1214

Regular Article

Chem. Pharm. Bull. 59(10) 12141220 (2011)

Vol. 59, No. 10

Preparation and Evaluation of Orally Rapidly Disintegrating Tablets Containing Taste-Masked Particles Using One-Step Dry-Coated Tablets Technology
Keita KONDO,*, a Toshiyuki NIWA,a Yuichi OZEKI,b Masaki ANDO,b and Kazumi DANJOa
a

Faculty of Pharmacy, Meijo University; 150 Yagotoyama, Tempaku-ku, Nagoya 4688503, Japan: and b OSDrC Division, Sanwa Kagaku Kenkyusho; 363 Shiozaki, Hokusei-cho, Inabe, Mie 5110406, Japan. Received April 23, 2011; accepted July 29, 2011 In this study, in order to address the problems with manufacturing orally rapidly disintegrating tablets (ODT) containing functional (taste masking or controlled release) coated particles, such as the low compactability of coated particles and the rupture of coated membrane during compression, a novel ODT containing tastemasked coated particles (TMP) in the center of the tablets were prepared using one-step dry-coated tablets (OSDrC) technology. As a reference, physical-mixture tablets (PM) were prepared by a conventional tableting method, and the properties of the tablets and the effect of compression on the characteristics of TMP were evaluated. OSDrC was found to have higher tensile strength and far lower friability than PM, but the oral disintegration time of OSDrC is slightly longer than that of PM following high compression pressure. Consequently, OSDrC approaches the target tablet properties of ODT, whereas PM does not. The deformation of TMP in OSDrC due to compression is slight, and the release rate of acetaminophen (AAP) from OSDrC is the same as from TMP. However, TMP on the surface of PM are considerably deformed, and the release rate of AAP from PM is faster than from TMP. These ndings suggest that OSDrC technology is a useful approach for preparing ODT containing functional coated particles. Furthermore, we demonstrate that the elastic recovery of tablets can affect differences in the properties of OSDrC, PM and placebo tablets (PC).
Key words orally rapidly disintegrating tablet; one-step dry-coated tablet; taste-masking; acetaminophen

As the population ages, a higher percentage of patients nd it difcult to swallow conventional solid, orally administered drug forms such as tablets and capsules, resulting in decreased drug regimen compliance. To address this problem, tablets which rapidly disintegrate in the oral cavity (ODT) were developed.13) Several manufacturing technologies for ODT have been reported, such as freeze-drying,4,5) tabletmolding,6) crystalline transition,7,8) the addition of a disintegrant,9,10) and external lubrication.11) In general, since ODT need to disintegrate in the oral cavity, manufacturing ODT with functions such as taste masking or controlled release (sustained release and site-specic release) is very difcult. However, it may be possible to prepare functional (tastemasking or controlled-release) ODT by tableting powders containing lm-coated drug particles, although it has been reported that such methods has the problems that robust tablets are hard to obtain due to the low compactability of coated particles and the release prole of coated particles changes when the coated membrane is ruptured during compression.1214) In this study, we focused on one-step dry-coated tablets (OSDrC) technology to address these problems, since OSDrC technology can prepare dry-coated tablets of low compactable powders in a single run with a rotary tableting machine using a double-structure punch (center punch and outer punch).1518) In order to investigate the utility of OSDrC technology for preparing functional ODT containing lm-coated particles, using relatively large 500710 m m taste-masked coated particles (TMP) which are likely to cause above problems, we prepared a novel ODT consisting of a core of TMP covered with an outer layer of highly compactable excipient by OSDrC technology. As a reference, physical-mixture tablets (PM) were prepared by a conventional tableting method. The tablet properties and the effect
To whom correspondence should be addressed.

of compression on the characteristics of taste-masked coated particles were evaluated.

Experimental Materials Acetaminophen (AAP) (API Corporation Ltd., Japan) was used as the bitter-taste model drug. Sucrose-corn starch spheres (Nonpareil101 (3242), Freund Industrial Co., Ltd., Japan) were used as core particles. Hydroxypropylcellulose (HPC L, Nippon Soda Co., Ltd., Japan) and polyethylene glycol polyvinyl alcohol (PEGPVA) graft copolymer (Kollicoat IR, BASF Japan Ltd., Japan) were used as coating agents. Spray drying products composed of sugars, disintegrants and inorganic ingredients (FMELT type C, Fuji Chemical Industry Co., Ltd., Japan) were used as excipients for ODT. Magnesium stearate (Mg-St) (Wako Pure Chemical Industries Ltd., Japan) was used as a lubricant. All other chemicals and solvents were of analytical reagent grade. Preparation of Drug-Layering Particles (DLP) The formulation of DLP is shown in Table 1. The rst coating uid was prepared by suspending AAP in hydroxypropylcellulose solution using a rotational homogenizer (POLYTRON PT-3100, Kinematica Ag, Switzerland). Sucrose-corn starch spheres were coated by spraying the rst coating uid using a multifunctional uidized bed granulator (Agglomaster AGM-PJ/SD-2M, Hosokawa Micron Co., Ltd., Japan) to produce DLP. The operating conditions for the rst coating are shown in Table 2. DLP retained between 355- and 710-m m sieves was subjected to a second coating process. Table 1. Formulation of DLP and TMP DLP Charging materials Nonpareil-101 (3242) DLP Spray coating uid AAP Hydroxypropylcellulose PEGPVA graft copolymer Puried water Total TMP

(g) (g) (g) (g) (g) (g) (g)

500 450 45 ad. 2250

500 300 ad. 1500

e-mail: 103674501@ccalumni.meijo-u.ac.jp

2011 Pharmaceutical Society of Japan

October 2011 Table 2. Operating Conditions for the Fluidized Bed Granulator DLP Inlet air temperature Product temperature Outlet air temperature Inlet air volume Spray rate Atomizing air volume Rotor speed (C) (C) (C) (m3/min) (g/min) (l/min) (rpm) 7075 ca. 45 ca. 35 0.8 10 40 300 TMP 7080 ca. 55 ca. 45 1.0 2.55.0 60 300

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Fig. 1. Schematic Diagrams of OSDrC (A), PM (B) and PC (C) Table 3. Formulation of OSDrC, PM and PC

Preparation of TMP The formulation of TMP is shown in Table 1. The second coating uid was prepared by solvating PEGPVA graft-copolymer in puried water. DLP were coated by spraying the second coating uid using the multifunctional uidized bed granulator to produce TMP. The operating conditions for the second coating are shown in Table 2. TMP retained between 500- and 710-m m sieves were subjected to a tableting process. Preparation of Tablets Schematic diagrams of OSDrC, PM and placebo tablets (PC) are shown in Fig. 1. 1) OSDrC: OSDrC were prepared using the technique described by Ozeki et al.1518) TMP, excipient and Mg-St were mixed at the weight ratio shown in Table 3 to provide a core powder and an outer layer powder. These powders were compressed using experimental at-face punches and a die, utilizing a universal tension and compression tester (Autograph AG-5000D, Shimadzu Co., Ltd., Japan) at a compression speed of 1 mm/min under various pressures (50, 75, 100 MPa) to produce OSDrC of 250 mg (core: 50 mg) in weight and 9 mm (core: 6 mm) in diameter. The obtained OSDrC were left at room temperature for 24 h in a desiccator over silica gel and then tested. 2) PM: TMP, excipient and Mg-St were mixed at the weight ratio shown in Table 3. The mixture was compressed using the experimental at-face punches, unied center and outer punches, and the die, utilizing the universal tension and compression tester at a compression speed of 1 mm/min under various pressures (50, 75, 100 MPa) to provide PM of 250 mg in weight and 9 mm in diameter. The obtained PM were left at room temperature for 24 h in a desiccator over silica gel and then tested. 3) PC: Excipient and Mg-St were mixed at the weight ratio shown in Table 3. The mixture was compressed in the same manner as above to provide PC of 250 mg in weight and 9 mm in diameter. The obtained PC were left at room temperature for 24 h in a desiccator over silica gel and then tested. Disintegration Test in an Oral Cavity Oral disintegration time was measured using ve volunteers. Each volunteer rinsed their mouth with water (100 ml), then gently rubbed a tablet against the upper palate using their tongue. After the tablet disintegrated completely, the remains were spat out and the mouth was washed with water. The time required to feel no fragment of the tablet was measured with a stopwatch. Measurement of Tensile Strength Tablet crushing load, which is the force required to break a tablet by compression in a radial direction, was measured using a tablet hardness tester (PC-30, Okada Seiko Co., Ltd., Japan) at a loading speed of 1.0 mm/s. Tensile strength (s ) was calculated using the following equation:

OSDrC PM Core TMP Excipienta) Mg-St Subtotal Total (mg) (mg) (mg) (mg) (mg) 25.00 24.75 0.25 50.00 Outer layer 199.00 1.00 200.00 250.00 25.00 223.75 1.25 250.00 248.75 1.25 250.00 PC

a) Spray drying products composed of sugars, disintegrants and inorganic ingredients.

and total elastic recovery (TER) were calculated using the following equation: IER 100 (He Hc)/Hc TER 100 (H24 Hc)/Hc (3) (4)

s 2L/(p DT )

(1)

where L is the tablet crushing load, and D and T are the diameter and the thickness of the tablet, respectively. Friability Test Ten tablets were put into a friability tester (Sugagaki Irika Industrial Co., Ltd., Japan) and rotated for 4 min at 25 rpm. Friability was calculated from the loss in total weight of the tablets after the test. Measurement of Tablet Porosity TMP, excipient and Mg-St were crushed in a mortar and the true density of each powder was measured using a pycnometer (Ultra pycnometer 1000, Quantachrome, U.S.A.) to calculate that of the tablet. Tablet porosity (e ) was calculated using the following equation:

100 {1 W/(Vr )}

(2)

where W, V and r are the weight, the bulk volume and the true density of the tablet, respectively. Measurement of Elastic Recovery The thickness of a tablet under maximal pressure (Hc ) immediately after ejection (He ) and 24 h after ejection (H24 ) were measured. The percentage of initial elastic recovery (IER)

Scanning Electron Micrograph Tablets were broken using the tablet hardness tester to obtain a cross section of each tablet. The surface and the cross section was coated with platinum using sputtering equipment (JFC1600, JEOL Ltd., Japan) and observed with a scanning electron microscope (SEM) (JSM-6060, JEOL Ltd., Japan). Dissolution Test The dissolution test was performed with a dissolution tester (NTR-3000, Toyama Sangyo Co., Ltd., Japan) using the paddle method according to JP15. The test uid was 900 ml of puried water at 37 0.5 C, and the rotation speed of the paddle was 50 rpm. Sample corresponding to 5.8 mg of AAP (DLP: 15 mg, TMP: 25 mg) was put into the test uid, then 1.0 ml of the test uid was collected through a rod-like glass lter (G3, pore size: 2030 m m, Toyama Sangyo Co., Ltd., Japan) at xed time intervals. The quantity of AAP in the test uid was assayed using HPLC (LC-10, Shimadzu Co., Ltd., Japan). The analytical conditions were as follows: column, reverse-phase column (Inertsil ODS-3, 5 m m, 4.6 150 mm, GL Sciences Inc., Japan); mobile phase, a mixture of KH2PO4 solution (0.05 mol/l, pH 4.7)/methanol (4 : 1); ow rate, adjusted to provide a retention time for AAP of around 5 min; measurement wavelength, 244 nm. Taste-Masking Tests of the Preparations Gustatory tests were performed for the in vivo taste-masking test. Five volunteers rinsed their mouth with water (100 ml), then placed DLP or TMP corresponding to 5.8 mg of AAP into their mouth. The score for bitterness (dened as , no bitterness; , slightly bitter; , moderately bitter; , strongly bitter) was recorded after 20 s. After nishing the test, the sample was spat out and the mouth was rinsed with water. The gustatory test of OSDrC and PM was carried out along with the oral cavity disintegration test. The score for bitterness was recorded after the tablets had disintegrated. The syringe-inverting method19,20) was performed for the in vitro tastemasking test. Sample corresponding to 5.8 mg of AAP (DLP, 15 mg; TMP, 25 mg; OSDrC and PM, one tablet each) were put into a 10-ml syringe together with 10 ml of puried water at 37 0.5 C, then the sample and water was mixed by 10 repeated inversions of the syringe for 30 s. The dispersion was immediately pre-ltered through a rod-like glass lter (G4, pore size: 510 m m, Toyama Sangyo Co., Ltd., Japan) to avoid clogging the membrane lter, and then ltered through a membrane lter (pore size: 0.45 m m, DISMIC-13HP, Toyo Roshi Kaisha Ltd., Japan). The quantity of AAP in the uid was assayed using HPLC as described above.

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Results and Discussion Comparison of Tablet Properties of OSDrC and PM. Effect of Compression Pressure on Tensile Strength and Porosity The tensile strength of OSDrC, PM and PC compressed at various pressures were measured. The target tensile strength, required for adequate durability during handling, was set at more than 1.0 N/mm2. The results of the tensile strength are shown in Fig. 2. The tensile strength of the tablets increased with increasing compression pressure in the order PM, OSDrC and PC. The low tensile strength of tablets (OSDrC and PM) containing TMP is probably due to the low compactability of TMP. However, OSDrC exhibited higher tensile strength than PM, although OSDrC contained the same amount of TMP as PM. These results indicate that OSDrC technology can prepare tablets of the same tensile strength under lower pressure than a conventional tableting method, in agreement with the report by Ozeki et al.,16) which is the advantage in manufacturing ODT containing lm-coated particles. On the other hand, PM did not exhibit high tensile strength under low pressure, and PM compressed at 50 MPa did not achieve the target tensile strength. The porosity of OSDrC, PM and PC compressed at various pressures is shown in Fig. 3. Porosity decreased as compression pressure increased in the order PM, OSDrC and PC. These results suggest that the difference in tensile strength between OSDrC, PM and PC corresponds to the differences in porosity: i.e., the tensile strength of tablets easily compacted under low pressure tends to be large. Furthermore, since OSDrC and PM containing TMP have higher porosity than PC without TMP, the TMP in tablets may cause the porosity of tablets to increase and their tensile strength to decrease. Effect of the Elastic Recovery of Tablets Containing TMP on Tablet Properties Since it has been reported that coated particles tend to undergo elastic recovery,1214) we expected that the elastic recovery of the coated particles in a tablet can result in unwanted tablet characteristics such as capping and lamination. Thus, the elastic recovery of OSDrC, PM and PC compressed at various pressures was measured. The results are shown in Fig. 4. IER and TER rep-

resent the percentage of elastic recovery from compression immediately after ejection and 24 h after ejection, respectively. The data in Fig. 4 show that OSDrC and PM containing TMP exhibit higher percentages of elastic recovery than PC without TMP, since the elastic recovery of tablets containing TMP continued after ejection, while that of tablets without TMP changed little after ejection. These results suggest that the TMP in the tablets slowly undergoes elastic recovery for a long period of time as compared to the other components. Moreover, these ndings suggest that the elastic recovery of the TMP in a tablet after ejection negatively inuences tablet properties, since the lag time of the elastic recovery between the TMP and the other components in the tablet can cause the structure of the tablet to break. Furthermore, OSDrC exhibited a lower percentage of elastic recovery after ejection than PM, possibly indicating that elastic recovery of the TMP in the tablets after ejection has a larger inuence on the structure of PM than on OSDrC. In order to clarify the inuence of elastic recovery after ejection on the structure of tablets, the relationship between

Fig. 3. Effect of Compression Pressure on the Porosity of Tablets

Each point represents the mean S.D. (n 5). ( ), OSDrC; ( ), PM; ( ), PC.

Fig. 2. Effect of Compression Pressure on the Tensile Strength of Tablets

Each point represents the mean S.D. (n 5). Dotted area indicates the target tensile strength. ( ), OSDrC; ( ), PM; ( ), PC.

Fig. 4. Percentage of Initial and Total Elastic Recovery of Tablets Compressed at 50 MPa
Each column represents the mean S.D. (n 5). ( ), IER; ( ), TER.

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Fig. 5. Relationship between the Increment in Elastic Recovery (DER) and Porosity (D e ) from Immediately after Ejection to 24 h after Ejection
Each point represents the mean S.D. (n 5). The solid line indicates the regression line. ( , , ), OSDrC; ( , , ), PM; ( , , ), PC. Compression pressure: 50 MPa (open symbols); 75 MPa (gray symbols); 100 MPa (closed symbols).

Fig. 6. Result of Friability Test on Tablets

Each point represents the mean S.D. (n 10). Dotted area indicates the target friability. ( ), OSDrC; ( ), PM; ( ), PC.

Fig. 7. Photographs of the Surface of OSDrC (A) and PM (B) after the Friability Test

the increment of elastic recovery (DER) and porosity (D e ) immediately after ejection and 24 h after ejection was investigated; the results are shown in Fig. 5. DER was dened as the difference between TER and IER. D e increased almost linearly as DER increased in the rank order PC, OSDrC and PM. These results show that the porosity of tablets containing TMP increased with increasing percentage of elastic recovery after ejection, and may explain the difference in porosity between OSDrC, PM and PC shown in Fig. 3. Based on these ndings, it is concluded that the elastic recovery by TMP may result in the low tensile strength of tablets containing TMP, and that the low compactability of TMP appears to be due to its elastic recovery. Friability Test A friability test of OSDrC, PM and PC compressed at various pressures was performed. The target friability was set at less than 0.5%. The results of the friability test are shown in Fig. 6. OSDrC and PC provided very similar results and approached the target friability, while PM was far more friable. The appearance of OSDrC and PM after the friability test is shown in Fig. 7. The edge of the PM tablet was signicantly more damaged than that of the OSDrC tablet, consistent with the results of the friability test. These results indicate that the very high friability of PM

Fig. 8. Effect of Compression Pressure on the Oral Disintegration Time of Tablets

Each point represents the mean S.D. (n 5). Dotted area indicates the target oral disintegration time. ( ), OSDrC; ( ), PM; ( ), PC.

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Vol. 59, No. 10

Fig. 9. Stability of Oral Disintegration Time of Non-packaging Tablets Compressed at 50 MPa under 25 C 75% RH Storage Conditions for 1 Week
Each column represents the mean S.D. (n 5). ( ), OSDrC; ( ), PM; ( ), PC.

Fig. 10. Relationship between Tensile Strength and Oral Disintegration Time of Tablets
Each point represents the mean S.D. (n 5). ( ), OSDrC; ( ), PM; ( ), PC.

probably results from the loss of TMP at the edge of PM. In contrast, the TMP in OSDrC were covered with the rigid outer layer of the OSDrC, so the friability of OSDrC containing TMP was similar to that of PC without TMP. Comparison of the Disintegration Properties of OSDrC and PM Oral cavity disintegration tests of OSDrC, PM and PC compressed at various pressures were performed. The target oral disintegration time, which was the time required for an ODT to disintegrate in the oral cavity, was set at less than 30 s. The results of the disintegration test are shown in Fig. 8 and show that oral disintegration time increased as compression pressure increased, and that a sharp increase occurred above 100 MPa. PM compressed at 50 75 MPa achieved the target oral disintegration time. The long disintegration time of tablets compressed at 100 MPa might be due to a decrease in the size of pores in the tablets due to fragmentation of excipient particles under high pressure. PM compressed at 75100 MPa achieved the target oral disintegration time, but PM could not have both orally rapidly disintegrating properties and adequate durability during handling, since PM must be compressed over 100 MPa to obtain the target tensile strength and friability. Meanwhile, OSDrC compressed at 50 MPa approximately achieved the target oral disintegration time, tensile strength and friability. The results suggest the utility of OSDrC technology in manufacturing ODT. However, the oral disintegration time of OSDrC was longer than that of PM and PC in the range 75100 MPa. It is possible that saliva may fuse TMP because PVA-PEG graft copolymer is a water-soluble binder. This binder, which is composed of TMP particles, generates a gel when dissolved in a little water, and this gelling tends to occur when the distance between TMP-TMP in tablets is small. Therefore, the long disintegration time of OSDrC compressed at high pressure appears to be caused by agglomeration of TMP in the mouth, since the TMP in OSDrC are located in the core of OSDrC. Furthermore, oral cavity disintegration tests were performed after non-packaging tablets compressed at 50 MPa were stored at 25 C and 75% RH for 1 week, since there is concern that the oral disintegration time of tablets increase under humidied conditions. The results of the disintegration

test after storage are shown in Fig. 9. The oral disintegration time of OSDrC, PM and PC after storage was almost the same that before storage, indicating that the disintegration properties of these tablets compressed at 50 MPa are not affected by humidity at least for 1 week, and agglomeration of TMP in OSDrC may be not caused, probably because TMP in OSDrC compressed at 50 MPa is large are not too compacted. The relationship between tensile strength and oral disintegration time is shown in Fig. 10. The oral disintegration time of PM was about the same as that of PC, while the tensile strength of PM was less than that of PC. The results suggest that the increase in porosity by elastic recovery of the TMP in the tablet after ejection has little inuence on the disintegration property, even though tensile strength is decreased, probably because the elastic recovery by the TMP breaks local interparticle bonding in the tablet (around TMP) rather than throughout the tablet. From these results, it appears that oral disintegration time is dependent on compression pressure rather than porosity under the conditions tested. Effect of Compression Method on the Characteristics of TMP. Morphological Structure of the TMP in Tablets Scanning electron micrographs of the surface and cross sections of OSDrC and PM compressed at 100 MPa are shown in Fig. 11, and show that the TMP in OSDrC is present only in the center of the tablet, whereas the TMP in PM is present throughout the tablet. These results conrm that OSDrC technology can produce unique tablets in which the TMP is located only in the center of the tablet. Observation of the morphological structure of the TMP in the tablets showed that the TMP in OSDrC was only slightly deformed, while the TMP in PM were remarkably deformed, especially on the surface of PM, as shown by arrows in Fig. 11. The plastic deformation of the TMP on the surface of PM is probably due to the contact of these TMP with the punches and die during compression. Effect of Compression on the Release Prole of AAP The release proles of AAP from DLP, TMP, OSDrC and PM compressed at 50 MPa are shown in Fig. 12. The initial

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Fig. 11. Scanning Electron Micrographs of the Surface (1) and a Cross Section (2) of OSDrC (A) and PM (B) Compressed at 100 MPa
Arrows indicate deformation of TMP.

Table 4. Release Rate of AAP from Samples T10% (min) DLP TMP OSDrC PM 0.26 0.79 1.26 1.08 0.00 0.08 0.07 0.00 T80% (min) 2.84 4.92 5.49 4.07 0.21 0.30 0.19 0.08 Release rate (%/min) 27.2 17.0 16.5 23.4 2.3 1.3 a ] 0.7 ]b 0.6

Each value represents the mean S.D. (n 3). a p 0.05, b p 0.001, c p 0.01.

release rate (80% 10%)/(T80% min T10% min)

(5)

Fig. 12. Release Proles of AAP from Samples in Puried Water

Each point represents the mean S.D. (n 3). ( ), DLP; ( ), TMP; ( ), OSDrC; ( ), PM.

release of AAP from TMP was slower than from DLP, but 100% was released from TMP in less than 10 min. The results indicate that the initial release of AAP from TMP is suppressed by the layer of PEG-PVA graft copolymer, which not causes over suppression of the drug release. To clarify the difference in the release proles of TMP, OSDrC and PM, the release rate of each sample was calculated, and obtained values were statistically estimated by t-test. Since the release proles of OSDrC and PM were delayed by the disintegration process, the release rate of AAP from the TMP in tablets was calculated using the slope of the linear portion in release proles i.e. the following equation:

where T10% and T80% are the time when the percent released is 10% and 80%, respectively. The release rates are shown in Table 4. The release rate of PM was signicantly faster than that of TMP and OSDrC (p 0.01). This result indicates that the PEG-PVA graft copolymer membrane around TMP particles might be damaged by compression, as suggested by the deformation evident in Fig. 11, resulting in the permeability of the membrane increasing. Furthermore, the comparable release rate of OSDrC and TMP suggests that the permeability of the membrane around the TMP particles in OSDrC is essentially unaffected by compression. Taste-Masking Evaluation of the Preparations The gustatory test was used for the in vivo taste-masking evaluation of DLP, TMP, OSDrC and PM compressed at 50 MPa. The results are shown in Table 5. Most volunteers felt TMP to be less bitter than DLP, indicating that the bitterness of TMP is masked by the layer of PEG-PVA graft copolymer. However, volunteers did not feel the difference in bitterness between TMP, OSDrC and PM, although the release rate of AAP from PM is increased by compression, as shown in Table 4. These results are probably because the difference in

1220 Table 5. In Vivo and in Vitro Taste-Masking Evaluation Volunteer A DLP TMP OSDrC PM
Each value represents the mean S.D. (n 8). a p 0.012.

Vol. 59, No. 10

D30s D E (m g/ml) 311.1 80.5 50.9 69.1 60.5 15.1 13.8 a ] 11.5

bitterness between taste-masked preparations (TMP, OSDrC and PM) is small unlike with that between non-masking and taste-masked preparations (DLP and TMP); furthermore, the bitterness of AAP is masked by the sweetness of the excipient. Therefore, it may be difcult to nd the difference in the taste-masking effect of TMP between OSDrC and PM by the gustatory test. So, in order to clarify the difference in the taste-masking effects of the preparations, a syringe-inverting method was used for in vitro taste-masking evaluation, and then the percent released after 30 s (D30s) was measured, and obtained values were statistically estimated by t-test. The results of DLP, TMP, OSDrC and PM compressed at 50 MPa are shown in Table 5. The rank order of D30s was OSDrC PM TMP. The low D30s of the tablets is likely due to the delay in the wetting of TMP in the test uid, which is followed by the disintegration process. Furthermore, the statistically signicant difference in the D30s between OSDrC and PM (p 0.012) is probably attributed to the release rate of AAP from the TMP in tablets as shown in Table 4, since the oral disintegration time of OSDrC and PM compressed at 50 MPa was about the same. From these results, it is concluded that the TMP compressed using OSDrC technology may exhibit the lower initial drug release or the better taste-masking effect than these using PM method, probably because the damage caused by compression to TMP in OSDrC is small. Conclusion In this study, ODT containing TMP using OSDrC technology and a conventional tableting method were prepared, and the tablet properties and the inuence of compression on the characteristics of TMP were compared. OSDrC provided higher tensile strength and far lower friability than PM, indicating that OSDrC technology can prepare tablets under lower pressure than PM method, and it may be able to increase the porosity of tablets and decrease the damage of coating lm by compression. Therefore, OSDrC compressed at 50 MPa approximately achieved the target tensile strength, friability and oral disintegration time, in contrast to PM. However, the oral disintegration time of OSDrC was slightly longer than that of PM following high

compression pressure. The elastic recovery of tablets containing TMP continued after ejection and impacted the differences in porosity between OSDrC, PM and PC. Therefore, it appears that elastic recovery of the TMP in the tablets after ejection caused the porosity of the tablets to increase and their tensile strength to decrease. However, elastic recovery appears to have little inuence on the disintegration properties of tablets. The TMP in OSDrC were only slightly deformed by compression, and the release rate of AAP from OSDrC was the same as that from TMP. Meanwhile, the TMP in PM were considerably deformed, especially on the surface of the tablet, resulting in the faster release rate than TMP before compression and the lower taste-masking effect than OSDrC. These ndings suggest that OSDrC-technology is a useful approach for preparing ODT containing functional coated particles.
Acknowledgments The authors thank Freund Industrial Co., Ltd., BASF Japan Ltd. and Fuji Chemical Industry Co., Ltd. for gift samples of Nonpareil-101 (3242), Kollicoat IR and F-MELT, respectively. References 1) Sugihara M., Farumashia, 30, 13961400 (1994). 2) Hanawa T., Jpn. J. Geriatr., 45, 485488 (2008). 3) Watanabe A., Hanawa T., Sugihara M., Yakuzaigaku, 54, 103110 (1994). 4) Katou S., Kearney P., Yarwood R. J., Pharm. Tech. Jpn., 9, 713719 (1993). 5) Seager H., J. Pharm. Pharmacol., 50, 375382 (1998). 6) Tsushima Y., J. Jpn. Soc. Pharm. Mach. Eng., 10, 305315 (2001). 7) Sugimoto M., Matsubara K., Koida Y., Kobayashi M., Pharm. Dev. Technol., 6, 487493 (2001). 8) Mizumoto T., Masuda Y., Yamamoto T., Yonemochi E., Terada K., Int. J. Pharm., 306, 8390 (2005). 9) Ishikawa T., Mukai B., Shiraishi S., Utoguchi N., Fuji M., Matsumoto M., Watanabe Y., Chem. Pharm. Bull., 49, 134139 (2001). 10) Shu T., Suzuki H., Hironaka K., Ito K., Chem. Pharm. Bull., 50, 193 198 (2002). 11) Oneda Y., Kubota M., Kitamura N., Fujita K., Suzuki H., J. Jpn. Soc. Pharm. Mach. Eng., 18, 295307 (2009). 12) Aulton M. E., Dyer A. M., Khan K. A., Drug Dev. Ind. Pharm., 20, 30693104 (1994). 13) Debunne A., Vervaet C., Mangelings D., Remon J. P., Eur. J. Pharm. Sci., 22, 305314 (2004). 14) Maganti L., elik M., Int. J. Pharm., 103, 5567 (1994). 15) Ozeki Y., Watanabe Y., Inoue S., Danjo K., Int. J. Pharm., 259, 69 77 (2003). 16) Ozeki Y., Watanabe Y., Inoue S., Danjo K., Int. J. Pharm., 267, 69 78 (2003). 17) Ozeki Y., Ando M., Watanabe Y., Danjo K., J. Controlled Release, 95, 5160 (2004). 18) Ozeki Y., Kondo Y., Watanabe Y., Danjo K., J. Jpn. Soc. Pharm. Mach. Eng., 13, 8089 (2004). 19) Shirai Y., Sogo K., Yamamoto K., Kojima K., Fujioka H., Makita H., Nakamura Y., Biol. Pharm. Bull., 16, 172177 (1993). 20) Nakamura Y., Makita H., Imasato Y., Pharm. Tech. Jpn., 6, 841850 (1990).