2015 年 38 巻 1 号 p. 17-22
Orally disintegrating tablets (ODTs) containing propiverine hydrochloride (which is extremely bitter and leaves a feeling of numbness in the mouth) were prepared with a combined use of physical and organoleptic taste masking. Propiverine-loaded masking particles (PLMPs) were prepared with different amounts of gastric-soluble coatings as physical masking. ODTs without organoleptic masking were prepared by mixing each group of PLMPs with Ludiflash®, crospovidone, and magnesium stearate. ODTs with organoleptic masking were also prepared by addition of L-menthol, aspartame, thaumatin, and cinnamon. Fifteen-minute dissolution of propiverine in solutions with pH 1.2 was ≥85% for all ODTs, whereas that in pH 6.8 solutions was ≤85% and increased with physical masking. A single blind randomized crossover trial was conducted. Ten healthy volunteers were asked to quantify the bitterness, numbness, and overall palatability using a 100-mm visual analog scale (VAS) at the period of disintegration as well as 1 and 5 min later. VAS scores of bitterness, numbness, and overall palatability improved along with increasing amounts of physical masking, and the effects persisted for 5 min. VAS scores for numbness increased over time regardless of the amount of physical masking. Bitterness, numbness, and overall palatability were significantly improved by organoleptic masking if the amount of physical masking was small. Combined use of physical and organoleptic masking is useful for improving palatability of ODTs containing propiverine.
Propiverine hydrochloride is an antimuscarinic agent and used widely for the management of overactive bladder (OAB). OAB is defined as a syndrome of urinary urgency accompanied by urinary frequency and nocturia.1) Symptoms of urinary incontinence are not required for a diagnosis of OAB. However, OAB occurs with increasing frequency with advancing age in a similar manner to symptoms in the lower urinary tract.2) According to a recent epidemiological survey, 12% of Japanese adults aged >40 years were estimated to have OAB.3) OAB is not a life-threatening disease, but symptoms such as nocturia markedly impair QOL.4)
In recent years, propiverine has been reported to improve stress urinary incontinence, a symptom unique to women, resulting in improved QOL for such patients.5,6) In addition, propiverine appears to have a more favorable tolerability profile compared to those of other antimuscarinic drugs.7)
A film-coated tablet has been used as a formulation of propiverine hydrochloride. Poor compliance with regimens containing such tablets may be observed in some individuals: OAB patients who are reluctant to drink water, patients with renal disease requiring fluid restriction, and patients with swallowing difficulties (e.g., elderly subjects). Recently, several orally disintegrating tablets (ODTs) for OAB management have become available in addition to conventional tablets.8–11) The ODT formulation disintegrates immediately in the mouth so that patients can ingest it without water. This characteristic of ODTs is beneficial for patients who have difficulty swallowing conventional tablets or those who do not have immediate access to water.12) Ingestion of ODTs without water may be important, particularly for OAB patients, because many of them are thought to experience discomfort with water intake. Therefore, ODTs require a lower volume of water intake than conventional tablets do, which results in enhanced medication adherence for patients and an increase in the prevalence of good clinical responses.
However, propiverine hydrochloride typically leaves a taste of extreme bitterness and feeling of persistent numbness after being placed in the mouth. Therefore, masking of the unpleasant taste of propiverine is necessary to obtain acceptable palatability for the ODT. In general, the masking methods for the bitterness of the ODTs are physical (particle coating using a matrix), chemical (chemical modification of the drug), and organoleptic masking (addition of flavor and sweetener).13–16) Recent clinical studies have proved the efficacy of organoleptic masking methods for improving the taste of drugs. However, complete masking only with organoleptic masking is difficult if the drug leaves an extremely bitter, persistent, and strong unpleasant taste. In such cases, combined use of physical and organoleptic masking may be effective in improving palatability.17)
In the present study, ODTs of propiverine hydrochloride were prepared using physical masking (using gastric-soluble coating particles) in combination with organoleptic masking (addition of sweetener and flavor). Effects of combined use of physical and organoleptic masking on metachronic palatability were evaluated in a gustatory sensation study.
Propiverine hydrochloride was purchased from Sanyo Chemical Laboratory Co., Ltd. (Toyama, Japan). Crystal cellulose spheres (Celphere® CP-102; Asahi Chemical Industry Co., Ltd., Tokyo, Japan) were used as core particles of propiverine-loaded masking particles (PLMPs). Hypromellose (TC-5E; Shin-Etsu Chemical Co., Ltd., Tokyo, Japan) and macrogol 6000 (Sanyo Chemical Industries, Ltd., Kyoto, Japan) were used as the drug layer. Sodium lauryl sulfate (Emal OS; Kao Corp., Tokyo, Japan), stearic acid (Higuchi Inc., Tokyo, Japan), aminoalkyl methacrylate copolymer E (Eudragit® E PO; Evonik Japan Co., Ltd., Tokyo, Japan), and talc (Muramatsu Sangyo Co., Ltd., Osaka, Japan) were used as gastric-soluble coating layers. D-Mannitol (Mannit P, Mitsubishi Shoji Foodtech Co., Ltd., Tokyo, Japan) was used as an adherence-prevention agent of coating particles. Ludiflash® (BASF Japan Ltd., Tokyo, Japan), crospovidone (Kollidon® CL-SF; BASF Japan Ltd.), and magnesium stearate (Wako Pure Chemical Industries, Ltd., Osaka, Japan) were used as the base of ODTs. Aspartame (Ajinomoto Healthy Supply Co., Ltd., Tokyo, Japan) and thaumatin (San-Ei Gen F.F.I. Inc., Osaka, Japan) were used as sweeteners. L-Menthol (Nagaoka & Co., Ltd., Hyogo, Japan) and cinnamon (Nikki flavor, Naigai Flavors Co., Ltd., Tokyo, Japan) were used as flavorings. All other materials used were of Japanese Pharmacopoeia grade.
Preparation of PLMPsCrystal cellulose spheres were coated with propiverine hydrochloride solution dissolved in hypromellose, macrogol 6000 and water using a fluidized-bed granulator (MP-01; Powrex Corp., Hyogo, Japan).16) Propiverine-loaded particles were coated with a gastric-soluble coating solution comprising Eudragit® E PO, stearic acid, sodium lauryl sulfate and talc. The amount of gastric-soluble coating solution was changed as 0, 4.4, 17.5, 35, and 64% (N, VSM, SM, MM, and LM, respectively) against the amount of drug-loaded particle. Gastric-soluble coating-masking particles (VSM, SM, MM, and LM) except N were coated with D-mannitol to prevent the adhesion of particles to each other (Table 1). Finally, each PLMP was passed through a number-42 sieve. Measurement using a sonic sieving particle size analyzer (Robot Sifter RPS-205; Seishin Enterprise Co., Ltd., Tokyo, Japan) revealed a 50% particle size. Furthermore, the content of propiverine hydrochloride in 1 g of PLMP was determined by HPLC.
| Function | Composition | Formulation (%) | ||||
|---|---|---|---|---|---|---|
| N | VSM | SM | MM | LM | ||
| Core | Crystal cellulose spheres | 87.8 | 80.8 | 70.8 | 60.0 | 48.0 |
| Drug layer | Propiverine hydrochloride | 10.0 | 10.0 | 10.0 | 10.0 | 10.0 |
| Hypromellose | 2.0 | 2.0 | 2.0 | 2.0 | 2.0 | |
| Macrogol 6000 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | |
| Gastric-soluble coating layer | Eudragit® E PO | — | 2.6 | 9.1 | 16.0 | 24.0 |
| Stearic acid | — | 0.4 | 1.4 | 2.4 | 3.6 | |
| Sodium lauryl sulfate | — | 0.3 | 0.9 | 1.6 | 2.4 | |
| Talc | — | 0.9 | 3.2 | 5.6 | 8.4 | |
| Adherence prevention | D-Mannitol | — | 2.7 | 2.5 | 2.2 | 1.4 |
| Total (%) | 100 | 100 | 100 | 100 | 100 | |
ODTs (300 mg) containing 10 mg propiverine hydrochloride calculated from the content in PLMPs were prepared by a direct powder compression method using a tablet compressor (Handtub, Ichihashi Seiki Co., Ltd., Kyoto, Japan). This method yielded ODTs with a diameter of 9 mm mixed with Ludiflash (amount controlled by PLMP amount), 0.5% magnesium stearate, and 5% crospovidone without organoleptic masking (N-OD(−), VS-OD(−), S-OD(−), M-OD(−), and L-OD(−)). ODTs with organoleptic masking (N-OD(+), VS-OD(+), S-OD(+), M-OD(+), and L-OD(+)) were also prepared in the same manner with each PLMP, Ludiflash, 0.5% magnesium stearate, 5% crospovidone, 0.1% L-menthol, 0.5% aspartame, 0.5% thaumatin, and 0.1% cinnamon flavoring.
Hardness of ODTsThe hardness of ODTs was measured using a load cell-type hardness tester (PC-30; Okada Seiko Co., Ltd., Tokyo, Japan). This measurement was conducted on 10 tablets of each type of ODT and the mean hardness calculated.
Disintegration Time of ODTs in VitroDisintegration time of ODTs in vitro was measured by Tricorptester (Okada Seiko Co., Ltd.).18) Artificial saliva (NaCl, 1.44 g/L; KCl, 1.47 g/L; Tween 80, 0.3%) warmed to 37°C was used as the test solution, and dripped from a height of 80 mm at a flow rate of 6.0 mL/min. This measurement was conducted on 10 tablets of each type of ODT and the mean disintegration time was measured.
Dissolution Test of Organoleptic Taste-Masking ODTsA dissolution test was conducted in accordance with JP Dissolution Test Method 2 (paddle method) using a JP dissolution tester (VK7010; Varian, Inc., Cary, NC, U.S.A.). The study was conducted in 900 mL of JP 1st and JP 2nd fluids (pH 1.2 and 6.8, respectively) as the dissolution medium with a paddle speed of 50 rpm at 37±0.5°C for one tablet. Samples of dissolved solutions were withdrawn at 1, 5, 10, 15, 30, 45, and 60 min, and the concentration of propiverine in the sample was determined using HPLC.
HPLC ConditionsPropiverine concentration was determined using a HPLC system (Prominence UFLC; Shimadzu, Kyoto, Japan) comprising a pump (LC-20AD; Shimadzu), photodiode array detector (SPD-M20A; Shimadzu), and a packed column (Capcell Pak® C18 MGIII; 3 µm, 3 mm i.d.×150 mm; Shiseido, Tokyo, Japan), and integrated using a system controller (CBM-20A; Shimadzu). The mobile phase was acetonitrile/distilled water (50 : 50, v/v) containing 0.1% phosphoric acid and 5 mmol/L sodium octanesulfonate. Acetonitrile was of HPLC grade (Wako Pure Chemical Industries, Ltd.). The flow rate was 0.5 mL/min. Detection was based on UV absorbance at 210 nm.
A Metachronic Analysis of Gustatory Sensation in Healthy VolunteersThe 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 (Shizuoka, Japan). All subjects provided written consent to participate in the study.
A metachronic analysis of gustatory sensation was conducted by modifying part of the methods detailed by Sugiura et al.16) and Nakano et al.17) (Fig. 1). Ten healthy volunteers (5 males and 5 females; age, 23.2±1.3 years, mean±standard deviation (S.D.)) were enrolled in a randomized crossover single-blind study. The subjects put each ODT in their mouth and the ODT disintegrated. The subjects evaluated the feeling in the mouth as well as the bitterness, numbness, and overall palatability of the ODT using a visual analog scale (VAS)16,19) (Fig. 2). All subjects were asked to place a mark along the VAS line. The strongest sensation for each parameter was marked at 100 mm. The first evaluation was from placement of one ODT in the mouth to completion of disintegration. After the subjects spat out the disintegrated tablet, the second evaluation was conducted 1 min after placement of the ODT in the mouth. Then, the subjects rinsed the oral cavity with 120 mL of water while maintaining the rest. The final evaluation was conducted 5 min after insertion in the mouth. The one-formulation-per-day study was carried out for 10 d for all ODT formulations.
Data are the mean±S.D. except for 50% particle size, propiverine content, hardness, and disintegration time. Statistical analyses for physical masking were conducted using the paired t-test with Bonferroni correction to detect differences among taste-improvement effects. A statistically significant difference was noted at p<0.0125. Statistical analyses for organoleptic masking were conducted using the paired t-test to detect differences among taste-improvement effects. A statistically significant difference was noted at p<0.05.
The 50% particle size of PLMPs increased with respect to the amount of gastric-soluble coating, with a maximum diameter of 240 µm. The percentage of propiverine contained in PLMPs was 8.1–12.4% (N, 12.4; VSM, 8.7; SM, 8.1; MM, 10.3; LM, 10.3%).
Hardness and in Vitro Disintegration Time of ODTsThe hardness of ODTs was confirmed to be nearly 50 N (47.4–57.9 N as a mean of each ODT). In vitro disintegrating times of ODTs without organoleptic masking (N-OD(−), VS-OD(−), S-OD(−), M-OD(−), and L-OD(−)) were 22.6, 26.8, 15.4, 13.9, and 16.8 s, respectively. Those for ODTs with organoleptic masking (N-OD(+), VS-OD(+), S-OD(+), M-OD(+), and L-OD(+)) were 32.5, 36.6, 25.5, 20.5, and 19.7 s, respectively.
Dissolution Rate of Propiverine from ODTs with Organoleptic Taste MaskingAll of the ODTs disintegrated completely in 30 s in the JP 1st fluids, and dissolution in 15 min was ≥85%. Dissolution in JP 2nd fluids decreased with increases in the amount of gastric-soluble coating, and dissolution in 15 min was as follows: N-OD(+), 93.1%; VS-OD(+), 90.9%; S-OD(+), 72.5%; M-OD(+), 62.0%; and L-OD(+), 32.3% (Fig. 3).
Each point represents the mean±S.D. (n=4).
VAS scores of bitterness of ODTs after placement in the mouth decreased with increasing amounts of physical masking regardless of organoleptic masking. VAS scores during disintegration of ODTs were significantly decreased in M- and L-OD(−) compared with N-OD(−), or M- and L-OD(+) compared with N-OD(+). VAS scores of ODTs with organoleptic masking were significantly decreased in S-OD(+) at all evaluation periods compared with those without organoleptic masking (Figs. 4A–C).
The evaluation period in (A) and (D) are 1st evaluation (during disintegration), (B) and (E) are 2nd evaluation (1 min after insertion), and (C) and (F) are final evaluation (5 min after insertion). Data are the mean+S.D. (n=10). Asterisks denote a significant difference in values compared with each N-OD(−) or N-OD(+) using the paired t-test with Bonferroni correction to detect differences among taste-improvement effects (* p<0.0125, ** p<0.0025, *** p<0.00025). Hash symbols denote a significant difference in values compared with each ODT without organoleptic masking formulation using the paired t-test to detect differences among taste-improvement effects (# p<0.05).
VAS scores of numbness of ODTs after placement in the mouth increased. However, VAS scores were decreased significantly in M-, and L-OD(−) compared with N-OD(−), or M- and L-OD(+) compared with N-OD(+). VAS scores of VS-OD(+) were decreased significantly in comparison with VS-OD(−) at 1 min and 5 min after insertion in the mouth (Figs. 4D–F).
Evaluation of VAS Score for Gustatory Sensation of the Overall Palatability of ODTsVAS scores of the overall palatability of ODTs after insertion in the mouth increased with increasing amounts of physical masking regardless of organoleptic masking. VAS scores of VS-OD(+) increased significantly in comparison with those of VS-OD(−) in all periods. VAS scores of S-OD(+) increased significantly in comparison with those of S-OD(−) at 1 min (Table 2).
| ODT | 1st evaluation | 2nd evaluation | Final evaluation | |||
|---|---|---|---|---|---|---|
| OD(−) | OD(+) | OD(−) | OD(+) | OD(−) | OD(+) | |
| N | 29.7±29.4 | 31.4±20.2 | 22.9±19.6 | 29.9±21.1 | 17.2±13.9 | 22.7±19.5 |
| VS | 10.0±8.2 | 33.7±22.2## | 8.3±8.6 | 33.2±26.5# | 9.5±12.3 | 28.4±21.7# |
| S | 28.2±27.5 | 40.2±28.8 | 23.4±14.9 | 41.7±28.6 | 32.5±16.1* | 34.6±30.6 |
| M | 59.9±20.0* | 48.9±22.9 | 54.1±21.6* | 47.2±25.1 | 62.0±21.2*** | 45.1±23.9 |
| L | 57.6±24.8* | 54.3±22.6 | 52.9±28.4* | 63.7±23.6* | 53.6±28.0* | 60.7±24.0* |
Data are the mean±S.D. (n=10). Asterisks denote a significant difference in values compared with each N-OD(−) or N-OD(+) using the paired t-test with Bonferroni correction to detect differences among taste-improvement effects (* p<0.0125, *** p<0.00025). Hash symbols denote a significant difference in values compared with each OD(−) using the paired t-test to detect differences among taste-improvement effects (# p<0.05, ## p<0.01).
Propiverine hydrochloride leaves an extremely bitter taste and persistent numbness after being placed in the mouth. We conducted a gustatory sensation study on ODTs containing propiverine hydrochloride. Various ODTs were prepared containing different amounts of physical masking of PLMPs as well as with or without organoleptic masking (sweetener and flavor).
The 50% particle size of PLMPs, hardness, and in vitro disintegrating time of ODTs were ≤240 µm, ≈50 N, and ≈30 s, respectively. These data suggested that there was no difference in ODTs with regard to the physical sensations of disintegration in the mouth.
In the present study, a metachronic evaluation of gustatory sensation was conducted at the time of disintegration as well as 1 min and 5 min after placing the ODT in the mouth to evaluate the time–course for the bitterness, numbness, and overall palatability of propiverine. Usually, gustatory sensation studies of ODTs are conducted immediately after their disintegration. In addition, a quantitative evaluation was attempted to clarify the relationship between the unpleasant taste of the drug and the effect of the masking methods by evaluation of VAS scores.
The results of the gustatory sensation study suggested that the VAS scores of bitterness and numbness improved significantly with increasing amounts of physical masking, and a significant improvement in overall palatability was also noted. Therefore, the amounts of physical masking are important element to improve the unpleasant taste of propiverine. However, in the result of metachronic evaluation, the VAS scores of bitterness, numbness and overall palatability showed no significant change over time of each ODT. In addition, the VAS scores of numbness were observed in the tendencies to increase during 5 min. It was indicated that the different masking are required to further improve. Thus, organoleptic masking was used by mixing flavors and sweeteners in the present study. Sweeteners, blended with the thaumatin that in addition to the aspartame which is often used for taste-masking and feel sustained sweetness is known. On the other hand, since some flavors can increase the sweetness of the sweetener has been reported by Sugiura et al.,16) L-menthol and cinnamon flavor were used in expectation to obtain effective organoleptic masking by mixing of flavors and sweeteners. It was suggested that the mixing of sweeteners and flavors in combination with physical masking could improve bitterness and overall palatability even 5 min. Interestingly, in samples with smaller amounts of physical-masking ODT (VS-OD), organoleptic masking significantly improved in 3 times VAS value of overall palatability after 5 min. This improvement was suggested that the effect of combined organoleptic masking was not clear when the amount of physical masking is sufficient even sustained sweetness. Therefore, optimization of organoleptic masking is crucial to obtain a persistent effect to improve the taste of propiverine. This is especially important for ODTs with relatively smaller amounts of physical masking.
From the viewpoint of the dissolution properties of propiverine, all ODTs disintegrated immediately at pH 1.2 and dissolution was ≥85% in 15 min. These results suggested that PLMPs coated with Eudragit® E PO improved bitterness and numbness even after disintegration of ODTs in the mouth, and then dissolved propiverine immediately after they reached the stomach. However, from a clinical perspective, dissolution properties in ODTs that had a larger amount of physical masking at pH 6.8 were not satisfactory. If ODTs with a larger amount of physical masking are given to patients suffering from low secretion of gastric acid, the bioavailability of the drug may be low. With respect to the amount of physical masking of these ODTs, there was a trade-off between the VAS scores of bitterness and percentage dissolution in 15 min at pH 6.8 (Fig. 5). This relationship suggests that organoleptic masking was very effective in improving bitterness (especially if the ODT contained a smaller amount of physical masking). If a VAS score of 40% is defined to be an acceptable limit of bitterness, preparation of an ODT allowing dissolution of ≥85% at pH 6.8 cannot be achieved without organoleptic masking. An ODT with both properties (acceptable bitterness and dissolution at pH 6.8) can be prepared by combined use of physical and organoleptic masking if the percentage of physical masking is ca. 6–8%.
Data are the mean. (n=10).
Recently, the electric tongue has used for the evaluation of taste of ODTs. The present study, although it was not compared between VAS score and electric tongue evaluation, we think the VAS score can evaluate not only taste but also cognitive function. Thus, it was very interesting to compare with VAS and electric tongue evaluation of ODTs taste for improve adherence.
The present study suggests that an ODT of propiverine can be developed to evaluate the effects of combined use of physical and organoleptic masking on palatability. Metachronic analyses of a clinical gustatory sensation study can provide useful information for the development of ODTs with sufficient dissolution and acceptable palatability.
The authors are grateful to Ms. Yuka Suzuki, Mr. Wataru Suzuki, and Mr. Takuya Murao for their excellent technical assistance. We would also like to thank Dr. Kazuki Mimura for his valuable suggestions in developing these formulations.
The authors declare no conflict of interest.
