT is taken easily just like an ODT. However, if a CT is changed to MTs, and if their weights are identical, MTs are not acceptable. From our results, it could be stated that b 5 MTs were preferred. If the weight of a CT or MT changed, the appropriate number of MTs would also change. In any case, the total weight of MTs should be less than that of a CT, so the concentration of drug substance is increased. MTs can enable the
concentration of drug substance to increase due to the high ratio of surface area:volume (Tissen et al., 2011). An ODMT, which has the advantages of MTs and ODTs, is the most acceptable if its taste is not unpleasant and unstable. One limitation of our study was that it was conducted in young, healthy adults. The swallowing function of children is underdeveloped, whereas that of elderly patients deteriorates with increasing age. Thus, in pediatric or elderly patients, the difference between each type of tablet or the number of tablets could become more apparent. We tested MTs with a diameter of 3 mm, but perhaps MTs of smaller diameter may have been preferable. In a different perspective, counting MTs may be difficult because of their diameter; packages or counting devices may be needed (Bredenberg et al., 2003). In addition to these study limitations, we prepared placebo tablets that did not contain active pharmaceutical ingredients that commonly have an unpleasant taste. In this case, film coating would be important for taste masking. Carrying out a similar trial as the present study in clinical settings would be very interesting. 5. Conclusion Our study suggested that the VAS score for the ease and amount of water required for the intake of MTs was significantly lower compared with those of CTs. MTs could be taken more readily and were more
Fig. 4. Visual analog scale (VAS) score for ease (A) and amount of the water required (B) for ingestion of each unit of tablets in the second trial. Volunteers randomly took a conventional tablet (CT) or one unit containing 1, 2, 5 or 10 mini-tablets (MTs) with water. Amounts of water intake and VAS score for ease of intake were measured. Each point represents a value for volunteers. The horizontal line in each column indicates the median value for 18 volunteers.
Y. Hayakawa et al. / European Journal of Pharmaceutical Sciences 84 (2016) 157–161
acceptable to volunteers. In particular, ODMTs required the least amount of water and smallest VAS score for the ease of taking tablets. If the taste of the pharmaceutical agent contained in the tablet or storage stability is not a problem, then ODMTs could be most acceptable of the tablets tested. Advantages of MTs for the ease of taking and decreased amount of water required was exerted for a unit of dosing comprising b 5 tablets. Our study suggested the usefulness of MTs and the importance of the number of MTs that a patient can take comfortably. MTs and ODMTs could reduce the problems and risks associated with taking medicines (e.g., aspiration) and improve patient adherence (especially pediatric and geriatric patients who have difficulty taking CTs). Acknowledgments The authors thank Ms. Sayuri Nakajima and Ms. Wakana Shibakiri for their excellent technical assistance. References Bredenberg, S., Nyholm, D., Aquilonius, S.M., Nyström, C., 2003. An automatic dose dispenser for microtablets—a new concept for individual dosage of drugs in tablet form. Int. J. Pharm. 11, 137–146. Goole, J., Deleuze, P., Vanderbist, F., Amighi, K., 2008. New levodopa sustained-release floating minitablets coated with insoluble acrylic polymer. Eur. J. Pharm. Biopharm. 68, 310–318. Hirani, J.J., Rathod, D.A., Vadalia, K.R., 2009. Orally disintegrating tablets: a review. Trop. J. Pharm. Res. 8, 161–172. Klingmann, V., Spomer, N., Lerch, C., Stoltenberg, I., Frömke, C., Bosse, H.M., Breitkreutz, J., Meissner, T., 2013. Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children. J. Pediatr. 163, 1728–1732.
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Kluk, A., Sznitowska, M., Brandt, A., Sznurkowska, K., Plata-Nazar, K., Mysliwiec, M., Kaminska, B., Kotlowska, H., 2015. Can preschool-aged children swallow several minitablets at a time? Results from a clinical pilot study. Int. J. Pharm. 485, 1–6. Lennartz, P., Mielck, J.B., 1998. Minitabletting: improving the compactability of paracetamol powder mixtures. Int. J. Pharm. 173, 75–85. Mizumoto, T., Tamura, T., Kawai, H., Kajiyama, A., Itai, S., 2008. Formulation design of taste-masked particles, including famotidine, for an oral fast-disintegrating dosage form. Chem. Pharm. Bull. 56, 530–535. Mohamed, F.A.A., Roberts, M., Seton, L., Ford, J.L., Levina, M., Rajabi-Siahboomi, A.R., 2013. Production of extended release mini-tablets using directly compressible grades of HPMC. Drug Dev. Ind. Pharm. 39, 1690–1697. Schmitz, T., Leitner, V.M., Bernkop-Schnürch, A., 2005. Oral heparin delivery: design and in vivo evaluation of a stomach-targeted mucoadhesive delivery system. J. Pharm. Sci. 94, 966–973. Spomer, N., Klingmann, V., Stoltenberg, I., Lerch, C., Meissner, T., Breitkreutz, J., 2012. Acceptance of uncoated mini-tablets in young children: results from a prospective exploratory cross-over study. Arch. Dis. Child. 97, 283–286. Stoltenberg, I., Breitkreutz, J., 2011. Orally disintegrating mini-tablets (ODMTs) — a novel solid oral dosage form for paediatric use. Eur. J. Pharm. Biopharm. 78, 462–469. Sugiura, T., Uchida, S., Namiki, N., 2012. Taste-masking effect of physical and organoleptic methods on peppermint-scented orally disintegrating tablet of famotidine based on suspension spray-coating method. Chem. Pharm. Bull. 60, 315–319. Thomson, S.A., Tuleu, C., Wong, I.C.K., Pitt, K.G., Sutcliffe, A.G., 2009. Minitablets: new modality to deliver medicines to preschool-aged children. Pediatrics 123, 235–238. Tissen, C., Woertz, K., Breitkreutz, J., Kleinebudde, P., 2011. Development of mini-tablets with 1 mm and 2 mm diameter. Int. J. Pharm. 416, 164–170. Uchida, S., Yoshita, T., Namiki, N., 2013. Reduction in the volume of water for ingesting orally disintegrating tablets of solifenacin (Vesicare® OD), and the clinical disintegration time of Vesicare® OD after unit-dose packaging. Int. J. Pharm. 446, 1–5. van Riet-Nales, D.A., de Neef, B.J., Schobben, A.F., Ferreira, J.A., Egberts, T.C., Rademaker, C.M., 2013. Acceptability of different oral formulations in infants and preschool children. Arch. Dis. Child. 98, 725–731. Yoshita, T., Uchida, S., Namiki, N., 2013. Clinical disintegration time of orally disintegrating tablets clinically available in Japan in healthy volunteers. Biol. Pharm. Bull. 36, 1488–1493.
Contents lists available at ScienceDirect
European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps
Evaluation of the ease of taking mini-tablets compared with other tablet formulations in healthy volunteers Yoshiyuki Hayakawa a,b, Shinya Uchida a, Noriyuki Namiki a,⁎ a b
Department of Pharmacy Practice and Science, School of Pharmaceutical Sciences University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan
a r t i c l e
i n f o
Article history: Received 29 July 2015 Received in revised form 26 October 2015 Accepted 26 December 2015 Available online 29 December 2015 Keywords: Mini-tablet Orally disintegrating tablet Water intake VAS score
a b s t r a c t “Mini-tablets” (MTs) are tablets of diameter ≤ 3 mm and have been widely studied and developed. However, reports comparing MTs with other tablet formulations are few. We wished to evaluate the ease of taking a MT quantitatively in comparison with an orally disintegrating mini-tablet (ODMT), conventional tablet (CT) and conventional orally disintegrating tablet (ODT). Four types of tablets were prepared. We prepared tablets of two diameters (3 mm for MTs and ODMTs vs. 8 mm for CTs and ODTs) and two formulations (MTs and CTs vs. ODMTs and ODTs). Our randomized crossover trial in 18 healthy volunteers (8 men and 10 women; mean age, 22.5 years) indicated that the visual analog scale (VAS) score for the ease and amount of water required for intake of MTs was significantly lower than those of CTs. An ODMT required the least amount of water and smallest VAS score for the ease of taking a tablet. Our results showed that the advantage of MTs with regard to the ease of taking and decreased amount of water required was exerted for a unit of dosing comprising b 5 tablets. These data suggested the usefulness of MTs and the importance of the number of MTs for comfortable consumption by patients. © 2015 Published by Elsevier B.V.
1. Introduction Tablets are the most widely used drug formulation among various types of formulation (e.g., tablets, capsules, granules). They are easy to handle and convenient to carry and store. However, problems may arise in pediatric or elderly patients whose swallowing functions are inferior to those of adult patients. Orally disintegrating tablets (ODTs) are a user-friendly formulation (Hirani et al., 2009). ODTs could be beneficial for patients who have difficulty swallowing conventional tablets (CTs). Furthermore, ingestion of ODTs with little water or without water may be beneficial for patients with disorders for which water intake must be restricted (e.g., overactive bladder). Several commercial types of ODTs have become popular in the last decade. However, taste-masking is required for ODTs if the drug substance has an unpleasant taste (Mizumoto et al., 2008). In this case, any other formulation without taste masking is needed. Mini-tablets (MTs) have a diameter ≤3 mm. They have been studied widely and developed (Lennartz and Mielck, 1998). MTs are considered to be easier to swallow than CTs, whose diameter is N3 mm. This decrease in tablet diameter could improve patient adherence to
⁎ Corresponding author. E-mail address: [email protected] (N. Namiki).
http://dx.doi.org/10.1016/j.ejps.2015.12.029 0928-0987/© 2015 Published by Elsevier B.V.
medication and decrease the risk of aspiration. Many studies on different types of MTs, such as orally disintegrating mini-tablets (ODMTs), sustained-release MTs, “floating” MTs, and bioadhesive MTs, have been carried out (Stoltenberg and Breitkreutz, 2011; Mohamed et al., 2013; Goole et al., 2008; Schmitz et al., 2005). Several clinical trials of MTs in preschool-aged children have been reported (Thomson et al., 2009; Spomer et al., 2012; Klingmann et al., 2013; van Riet-Nales et al., 2013). These reports suggest that MTs are the most acceptable and preferred oral formulation compared with powder or syrup formulations. Kluk et al. (2015) reported recently that ≤ 10 MTs mixed with jelly were acceptable to children aged 2–3 years. However, reports of clinical trials comparing MTs and other tablet formulations (e.g., CTs, ODTs) are lacking. In many cases, MTs are administered as a unit of several tablets, but quantitative data for evaluation of the ease of intake of such units are lacking. We aimed to evaluate the ease of taking MTs quantitatively in comparison with other tablet formulations, as well as the intake of different numbers of MTs. First, one tablet of each formulation was evaluated. We compared 1 MT with 1 ODMT, 1 CT and 1 ODT by measuring the volume of water required for ingestion and the ease of intake using a visual analog scale (VAS), methods that have been employed by our research team previously (Uchida et al., 2013; Sugiura et al., 2012). Next, we evaluated the volume of water required for the intake and ease of taking tablets when units of 1, 2, 5 and 10 MTs were administered.
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2. Materials and methods 2.1. Materials D-Mannitol (Mannit Q™) was kindly provided by the Mitsubishi Shoji Foodtech Co., Ltd. (Tokyo, Japan). All other samples were obtained commercially. α-Lactose monohydrate (Dilactose®S) was from the Freund Corporation (Tokyo, Japan). Microcrystalline cellulose (CEOLUS™ UF-702) was from the Asahi Kasei Chemicals Corporation (Tokyo, Japan). Low-substituted hydroxypropyl cellulose (L-HPC LH21) was from the Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). Crospovidone (Kollidone® CL) wasfrom the BASF (Rhineland-Palatinate, Germany). Magnesium stearate (Parteck® LUB MST (magnesium stearate vegetable grade)) was from the Merck KGaA (Darmstadt, Germany).
2.2. Preparation of tablets Compositions of each formulation are shown in Table 1. Shapes of a CT and MTs are depicted in Fig. 1. All excipients were mixed together and compacted. MTs and ODMTs were prepared on a Single-punch Tablet Machine (HANDTAB; Ichihashiseiki, Kyoto, Japan) with a 3-mm, six-tip mini-tableting tool. Six MTs were compacted together, and the force was 6 kN. One MT weighed 20 mg, and average compaction was 1 kN. CTs and ODTs were prepared on the same tablet machine with an 8-mm tableting tool with compaction forces of 8 kN and weight of 200 mg per tablet. Hardness of tablets was measured using a Tablet Hardness Tester (PC-30; Okada Seiko Co. Ltd., Tokyo, Japan). Hardness, weight and thickness were measured on 10 tablets of each type and the mean value was calculated. 2.3. Clinical trial All volunteers provided written informed consent to participate in this study. The study was conducted in accordance with the Declaration of Helsinki and its amendments. The study protocol was approved by the Ethics Committee of the University of Shizuoka (protocol number 25–41; Shizuoka, Japan). 2.3.1. Measurement of the clinical disintegration time of tablets The clinical disintegration time was measured for four types of tablet (MT, ODMT, CT, ODT) as described previously (Yoshita et al., 2013). Ten healthy volunteers (3 men and 7 women; age (mean ± SD), 22.0 ± 1.2 years) participated in this randomized crossover study. Before the test, the oral cavity of the participants was rinsed with a cup of water (120 mL). Each tablet was placed on the tongue and disintegrated in the oral cavity. The clinical disintegration time of each tablet was measured by an investigator using a stopwatch. Remnants of each tablet were removed and rinsed from the mouth with water after each test.
2.3.2. Measurement of the amount of water required for the ingestion and ease of taking tablets Eighteen healthy volunteers (8 men and 10 women; age, 22.5 ± 1.0 years) participated in this randomized crossover trial. Measurement of the amount of water required for ingestion of CTs and ODTs was conducted as described previously (Uchida et al., 2013). Subjects were asked to consume 1 MT and 1 CT with drinking water. In the case of 1 ODMT and 1 ODT, they were asked to drink water after these tablets had disintegrated in the oral cavity. Subjects freely filled the cup with water from a 500-mL bottle and then drank the minimum volume of water required to consume each tablet smoothly. The amount of water was measured using the weight of the cup and bottle. After drinking water, they were asked to evaluate the ease of taking a tablet using a VAS with the most difficult sensation for taking a tablet marked at 100 mm (Fig. 2). In the second trial, all volunteers randomly took 1 CT or one unit containing 1, 2, 5 or 10 MTs (Fig. 1) with water. Ten MTs and 1 CT are the same weight. One unit of MTs or 1 CT was placed into the mouth simultaneously. After drinking water, the amount of water required and VAS score for the ease of intake of each unit of tablets were measured by the same methods as the first trial. 2.4. Statistical analyses Data for tablet characteristics are the mean ± standard deviation (S.D.), whereas data from the clinical study (VAS and amount of water) are the median value. Statistical analyses were undertaken using a Graphpad Prism v5.02 (Graphpad Software, San Diego, CA, USA). Each pair of samples was analyzed separately and compared using the non-parametric Wilcoxon signed rank test with the Bonferroni correction to detect differences among the amount of water required for ingestion of tablets and the ease of taking tablets. p b 0.017 was considered significant for the first trial, and p b 0.0125 for the second trial. 3. Results 3.1. Characteristics of each tablet Weight, thickness, hardness and clinical disintegration time of each tablet are shown in Table 2. One ODMT disintegrated in b10 s. One MT and one ODT disintegrated in ≈20 s. One CT disintegrated in ≈1 min. 3.2. VAS score for ease and amount of the water required for the ingestion of each tablet in the first trial The VAS score for the ease and amount of water required for ingestion of a single tablet is shown in Fig. 3. VAS score for 1 CT was the
Table 1 Composition of a mini-tablet, orally disintegrating mini-tablet, conventional tablet and orally disintegrating tablet. Ingredients (mg)
MT (3 mm)
ODMT (3 mm)
CT (8 mm)
ODT (8 mm)
Dilactose® S L-HPC LH-21 Kollidone® CL Mannit Q™ CEOLUS™ UF-702 Parteck® LUB MST Total
13.8 2 – – 4 0.2 20
– – 2 13.8 4 0.2 20
138 20 – – 40 2 200
– – 20 138 40 2 200
MT, mini-tablet; ODMT, orally disintegrating mini-tablet; CT, conventional tablet; ODT, orally disintegrating mini-tablet.
Fig. 1. Conventional tablet and mini-tablet used in this study. The diameters of a conventional tablet (CT) and mini-tablet (MT) were 8.0 and 3.0 mm, respectively. The total weight of tablets between 1 CT and 10 MTs was equal. Volunteers took 1 CT or 1, 2, 5, and 10 MTs in the second trial. Scale is in mm.
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Fig. 2. Visual analog scale to evaluate the ease of taking a tablet.
largest value (54.5) of all the tablets tested, and the difference from the value of 1 MT (9.0) was significant (p = 0.0013). VAS score for 1 ODT (32.0) was significantly higher than that for 1 MT (p = 0.0060), but it was not significant for 1 ODMT (2.0; p = 0.0735). Median amount of water required for taking 1 ODMT (6.6 mL) and 1 CT (29.9 mL) was significantly lower and higher than that of 1 MT (12.1 mL), respectively (p = 0.0069 and p = 0.0004, Fig. 3(B)). There was no significant difference between 1 ODT (19.1 mL) and 1 MT (p = 0.0894). Only one volunteer took 1 MT and 1 ODMT with 60 mL of water. Other volunteers took 1 MT and 1 ODMT with b 30 mL of water. 3.3. VAS score for the ease and amount of water required for ingestion of each unit of tablets in the second trial The VAS score for the ease and amount of water required for ingestion of 1 CT or 1 unit of 1, 2, 5, and 10 MTs in the second trial is shown in Fig. 4. VAS scores of the ease of intake for 1 MT (4.0) and 2 MTs (21.0) were significantly lower than that of 1 CT (49.0; p = 0.0006 and 0.0028, respectively). VAS scores for 5 MTs (36.0) were similar to that of 1 CT, and that of 10 MTs (62.5) was slightly higher than that of 1 CT, but the difference was not significant (p = 0.0935). Median amounts of water required for ingestion of 1 MT (11.4 mL) and 2 MTs (15.9 mL) were significantly smaller than that of 1 CT (23.9 mL; p = 0.0004 and 0.0013, respectively, Fig. 4(B)). No significant differences in the amounts of water required between 1 CT and 5 MTs (24.7 mL) or 10 MTs (26.5 mL) were observed (p = 0.4431 and 0.1169, respectively). 4. Discussion We prepared four types of tablets in the present study. We prepared tablets of two diameters (3 mm for MTs and ODMTs vs. 8 mm for CTs and ODTs); we prepared two types of formulation (conventional formulation for MTs and CTs vs. orally disintegrating formulation for ODMTs and ODTs). An ODMT disintegrated the fastest because of its small diameter and formulation type (orally disintegrating). Disintegrating times of MTs and ODTs were similar to each other and shorter (≈20 s) compared with the disintegrating times of CTs (≈1 min). A MT and CT were
of the same formulation (same ingredients and same ratio). Hence, the ratio of surface area:volume of a MT was higher than that of a CT, and this higher surface area could affect the disintegrating time of a MT. The fast disintegration in the mouth and higher surface area of uncoated MTs could impact on taste-masking and storage (especially in high humidity). In the first trial, we compared four types of tablets to reveal the acceptability of each tablet to volunteers in terms of the ease of taking tablets and amount of water required for intake. A VAS is known to be more sensitive to small changes compared with a simple descriptive scale, and can be used to evaluate the feeling of ease of taking tablets by volunteers. The amount of water required for tablet intake is also thought to reflect their characteristics because patients need a larger amount of water if they feel that the medicine will be difficult to take. Compared with 1 MT, VAS scores for the ease of intake of 1 CT and 1 ODT were significantly higher, suggesting that subjects could take 1 MT than 1 CT and 1 ODT more readily. MTs have been reported to be more acceptable and preferred oral formulation compared with powder and syrup formulations in young children (Spomer et al., 2012; Klingmann et al., 2013; van Riet-Nales et al., 2013). Results from the present study are in accordance with those reports in children, and are the first evidence that MTs could be taken readily by adult patients (especially the elderly). The amount of water required to take 1 CT was significantly larger than that to take 1 MT, but a significant difference between 1 ODT and 1 MT was not observed. Thus, it is likely to result in no significant difference in the amount of water required between taking 1 MT and 1 ODT. Other features of an ODT (e.g., less feeling or fewer remnants in the mouth) could make the VAS score for the ease of taking an ODT worse. Interestingly, a larger inter-individual variability for the amount of water required for taking 1 ODT was detected in comparison with that for taking 1 MT. For instance, most people needed 10–20 mL water to take 1 MT. In contrast, 4 subjects (22%) took 1 ODT without water, whereas 7 subjects (39%) needed N 30 mL water. One ODMT required the least amount of water and smallest VAS score for ease of taking tablets. If issues such as the taste of the drug contained in the tablet or stability for storage were not problems, an ODMT could be the most acceptable type of tablet.
Table 2 Diameter, weight, thickness, hardness, and clinical disintegration time of a mini-tablet, orally disintegrating mini-tablet, conventional tablet and orally disintegrating tablet.
Diameter (mm) Weight (mg) Thickness (mm) Hardness (N) Clinical disintegration time (s)
MT
ODMT
CT
ODT
3.0 20.1 ± 0.6 2.44 ± 0.04 21.4 ± 3.8 23.2 ± 5.1
3.0 20.2 ± 0.5 2.64 ± 0.02 15.2 ± 6.2 8.1 ± 1.2
8.0 202.6 ± 1.2 3.55 ± 0.03 97.1 ± 4.4 63.5 ± 9.0
8.0 200.6 ± 1.8 4.09 ± 0.08 112.3 ± 9.5 23.5 ± 8.2
Data are the mean ± standard deviation (S.D.) for 10 determinations. MT, mini-tablet; ODMT, orally disintegrating mini-tablet; CT, conventional tablet; ODT, orally disintegrating tablet.
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Fig. 3. Visual analog scale (VAS) score for ease (A) and amount of the water required (B) for ingestion of each tablet in the first trial. Volunteers randomly took a mini-tablet (MT), an orally disintegrating mini-tablet (ODMT), a conventional tablet (CT) and an orally disintegrating tablet (ODT) with water. Then, the amounts of water intake and VAS score for ease of intake were measured. Each point represents a value for the volunteers. The horizontal line in each column indicates the median value for 18 volunteers.
MTs are usually not taken as single tablets but as a unit of several tablets. Next, we investigated the influence of the number of MTs in one unit of dosing on the acceptability of tablets in the second trial. Our preparations ensured that the weight of 10 MTs was equal to that of 1 CT. For the intake of MTs, VAS scores for the ease of intake and amount of water required increased with increasing numbers of tablets. Also, significant differences in these parameters against that of 1 CT were not observed if taken with a unit of 5 MTs or 10 MTs. Therefore, the advantage of MTs for the ease of taking and reduced amount of water required shown in the first trial was exerted for a unit of dosing comprising b5 tablets. Conversely, ingestion of a unit of 10 MTs, which was equal to the weight of 1 CT, needed slightly more water with a higher VAS score for ease of taking compared with that of 1 CT. Indeed, some volunteers commented that they could not take 10 MTs with a sip of water, and that a few MTs remained in their mouth. These results suggest that the effect of the number of tablets is as important as the diameter of tablets. Our study revealed the usefulness and risk of MTs. A MT is taken easily just like an ODT. However, if a CT is changed to MTs, and if their weights are identical, MTs are not acceptable. From our results, it could be stated that b 5 MTs were preferred. If the weight of a CT or MT changed, the appropriate number of MTs would also change. In any case, the total weight of MTs should be less than that of a CT, so the concentration of drug substance is increased. MTs can enable the
concentration of drug substance to increase due to the high ratio of surface area:volume (Tissen et al., 2011). An ODMT, which has the advantages of MTs and ODTs, is the most acceptable if its taste is not unpleasant and unstable. One limitation of our study was that it was conducted in young, healthy adults. The swallowing function of children is underdeveloped, whereas that of elderly patients deteriorates with increasing age. Thus, in pediatric or elderly patients, the difference between each type of tablet or the number of tablets could become more apparent. We tested MTs with a diameter of 3 mm, but perhaps MTs of smaller diameter may have been preferable. In a different perspective, counting MTs may be difficult because of their diameter; packages or counting devices may be needed (Bredenberg et al., 2003). In addition to these study limitations, we prepared placebo tablets that did not contain active pharmaceutical ingredients that commonly have an unpleasant taste. In this case, film coating would be important for taste masking. Carrying out a similar trial as the present study in clinical settings would be very interesting. 5. Conclusion Our study suggested that the VAS score for the ease and amount of water required for the intake of MTs was significantly lower compared with those of CTs. MTs could be taken more readily and were more
Fig. 4. Visual analog scale (VAS) score for ease (A) and amount of the water required (B) for ingestion of each unit of tablets in the second trial. Volunteers randomly took a conventional tablet (CT) or one unit containing 1, 2, 5 or 10 mini-tablets (MTs) with water. Amounts of water intake and VAS score for ease of intake were measured. Each point represents a value for volunteers. The horizontal line in each column indicates the median value for 18 volunteers.
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acceptable to volunteers. In particular, ODMTs required the least amount of water and smallest VAS score for the ease of taking tablets. If the taste of the pharmaceutical agent contained in the tablet or storage stability is not a problem, then ODMTs could be most acceptable of the tablets tested. Advantages of MTs for the ease of taking and decreased amount of water required was exerted for a unit of dosing comprising b 5 tablets. Our study suggested the usefulness of MTs and the importance of the number of MTs that a patient can take comfortably. MTs and ODMTs could reduce the problems and risks associated with taking medicines (e.g., aspiration) and improve patient adherence (especially pediatric and geriatric patients who have difficulty taking CTs). Acknowledgments The authors thank Ms. Sayuri Nakajima and Ms. Wakana Shibakiri for their excellent technical assistance. References Bredenberg, S., Nyholm, D., Aquilonius, S.M., Nyström, C., 2003. An automatic dose dispenser for microtablets—a new concept for individual dosage of drugs in tablet form. Int. J. Pharm. 11, 137–146. Goole, J., Deleuze, P., Vanderbist, F., Amighi, K., 2008. New levodopa sustained-release floating minitablets coated with insoluble acrylic polymer. Eur. J. Pharm. Biopharm. 68, 310–318. Hirani, J.J., Rathod, D.A., Vadalia, K.R., 2009. Orally disintegrating tablets: a review. Trop. J. Pharm. Res. 8, 161–172. Klingmann, V., Spomer, N., Lerch, C., Stoltenberg, I., Frömke, C., Bosse, H.M., Breitkreutz, J., Meissner, T., 2013. Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children. J. Pediatr. 163, 1728–1732.
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