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Novel use of insoluble particles as disintegration enhancers for orally disintegrating films
Journal of Drug Delivery Science and Technology 54 (2019) 101310
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Novel use of insoluble particles as disintegration enhancers for orally disintegrating films
T
Yoshiko Takeuchi∗, Tomoka Nishimatsu, Kohei Tahara, Hirofumi Takeuchi∗∗ Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu, 501-1196, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Orally disintegrating film Disintegration time Insoluble particle Hydroxypropyl methylcellulose Silica
The most important issue in the design of orally disintegrating films (ODFs) is the control of the ODFs' disintegration properties. A better understanding of the mechanisms of ingredients used to promote or disturb the disintegration time of ODFs would improve the development of ODF formulations. Here we focused on the advantage of adding insoluble particles (IPs) to improve the disintegration times of ODFs. We also verified the undesirable impact of the use of IPs on the mechanical properties of ODFs. We used hydroxyproplyl methylcellulose (HPMC), which is one of the most commonly used film-forming polymers for ODFs, as a film former. Films were prepared using the solution/solvent casting method. Microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and silica with different particle sizes and shapes were added in the film formulations as IPs. As expected, the addition of IPs shortened the disintegration times of the films. The larger particles had a greater impact compared to the smaller particles. However, the addition of larger particles decreased the films’ tensile strength. Our results demonstrate the effectiveness of IPs for shortening the disintegration times of HPMC films loaded with active pharmaceutical ingredients.
1. Introduction Various types of pharmaceutical thin films have been developed. Borges et al. [1] reviewed the status of oral films and their attributes in 2015. These dosage forms designated with the different terms and definitions described by Borges et al. should be carefully understood. For example, there are both mucoadhesive and non-mucoadhesive films. Pharmaceutical thin films can also be administered via oral absorption (i.e., by sublingual, buccal, and palatal administration), which does not subject the drug incorporated in the film to degradation from first-pass metabolism, or as gastrointestinal (GI) absorption films, which do subject the drug to first-pass metabolism. Hoffman et al. [2] pointed out that there are also some types of oral films that are distinguished based on their disintegration times and designs, and they noted that there was no clear dividing line. Orally disintegrating films (ODFs), which we investigated in the present study, are pharmaceutical thin films that disintegrate rapidly when placed in the oral cavity [2,3]. These films are very helpful in the treatment of dysphagic individuals such as those who cannot swallow medicines easily, bed-prone patients, geriatric patients, and pediatric patients [1]. ODFs were initially developed as over-the-counter (OTC) drugs, but ODFs for prescription drugs for children have also been ∗
developed [4]. Many types of ODFs are now available on the OTC drug market and for prescription drugs [5,6]. ODFs are prepared with polymers and other additives such as plasticizers, flavors, colors, sweeteners, surfactants, thickening agents, disintegrants (disintegration enhancers), and antioxidants as well as active pharmaceutical ingredients (APIs) [7]. The major ingredients that determine film's properties are the film-forming water-soluble polymers used, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and pullulan (PUL) [2]. The addition of the other agents mentioned above and APIs is well known to affect to the properties of ODFs [8,9]. We demonstrated that two additives formulated in films affected the films' tensile strength and disintegration time [10]. In the pharmaceutical preparations research field, water-soluble polymers and the properties of free films made of those polymers have been well investigated as film-formers in the formulations of filmcoated tablets. In those investigations of free films, some insoluble particles (IPs) were usually added to the film-forming polymer solution and dispersion as pigments and as opacifying agents [11–13]. The size and shape of the IPs were also reported to affect the dissolution of a drug from coated tablets, and it was noted that the larger the IPs in the polymer were, the more slowly that the drug was released [2,11,12].
Corresponding author. Corresponding author. E-mail address: [email protected] (Y. Takeuchi).
∗∗
https://doi.org/10.1016/j.jddst.2019.101310 Received 3 July 2019; Received in revised form 18 September 2019; Accepted 1 October 2019 Available online 09 October 2019 1773-2247/ © 2019 Elsevier B.V. All rights reserved.
Journal of Drug Delivery Science and Technology 54 (2019) 101310
Y. Takeuchi, et al.
In the design and development of ODF formulations, it is of paramount importance that the disintegration time be decreased. Disintegrants for orally disintegrating tablets (ODTs) have been reported to enhance the disintegration based on various mechanisms, i.e., swelling, wicking, and others [14]. However, we suspected that these mechanisms are not suitable for decreasing the disintegration times of ODFs, and that these disintegrants are usually not able to decrease the disintegration times of ODFs. Before ODFs are cast and dried, the disintegrants should be added into the solutions/dispersions of polymers, and, at this stage, the disintegrants have already absorbed water and swelled. Zhang et al. (2018) [15] investigated the impact of the use of two types of superdisintegrants on the disintegration time of strip films loaded with a poorly water-soluble drug. They observed that a large amount of added superdisintegrants decreased the disintegration time for all films, and that in the case of thick films (90–100 μm thick), the disintegration time was reduced from 280 s to 160 s. However, this decrease in the disintegration time is not large enough for ODFs, which ideally would disintegrate in < 30 s. We have observed that different types of insoluble additive particles, i.e., microcrystalline cellulose (MCC) and partially pregelatinized starch, affected the properties of ODFs prepared with HPMC and lowsubstituted hydroxypropyl cellulose (L-HPC) [10]. Liew et al. (2014) [9] also reported that a decrease in the concentration of HPMC produced films with rapid disintegration, and that the formulation with the highest amount of MCC disintegrated faster than the formulations with lesser amounts of MCC. The effects of insoluble ingredients on the disintegration time of ODFs should be evaluated systematically. We conducted the present study to clarify the feasibility of the addition of IPs to ODF formulations as a disintegration enhancer, i.e., for decreasing the disintegration times. At the same time, we evaluated the mechanical properties of ODFs to detect any undesirable impacts of IPs. We also evaluated the effects of IPs on the disintegration times of ODFs loaded with active pharmaceutical ingredients. Fig. 1 is a flow diagram of the material system used in this study.
Table 1 Size distribution of the insoluble particles. Code
D10
D50
D90
MCC
PH-F20JP PH-101 PH-102
MPF20 MP101 MP102
6.5 ± 0.3 20.7 ± 0.4 27.3 ± 1.0
16.1 ± 0.8 59.3 ± 1.1 83.3 ± 2.6
27.0 ± 0.9 116.0 ± 0.7 218.1 ± 2.9
L-HPC
LH-11 LH-21 LH-31
LH11 LH21 LH31
11.1 ± 1.2 11.9 ± 2.3 6.6 ± 0.3
31.2 ± 0.8 32.9 ± 2.5 17.0 ± 0.7
87.6 ± 7.4 106.3 ± 11.7 29.9 ± 3.8
Silica
Sylysia 350 Sylysia 380 Sylospher C1054 Sylospher C0809
SY350 SY380 S1054
1.7 ± 0.0 2.1 ± 0.0 2.3 ± 0.1
3.6 ± 0.0 5.6 ± 0.4 3.8 ± 0.0
5.8 ± 0.0 9.7 ± 0.6 5.8 ± 0.2
S0809
3.9 ± 0.2
7.2 ± 0.3
11.2 ± 0.6
Unit: μm.
2.2. Methods 2.2.1. Particle size measurement We conducted a laser diffraction scattering analysis (LDSA-2400A; Nikkiso, Tokyo) to determine the distributions of the IPs. The results are summarized in Table 1. 2.2.2. The preparation of the films Pharmaceutical films were formed by the solution/solvent casting method [16]. The formulations of the ODFs are shown in Tables 2–4. The ratio of polymer/IPs and the ratio of total solid ingredients/solvent are provided individually in these tables. The procedures are described briefly as follows: (a) HPMC powder was mixed with IPs (and, if necessary, other additives) before the solvent was used. (b) The solutions/dispersions were prepared by dispersing HPMC or an HPMC mixture into ethanol, and then dissolving with added water. (c) After the solutions/dispersions were degassed, the films were spread on a base film (polypropylene: Pylen®; Toyobo, Osaka, Japan), fixed onto a heat-resisting glass plate with the use of a YBAtype baker applicator (Yoshimitsu Seiki, Tokyo). The clearance between the bar of the applicator and the base film surface was adjusted depending on the targeted film thickness. (d) The films were kept in a dry chamber (KCV-4D; Advantec, Tokyo) with a 40 °C air current for ≥2 h to evaporate the solvent or water. (e) The films were cut into 20 mm × 30 mm pieces without removing the base films, in order to prevent the films and base films from sticking together. (f) The films were stored in a tight container (as defined in the 17th Japanese Pharmacopeia) at room temperature (1°–30 °C; as defined by the 17th Japanese Pharmacopeia) for ≥24 h to maintain the same evaluation condition, and the films were then evaluated.
2. Materials and methods 2.1. Materials Hydroxypropyl methylcellulose (HPMC; TC-5R, substitution type: 2910, viscosity; 6 (mPa s); Shin-Etsu Chemicals, Tokyo) was examined as a polymeric film former. These viscosity values were taken from the supplier's catalogue; they were determined for a 2.0% solid ratio in aqueous solution at 20 °C. As water-insoluble additives, we used microcrystalline cellulose (MCC; MPF20, MP101, MP102, MU711, MU702; Ceolus® PH-F20JP, PH-101, PH-102, UF-711, UF-702; Asahi Kasei Chemicals, Tokyo), low-substituted hydroxypropyl cellulose (LHPC; LH-11, LH-21, LH-31; Shin-Etsu Chemicals) and silica (SY350, SY380, S1054, S0809; Sylysia 350, Sylysia 380, Sylospher C-1054, Sylospher C-0809; Fuji Silysia, Tokyo). Donepezil hydrochloride (DNH; lot. no. DNPJN0K001), supplied as a gift sample, was used as an API.
2.2.3. The evaluation of the films 2.2.3.1. Film thickness. The film thickness was measured with a micrometer (Mitutoyo, Kawasaki, Japan) with 1-μm accuracy. Each sample film was measured at three different positions per strip. 2.2.3.2. Tensile strength. The mechanical property of tensile strength was measured with a creep meter (RE-3305S; Yamaden, Tokyo) as described [16]. The film strips (sample size: 20 mm × 30 mm) were vertically fixed with two grips 17 mm apart (i.e., the initial separation distance), and then pulled at a constant rate of 0.5 mm/s. The maximum fracture force, i.e., the force reached just before the film strips ruptured, was recorded. The measurements were repeated three times using three film samples for each type of formulation. The tensile
Fig. 1. Flow diagram of the material system. 2
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Table 2 Formulations and characteristics of ODFs with added insoluble particles. Polymer/Additives
HPMC %
MCC %
L-HPC %
Total %
Thickness μm
Weight mg
Tensile strength MPa
Elastic modulus MPa
Elongation %
100/0 80/20 60/40 40/60 20/80 80/20 60/40 40/60 20/80
100 80 60 40 20 80 60 40 20
– 20 40 60 80 – – – –
– – – – – 20 40 60 80
100 100 100 100 100 100 100 100 100
30.4 54.7 55.1 60.1 62.6 53.8 45.6 43.6 62.9
23.0 24.8 21.5 20.2 17.3 23.5 17.4 13.3 15.5
66.1 24.4 14.2 2.0 0.6 56.7 22.1 4.5 0.3
864.6 465.4 454.0 224.5 105.8 901.6 866.1 369.0 ND
8.1 6.5 3.4 0.9 0.4 8.4 2.8 1.2 ND
Ratio of total solid ingredients/solvent: solid/solvent = 1:10 (w/w). Solvent: ethanol/distilled water = 2:1(w/w).
formulated, and then their effects on the properties of ODFs were verified [10]. The morphologies of the MCC particles and the L-HPC particles are shown in Fig. 2. Silica particles are frequently added as a carrier for pharmaceutics, or as an anti-adhesive agent, a diluent, a glidant to improve flowability, and more, and these particles have an individualized small size and differing shapes (in the Fuji Silysia product catalog). The morphologies of the silica particles are shown in Fig. 3.
strength (MPa) was calculated as the fracture force divided by the crosssectional area of the film: Tensile strength (MPa) = fracture force (N)/cross-sectional area (mm2). The elastic modulus (MPa) and the elongation at break (%) were computed during the tensile test. 2.2.3.3. Disintegration time. We used the Petri dish method to determine the disintegration times [16]. The measurements were repeated three times using three film samples for each type of formulation. With this method, both the measurement of the disintegration time and the observation of the disintegrating behaviors can be performed during the tests.
3.1. The effect of insoluble particles (IPs) on the disintegration and mechanical properties of the unloaded ODFs 3.1.1. The effects of the polymer/MCC and L-HPC particles ratio The HPMC ODFs with added MCC (MPF20) and L-HPC (LH31) were prepared (based on the formulations in Table 2) and evaluated. These two IPs are very commonly used additives in the design of pharmaceutical tablets. The particle sizes of MPF20 and LH31 are approx. 17 μm (Table 1). The ratio of HPMC and each IP was in the range of 100:0 to 20:80 (Table 2). We attempted to design the ODFs with both high mechanical strength and a low disintegration time, even with the addition of IPs. We thus measured the tensile strength values and disintegration times to evaluate each of the designed ODFs. The disintegration times of the ODFs with the IPs (i.e., the MCC and L-HPC particles) are shown in Fig. 4. For the films without IPs, i.e., the HPMC films (100:0), the disintegration time was nearly 60 s. The addition of IPs reduced the disintegration time. The times were 42 s and 40 s for the films with MCC and L-HPC at the ratio of 80:20, respectively. The higher the amount of IPs was, the shorter the disintegration time became. The films for which the ratio of polymer/MCC and L-HPC was over 60:40 showed disintegration times > 30 s. In contrast, the films for which the ratio of polymer/IPs was under 40:60 showed the targeted disintegration time of approx. ≤30 s. At present, the quality control regarding the disintegration time of orally disintegrating formulations is recognized as “No specific guideline on quality available [17].” Therefore, ODF products should be
2.2.4. Morphological observation A scanning electron microscope (JSM-T6510LV; Japan Electron, Tokyo) was used to observe the particles. 3. Results and discussion ODFs are prepared from a water-soluble polymer. Among such polymers, HPMC, HPC, and PUL are considered suitable as film-formers because they have the advantages of being tasteless, odorless, and easily dissolved in water. HPMC, which is a nonionic water-soluble cellulose ether prepared from cellulose, does not interact with APIs and is the most frequently used as a film-forming polymer for the marketed ODFs [3,7]. We used HPMC as a film-forming polymer in the present study in the following sections. The three insoluble particles described below were added into the polymer solutions as a disintegration enhancer. Microcrystalline cellulose (MCC) is a representative filler and a disintegrant used for pharmaceutical solid-dosage forms. Low-substituted hydroxypropyl cellulose (L-HPC) is also a representative disintegrant used for pharmaceutical tablets, and it is water-insoluble. In our previous study, MCC as a filler and L-HPC as one of the film formers were Table 3 Formulation and characteristics of ODFs added silica particles. Code
No additives SY350 SY380 S1054 S0809
HPMC %
100 60 60 60 60
Silica % Sylysia 350
Sylysia 380
Sylospher C1054
Sylospher C0809
– 40 – – –
– – 40 – –
– – – 40 –
– – – – 40
Total %
Thickness μm
Weight mg
Tensile strength MPa
Elastic modulus MPa
Elongation %
100 100 100 100 100
30.4 40.9 38.6 31.3 34.4
23.0 24.8 17.0 20.9 18.0
66.1 32.6 15.5 31.1 23.9
864.6 467.3 464.6 675.2 586.9
8.1 9.0 3.9 5.2 4.9
Ratio of polymer/additives: HPMC/additive = 60/40 (w/w). Ratio of total solid ingredients/solvent: solid/solvent = 1:10 (w/w). Solvent: ethanol/distilled water = 2:1(w/w). 3
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Table 4 Formulation of films loaded with donepezil hydrochloride and added MCC particles. Content of donepezil hydrochloride
HPMC %
Microcrystallin cellulose MP102 %
Donepezil hydrochloride DH %
Total %
Thickness μm
Weight mg
Tensile strength MPa
Elastic modulus MPa
Elongation %
0% 13% 20% 26% 40%
60 52 48 44 36
40 35 32 30 24
– 13 20 26 40
100 100 100 100 100
84.2 101.0 111.3 117.2 ND
25.3 23.4 22.7 24.4 ND
5.6 6.3 5.2 4.7 ND
226.6 222.5 219.5 155.7 ND
2.6 2.4 2.4 3.2 ND
Ratio of polymer/additive: HPMC/MCC = 60/40. Ratio of total solid ingredients (except DH)/solvent: solid/solvent = 1:10 (w/w). Solvent: ethanol/distilled water = 2:1(w/w).
Fig. 2. Morphology observations of the insoluble particles (IPs). MCC particles. (a) PH-F20JP, (b) PH-101, and (c) PH-102. L-HPC particles: (d) LH-31, (e) LH-21, and (f) LH-11. Bars = 50 μm.
particles are usually added as pigments and opacifying agents. The study by Felton and McGinity [11] and references therein stated that the tensile properties of HPMC films were affected as a function of the titanium dioxide concentration. Our present findings are similar to the above described results regarding the influence of IPs on the mechanical properties of films. The addition of IPs decreased the tensile strength and shortened the disintegration times. Cilurtz et al. studied maltodextrin fast-dissolving films with an active drug and MCC (Avicel® PH 101, particle dia. 50 μm, in the Asahi Kasei Chemicals catalog). Based on their results, those authors suggested that the dispersion of MCC in the maltodextrin matrix caused the formation of a non-continuous film and originated the initial point of the break during the tensile stress testing [20]. The formation of polymer films is thought to be composed of an uninterrupted entanglement of coiled molecular chains, and the primary cause of instability of the coated film is the so-called internal stress in the film after it has dried [13]. It is thought that the addition of IPs to a polymer solution affects the formation of the entanglement of chains and contributes to the build-up of internal stress. The entanglement of the macromolecular chains in film is decreased by the addition of IPs, and this decreases the strength and promotes the film's disintegration under water.
developed based on the targeted disintegration time, i.e., < 30 s, in reference to the U. S. Food and Drug Administration (FDA) guidance [18]. The tensile strength values of the ODFs with IPs are also shown in Fig. 4. For the films without IPs, the tensile strength was > 60 MPa. The addition of IPs lowered the tensile strength. When the amount of IPs was increased, the tensile strength decreased. Table 2 provides the elastic modulus and elongation values with the tensile strength. The addition of IPs to the films also decreased the elastic modulus and the elongation along with the tensile strength, resulting in the higher brittleness of these films. For the ODFs with L-HPC with 20:80 as the ratio of polymer/IPs, the films’ tensile strength was not high enough to evaluate. In the case of the films for which the ratio of polymer/IPs was over 40:60, the strength could be maintained over the limit to ensure the ODF handling, i.e., 2 MPa [10]. During the tensile tests, we obtained the stress-strain curves, which provide information about the mechanical characteristics of the films. No stress-strain curve is provided herein due to a limitation of this article's length, but the curves of HPMC ODFs with or without IPs showed the same properties. This result suggested that the addition of IPs could change the strength but not the fracture characteristics [17,19]. In the pharmaceutical preparations research field, water-soluble polymers and the properties of free films made of those polymers have been well investigated as film-formers in formulations of film-coated tablets [11–13]. In a polymer solution and dispersion, some insoluble
3.1.2. The effect of the size of the IPs on the ODFs’ characteristics In their investigation of a film-coating system, Felton and McGinity 4
Journal of Drug Delivery Science and Technology 54 (2019) 101310
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Fig. 3. Morphology observations of the silica particles. (a) Sylysia 350, (b) Sylysia 380, (c) Sylospher C-1504, and (d) Sylospher C-0809. Bars = 10 μm.
(2002) [11] observed that films containing larger talc particles exhibited a higher modulus compared to films with smaller particles, and that the inclusion of more irregularly shaped particles in film-coating formulations resulted in greater increases in the elastic modulus of the polymer film compared to the inclusion of spherical particles. Here we added IPs (MCC and L-HPC) of different sizes to the film formulations and prepared and evaluated the films in order to investigate the effects of the IPs’ size on the ODF properties. The particle sizes of MCC and LHPC are shown in Table 1. As we noted above, the advantages and drawbacks of the addition of IPs can be determined, and our results demonstrated that the placebo ODFs prepared at an 80:20 ratio of polymer/IPs, did not show a suitable reduction in the disintegration time, and the placebo ODFs prepared at 40:60 could not maintain adequate strength. In this part of our study, the ratio of polymer/IPs for all films was kept at 60:40 (w/w). Fig. 5 illustrates the effects of the particle size of the IPs on the disintegration time and tensile strength of HPMC films. The disintegration time decreased with the increase in the particle size, and at the same time the tensile strength decreased. There was no significant
Fig. 5. The effect of the particle size of the IPs on the characteristics of the HPMC ODFs. The insoluble particles were MCC and L-HPC. The ratio of polymer/additive is shown in w/w as dry powder: HPMC/additives = 60:40 (w/w). Squares: Tensile strength on the first (left) vertical axis. Circles: Disintegration time on the second (right) vertical axis.
Fig. 4. The effects of the amount of additives on the characteristics of the HPMC ODFs. Insoluble particles: (a) MCC: MPF20, (b) L-HPC: LH31. The ratios of polymer/additive are shown in w/w as dry powder. Solvent: ethanol/distilled water = 2:1 (w/w). Bars: Tensile strength on the first (left) vertical axis. Circles: Disintegration time on the second (right) vertical axis.
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Journal of Drug Delivery Science and Technology 54 (2019) 101310
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HPC (Fig. 4, Table 2), respectively. Compared to those results, the tensile strength of the films with silica particles were higher (from 32.6 to 15.5 MPa), as expected, because the sizes of the silica particles are smaller than those of L-HPC and MCC particles. The elastic modulus of the films with silica particles was not much different from those of the films with MCC and L-HPC. Compared to the elongation of the films with larger IPs, the elongation values of the films with silica particles were slightly higher. According to these results, when IPs are added to improve the characteristics of ODFs, we must consider the sizes of the particles more than their shapes. In the design of ODF formulations, the IP size must be considered critically important to the palatability of the ODFs.
difference between the effects of MCC and those of L-HPC. When the particle size is larger, the macromolecular chain entanglement density would be more decreased, and thus water can easily permeate the films, improving the disintegration. On the other hand, increasing the particle size lowered the tensile strength. We speculate that the reason for this is because the structure, which is kept sturdy with the entanglement of the molecular chains, was disturbed by the existence of the IPs. 3.1.3. The effects of silica IPs with different sizes and shapes on the ODFs’ characteristics Studies of the film-coated tablets indicated that larger particles of a pigment disrupted the interfacial bonding between the polymer and the tablet surface and that the shape of the pigment influenced the elastic modulus of the polymeric films [12]. The size and shape of IPs were also reported to affect the dissolution of a drug from coated tablets [11]. The larger the IPs in the polymer were, the more slowly the drug was released. Felton and Porter [12] stated that the mechanical strength was affected by the addition of IPs, but they did not focus on the impact of the addition of IPs on the film disintegration properties. To investigate the effect of the IPs’ size and shape on ODF properties, we chose silica particles. Silica is a useful additive in pharmaceutical solid-dosage formulations, with many applications; e.g., as an anticaking agent, a diluent, a carrier, and an agent that improves flowability. Different sizes and different shapes of silica particles are available (Fuji Silysia Chemical catalog). The silica particles used herein were clearly smaller than the L-HPC and MCC particles described in the previous section. We added four types of silica particles to the formulation to investigate their effects on the enhancement of disintegration properties. The SY350 and SY380 particles had irregular shapes, and the S1054 and S0809 particles were spherical (Fig. 3). SY350 and S1054 were smaller than SY380 and S0809, respectively (Table 1). Fig. 6 illustrates the characteristics of the films to which these silica particles were added. The addition of silica particles decreased the disintegration time from approx. 60 s to < 40 s. The disintegration times of the films with larger silica particles were slightly lower than those of the films with smaller silica particles. In contrast, the difference in the particle shapes, i.e., irregular or spherical, did not affect the disintegration times of the films (from approx. 38 s–21 s). Compared to the size of the particles, the shape of the silica particles had less effect on the film characteristics. The results in Fig. 6 and Table 3 demonstrated that the addition of silica particles also lowered the tensile strength from 60 MPa to approx. ≤30 MPa, and that the addition of silica particles (except for SY350) decreased both the elastic modulus and the elongation along with the tensile strength. We noted above in Section 3.1.1 that the tensile strength of the films with the polymer/IPs ratio of 60:40 showed a decrease in tensile strength to 14.2 and 22.1 MPa for the films added with both MCC and L-
3.2. The effect of IPs on the disintegration and mechanical properties of ODFs loaded with APIs 3.2.1. Preparing ODFs loaded with APIs (as preliminary experiments) We verified the effects of IPs on the properties of ODF as described above, and it had already been indicated that drug loading affects the disintegration and mechanical properties of ODFs. For example, in our previous studies, ibuprofen loaded into HPC films delayed the disintegration more than ascorbic acid and acetaminophen loading, depending on the properties of the APIs [16]. The impact of the loading of drug (poorly water-soluble) nanoparticles on the mechanical properties of strip films was also investigated [21]. The tensile strength and elastic modulus did not change significantly, but the elongation decreased dramatically with the increase in the amount of drug nanoparticle loading. Liew et al. (2018) [9] also investigated that the impact of the additions of mannitol and MCC (Avicel® PH 102, particle dia. 100 μm in the company catalog) at different ratios (from 3:4 to 0:1) on the properties of ODFs loaded with APIs. Their results also demonstrated that the increase in the content of MCC decreased the tensile strength and the elongation, and slightly decreased the bending flexibility. It was also reported that a decrease in the mannitol content and an increase in the MCC content reduced the disintegration time [9]. As preliminary experiments, we prepared ODFs loaded with APIs. Donepezil hydrochloride (DH), ibuprofen (IBP), famotidine (FAM), ascorbic acid (ASA) and acetaminophen (AAP) were used as model drugs loaded into HPMC ODFs. Our evaluation of these ODFs revealed that DH loaded on HPMC ODFs without IPs decreased the disintegration time from approx. 55 s–13 s, whereas IBP loaded increased the disintegration time from 55 s to 59 s. In the case of ODFs with IPs, the loading of DH, FAM, ASA, or AAP also decreased the disintegration time from approx. 27 s to 12–19 s, but IBP loading increased the disintegration time to 43 s. The loading of APIs thus affected the disintegration time of the films depending on the types of APIs, as expected. It seemed that the impacts of the above APIs on the disintegration properties were due to their water solubility. For example, IBP is “practically insoluble in water” and DH is “soluble in water” (Japanese Pharmacopeia 17th edition). Based on these findings, we next investigated the effect of IPs on the disintegration times of ODFs under the condition of loading with APIs. 3.2.2. The effects of IPs on the characteristics of ODFs loaded with DH As noted above, the loading of APIs affects the ODFs characteristics, and it could also be predicted that the addition of IPs would improve the disintegration times of loaded films. We used DH as a model API; IBP could not be used due to the possibility of its crystallization in the films. MCC (MP102) was used as the IP. Donepezil hydrochloride is a very useful active ingredient for medication used to treat Alzheimer's disease, but it is known to have a strongly bitter taste [22,23]. It has been prescribed in commercial ODTs and ODFs, e.g., Aricept® (Eisai Co., Tokyo) and Donepezil Hydrochloride OD film (Elmed Eisai Co., Tokyo). The ODTs and ODFs are provided at doses of 3 mg, 5 mg and 10 mg and are generally required by elderly patients. Therefore, DH is
Fig. 6. The effect of silica particles on the characteristics of the HPMC ODFs. The ratio of polymer/additive is shown in w/w as dry powder: HPMC/silica = 60:40 (w/w). The ratio of total solid ingredients and solvent: solid/solvent = 1:10 (w/w). Solvent: ethanol/distilled water = 2:1 (w/w). Bars: Tensile strength on the first (left) vertical axis. Circles: Disintegration time on the second (right) vertical axis. 6
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Fig. 7. The effect of IPs on the disintegration time of the HPMC ODFs loaded with donepezil hydrochloride (DH). The ratios of polymer/API are shown in w/w as dry powder. The ratio of polymer/additives is shown in w/w as dry powder: HPMC/MCC = 60:40 (w/w). MCC particles: # MP102.
indicating the brittleness of these films. The increase in the DH concentration did not markedly impact the tensile strength, elongation, or elastic modulus (Table 4). Taking all of these results together, it is apparent that also in the case of HPMC films loaded with DH, the addition of IPs, i.e., MCC particles, decreased the disintegration time. The larger size of IPs decreased the disintegration time more, but the addition of large IPs more markedly reduced the mechanical strength of the films.
one of the most suitable APIs for ODF preparations. Although we have already evaluated ODFs loaded with DH using an electronic taste-sensing system [24], this oral dosage form should be further tested to obtain a more appropriate formulation in the future. The effects of the IPs on the disintegration properties of ODFs loaded with DH are illustrated in Fig. 7. First, the effect of loading DH on the HPMC films was clear, and it decreased the disintegration time from approx. 55 s–40 s. The results also elucidated that the addition of IPs (polymer/MCC [MP102] = 60:40) decreased the disintegration times of HPMC films from 55 s to 26 s. We then evaluated the addition of MCC (MP102) particles at the ratio of 60:40 in HPMC films loaded with 13%–40% DH (Table 4). For the HPMC films loaded with DH at any ratio, the addition of MCC decreased the disintegration time from approx. 27 s–15 s. However, the 26% DH weakened the films so much that they could not be handled at the mechanical test, and the 40% DH disturbed the film forming. Fig. 8 summarizes our observations of HPMC films with added MCC (MP102) without loading DH, and with 26% loading. A crack could be seen around the edge of the films with 26% DH,
4. Conclusions We prepared orally disintegrating films (ODFs) from HPMC and added water-insoluble particles (IPs) to enhance the films’ disintegration properties. MCC, L-HPC, and silica as insoluble particles were added to the formulations of ODFs. Donepezil hydrochloride was loaded as a model API. The disintegration times were determined by means of the Petri dish method, and mechanical properties (i.e., the tensile strength, elastic modulus and elongation) were characterized with the use of a creep meter. The results can be summarized as follows:
Fig. 8. Observation of ODFs. HPMC film with MCC (polymer/MCC = 60/40). a: Unloaded. b: Loaded with 26% DH. 7
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(1) The addition of IPs decreased the disintegration time, but it lowered the tensile strength, depending on the ratio of IPs per the filmforming polymer. (2) The larger the size of the IPs was, the more that the disintegration time of the ODFs decreased. In contrast, the shape of the particles in the case of silica did not markedly influence the characteristics of the ODFs. (3) Although the addition of APIs also affected the disintegration properties of the ODFs, the addition of IPs decreased the disintegration times even in the cases of ODFs loaded with APIs.
[7]
[8]
[9] [10]
[11]
We observed that the addition of IPs shortened the disintegration time of ODFs without further additives, and when a suitable amount of IPs was added, the mechanical strength was not significantly weakened. ODFs formulated with IPs to improve the disintegration properties were thus successfully designed, and we were able to verify that this formulation concept allows the application of various APIs to ODFs.
[12] [13] [14] [15]
Funding [16]
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
[17]
Declaration of competing interest
[18]
The authors report that they have no conflicts of interest regarding this study.
[19]
References
[20]
[1] A.F. Borges, C. Silva, J.F.J. Coelho, S. Simões, Oral films: Current status and future perspectives I – Galenical development and quality attributes, J. Control. Release 206 (2015) 1–19. [2] E.M. Hoffmann, A. Breitenbach, J. Breitkreutz, Advances in orodispersible films for drug delivery, Expert Opin. Drug Deliv. 8 (2011) 299–316. [3] R.P. Dixit, S.P. Puthli, Oral strip technology: overview and future potential, J. Control. Release 139 (2009) 94–107. [4] M. Slavkova, J. Breitkreutz, Orodispersible drug formulations for children and elderly, Eur. J. Pharm. Sci. 75 (2015) 2–9. [5] A.F. Borges, C. Silva, J.F.J. Coelho, S. Simões, Oral films: Current status and future perspectives II – Intellectual property, technologies and market needs, J. Control. Release 206 (2015) 108–121. [6] V. Reiner, N. Giarratana, N.C. Monti, A. Breitenbach, P. Klaffenbach, Rapidfilm®: an
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innovative pharmaceutical form designed to improve patient compliance, Int. J. Pharm. 393 (2010) 55–60. A.F. Borges, C. Silva, J.F.J. Coelho, S. Simões, Outlining critical quality attributes (CQAs) as guidance for the development of orodispersible films, Pharm. Dev. Technol. 22 (2017) 237–245. F. Kianfar, B.Z. Chowdhry, M.A. Antonijevic, J.S. Boateng, Novel films for drug delivery via the buccal mucosa using model soluble and insoluble drugs, Drug Dev. Ind. Pharm. 38 (2012) 1207–1220. K.B. Liew, Y.T.F. Tan, K. Peh, Effect of polymer, plasticizer and filler on orally disintegrating film, Drug Dev. Ind. Pharm. 40 (2014) 110–119. H. Takeuchi, R. Yamakawa, T. Nishimatsu, Y. Takeuchi, K. Hayakawa, N. Maruyama, Design of rapidly disintegrating drug-delivery films for oral doses with hydroxypropylmethylcellullose, J. Drug Deliv. Sci. Technol. 23 (5) (2013) 471–475. L.A. Felton, J.W. McGinity, Influence of insoluble excipients on film coating systems, Drug Dev. Ind. Pharm. 28 (2002) 225–243. L.A. Felton, S.C. Porter, An update on pharmaceutical film coating for drug delivery, Expert Opin. 10 (2013) 421–435. H.P. Osterwald, Properties of film-formers and their use in aqueous systems, Pharm. Res. 2 (1985) 14–18. P.M. Desai, C.V. Liew, P.W.S. Heng, Review of disintegrants and the disintegration phenomena, J. Pharm. Sci. 105 (2016) 2545–2555. L. Zhang, M. Aloia, B. Pielecha-Safira, H. Lin, P.M. Rajai, K. Kunnath, R.N. Davé, Impact of surperdisintegrants and film thickness on disintegration time of strip films loaded with poorly water-soluble drug microparticles, J. Pharm. Sci. 107 (2018) 2107–2118. Y. Takeuchi, K. Umemura, K. Tahara, H. Takeuchi, Formulation design of hydroxypropyl cellulose films for use as orally disintegrating dosage forms, J. Drug Deliv. Sci. Technol. 46 (2018) 93–100. F. Cilurzo, I.E. Cupone, P. Minghetti, F. Selmin, L. Montanari, Fast dissolving films made of maltodextrins, Eur. J. Pharm. Biopharm. 70 (2008) 895–900. FDA, U.S. Food and drug administration. Guidance for Industry – Orally disintegrating tablets, https://www.fda.gov/downloads/Drugs/.../Guidances/ ucm070578.pdf, (2008) , Accessed date: 1 March 2019. I. Fransceshini, F. Selmin, S. Pagani, P. Minghetti, F. Cilurzo, Nanofiller for the mechanical reinforcement of maltodextrins orodispersible films, Carbohydr. Polym. 136 (2016) 676–681. F. Cilurzo, U.M. Musazzi, S. Franze, F. Selmin, P. Minghetti, Orodispersible dosage forms: biopharmaceutical improvements and regulatory requirements, Drug Discov. Today 23 (2018) 251–259. S.M. Krull, R. Sularla, A. Afolabi, M. Li, Y. Ying, Z. Iqbal, E. Bilgili, R.N. Davé, Polymer strip films as a robust, surfactant-free platform for delivery of BCS Class II drug nanoparticles, Int. J. Pharm. 489 (2015) 45–57. Y. Yan, J.S. Woo, J.H. Kang, C.S. Young, H. Choi, Preparation and evaluation of taste-masked donepezil hydrochloride orally disintegrating tablets, Biol. Pharm. Bull. 33 (8) (2010) 1364–1370. K.B. Liew, Y.T.F. Tan, K.K. Peh, Characterization of oral disintegrating film containing donepezil for Alzheimer disease, AAPS PharmSciTech 13 (1) (2012) 134–142. Y. Takeuchi, R. Usui, H. Ikezaki, K. Tahara, H. Takeuchi, Advanced technique using an electronic taste-sensing system to evaluate the bitterness of orally disintegrating films and the evaluation of model films, Int. J. Pharm. 531 (2017) 179–190.
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Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst
Novel use of insoluble particles as disintegration enhancers for orally disintegrating films
T
Yoshiko Takeuchi∗, Tomoka Nishimatsu, Kohei Tahara, Hirofumi Takeuchi∗∗ Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu, 501-1196, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Orally disintegrating film Disintegration time Insoluble particle Hydroxypropyl methylcellulose Silica
The most important issue in the design of orally disintegrating films (ODFs) is the control of the ODFs' disintegration properties. A better understanding of the mechanisms of ingredients used to promote or disturb the disintegration time of ODFs would improve the development of ODF formulations. Here we focused on the advantage of adding insoluble particles (IPs) to improve the disintegration times of ODFs. We also verified the undesirable impact of the use of IPs on the mechanical properties of ODFs. We used hydroxyproplyl methylcellulose (HPMC), which is one of the most commonly used film-forming polymers for ODFs, as a film former. Films were prepared using the solution/solvent casting method. Microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and silica with different particle sizes and shapes were added in the film formulations as IPs. As expected, the addition of IPs shortened the disintegration times of the films. The larger particles had a greater impact compared to the smaller particles. However, the addition of larger particles decreased the films’ tensile strength. Our results demonstrate the effectiveness of IPs for shortening the disintegration times of HPMC films loaded with active pharmaceutical ingredients.
1. Introduction Various types of pharmaceutical thin films have been developed. Borges et al. [1] reviewed the status of oral films and their attributes in 2015. These dosage forms designated with the different terms and definitions described by Borges et al. should be carefully understood. For example, there are both mucoadhesive and non-mucoadhesive films. Pharmaceutical thin films can also be administered via oral absorption (i.e., by sublingual, buccal, and palatal administration), which does not subject the drug incorporated in the film to degradation from first-pass metabolism, or as gastrointestinal (GI) absorption films, which do subject the drug to first-pass metabolism. Hoffman et al. [2] pointed out that there are also some types of oral films that are distinguished based on their disintegration times and designs, and they noted that there was no clear dividing line. Orally disintegrating films (ODFs), which we investigated in the present study, are pharmaceutical thin films that disintegrate rapidly when placed in the oral cavity [2,3]. These films are very helpful in the treatment of dysphagic individuals such as those who cannot swallow medicines easily, bed-prone patients, geriatric patients, and pediatric patients [1]. ODFs were initially developed as over-the-counter (OTC) drugs, but ODFs for prescription drugs for children have also been ∗
developed [4]. Many types of ODFs are now available on the OTC drug market and for prescription drugs [5,6]. ODFs are prepared with polymers and other additives such as plasticizers, flavors, colors, sweeteners, surfactants, thickening agents, disintegrants (disintegration enhancers), and antioxidants as well as active pharmaceutical ingredients (APIs) [7]. The major ingredients that determine film's properties are the film-forming water-soluble polymers used, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and pullulan (PUL) [2]. The addition of the other agents mentioned above and APIs is well known to affect to the properties of ODFs [8,9]. We demonstrated that two additives formulated in films affected the films' tensile strength and disintegration time [10]. In the pharmaceutical preparations research field, water-soluble polymers and the properties of free films made of those polymers have been well investigated as film-formers in the formulations of filmcoated tablets. In those investigations of free films, some insoluble particles (IPs) were usually added to the film-forming polymer solution and dispersion as pigments and as opacifying agents [11–13]. The size and shape of the IPs were also reported to affect the dissolution of a drug from coated tablets, and it was noted that the larger the IPs in the polymer were, the more slowly that the drug was released [2,11,12].
Corresponding author. Corresponding author. E-mail address: [email protected] (Y. Takeuchi).
∗∗
https://doi.org/10.1016/j.jddst.2019.101310 Received 3 July 2019; Received in revised form 18 September 2019; Accepted 1 October 2019 Available online 09 October 2019 1773-2247/ © 2019 Elsevier B.V. All rights reserved.
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In the design and development of ODF formulations, it is of paramount importance that the disintegration time be decreased. Disintegrants for orally disintegrating tablets (ODTs) have been reported to enhance the disintegration based on various mechanisms, i.e., swelling, wicking, and others [14]. However, we suspected that these mechanisms are not suitable for decreasing the disintegration times of ODFs, and that these disintegrants are usually not able to decrease the disintegration times of ODFs. Before ODFs are cast and dried, the disintegrants should be added into the solutions/dispersions of polymers, and, at this stage, the disintegrants have already absorbed water and swelled. Zhang et al. (2018) [15] investigated the impact of the use of two types of superdisintegrants on the disintegration time of strip films loaded with a poorly water-soluble drug. They observed that a large amount of added superdisintegrants decreased the disintegration time for all films, and that in the case of thick films (90–100 μm thick), the disintegration time was reduced from 280 s to 160 s. However, this decrease in the disintegration time is not large enough for ODFs, which ideally would disintegrate in < 30 s. We have observed that different types of insoluble additive particles, i.e., microcrystalline cellulose (MCC) and partially pregelatinized starch, affected the properties of ODFs prepared with HPMC and lowsubstituted hydroxypropyl cellulose (L-HPC) [10]. Liew et al. (2014) [9] also reported that a decrease in the concentration of HPMC produced films with rapid disintegration, and that the formulation with the highest amount of MCC disintegrated faster than the formulations with lesser amounts of MCC. The effects of insoluble ingredients on the disintegration time of ODFs should be evaluated systematically. We conducted the present study to clarify the feasibility of the addition of IPs to ODF formulations as a disintegration enhancer, i.e., for decreasing the disintegration times. At the same time, we evaluated the mechanical properties of ODFs to detect any undesirable impacts of IPs. We also evaluated the effects of IPs on the disintegration times of ODFs loaded with active pharmaceutical ingredients. Fig. 1 is a flow diagram of the material system used in this study.
Table 1 Size distribution of the insoluble particles. Code
D10
D50
D90
MCC
PH-F20JP PH-101 PH-102
MPF20 MP101 MP102
6.5 ± 0.3 20.7 ± 0.4 27.3 ± 1.0
16.1 ± 0.8 59.3 ± 1.1 83.3 ± 2.6
27.0 ± 0.9 116.0 ± 0.7 218.1 ± 2.9
L-HPC
LH-11 LH-21 LH-31
LH11 LH21 LH31
11.1 ± 1.2 11.9 ± 2.3 6.6 ± 0.3
31.2 ± 0.8 32.9 ± 2.5 17.0 ± 0.7
87.6 ± 7.4 106.3 ± 11.7 29.9 ± 3.8
Silica
Sylysia 350 Sylysia 380 Sylospher C1054 Sylospher C0809
SY350 SY380 S1054
1.7 ± 0.0 2.1 ± 0.0 2.3 ± 0.1
3.6 ± 0.0 5.6 ± 0.4 3.8 ± 0.0
5.8 ± 0.0 9.7 ± 0.6 5.8 ± 0.2
S0809
3.9 ± 0.2
7.2 ± 0.3
11.2 ± 0.6
Unit: μm.
2.2. Methods 2.2.1. Particle size measurement We conducted a laser diffraction scattering analysis (LDSA-2400A; Nikkiso, Tokyo) to determine the distributions of the IPs. The results are summarized in Table 1. 2.2.2. The preparation of the films Pharmaceutical films were formed by the solution/solvent casting method [16]. The formulations of the ODFs are shown in Tables 2–4. The ratio of polymer/IPs and the ratio of total solid ingredients/solvent are provided individually in these tables. The procedures are described briefly as follows: (a) HPMC powder was mixed with IPs (and, if necessary, other additives) before the solvent was used. (b) The solutions/dispersions were prepared by dispersing HPMC or an HPMC mixture into ethanol, and then dissolving with added water. (c) After the solutions/dispersions were degassed, the films were spread on a base film (polypropylene: Pylen®; Toyobo, Osaka, Japan), fixed onto a heat-resisting glass plate with the use of a YBAtype baker applicator (Yoshimitsu Seiki, Tokyo). The clearance between the bar of the applicator and the base film surface was adjusted depending on the targeted film thickness. (d) The films were kept in a dry chamber (KCV-4D; Advantec, Tokyo) with a 40 °C air current for ≥2 h to evaporate the solvent or water. (e) The films were cut into 20 mm × 30 mm pieces without removing the base films, in order to prevent the films and base films from sticking together. (f) The films were stored in a tight container (as defined in the 17th Japanese Pharmacopeia) at room temperature (1°–30 °C; as defined by the 17th Japanese Pharmacopeia) for ≥24 h to maintain the same evaluation condition, and the films were then evaluated.
2. Materials and methods 2.1. Materials Hydroxypropyl methylcellulose (HPMC; TC-5R, substitution type: 2910, viscosity; 6 (mPa s); Shin-Etsu Chemicals, Tokyo) was examined as a polymeric film former. These viscosity values were taken from the supplier's catalogue; they were determined for a 2.0% solid ratio in aqueous solution at 20 °C. As water-insoluble additives, we used microcrystalline cellulose (MCC; MPF20, MP101, MP102, MU711, MU702; Ceolus® PH-F20JP, PH-101, PH-102, UF-711, UF-702; Asahi Kasei Chemicals, Tokyo), low-substituted hydroxypropyl cellulose (LHPC; LH-11, LH-21, LH-31; Shin-Etsu Chemicals) and silica (SY350, SY380, S1054, S0809; Sylysia 350, Sylysia 380, Sylospher C-1054, Sylospher C-0809; Fuji Silysia, Tokyo). Donepezil hydrochloride (DNH; lot. no. DNPJN0K001), supplied as a gift sample, was used as an API.
2.2.3. The evaluation of the films 2.2.3.1. Film thickness. The film thickness was measured with a micrometer (Mitutoyo, Kawasaki, Japan) with 1-μm accuracy. Each sample film was measured at three different positions per strip. 2.2.3.2. Tensile strength. The mechanical property of tensile strength was measured with a creep meter (RE-3305S; Yamaden, Tokyo) as described [16]. The film strips (sample size: 20 mm × 30 mm) were vertically fixed with two grips 17 mm apart (i.e., the initial separation distance), and then pulled at a constant rate of 0.5 mm/s. The maximum fracture force, i.e., the force reached just before the film strips ruptured, was recorded. The measurements were repeated three times using three film samples for each type of formulation. The tensile
Fig. 1. Flow diagram of the material system. 2
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Table 2 Formulations and characteristics of ODFs with added insoluble particles. Polymer/Additives
HPMC %
MCC %
L-HPC %
Total %
Thickness μm
Weight mg
Tensile strength MPa
Elastic modulus MPa
Elongation %
100/0 80/20 60/40 40/60 20/80 80/20 60/40 40/60 20/80
100 80 60 40 20 80 60 40 20
– 20 40 60 80 – – – –
– – – – – 20 40 60 80
100 100 100 100 100 100 100 100 100
30.4 54.7 55.1 60.1 62.6 53.8 45.6 43.6 62.9
23.0 24.8 21.5 20.2 17.3 23.5 17.4 13.3 15.5
66.1 24.4 14.2 2.0 0.6 56.7 22.1 4.5 0.3
864.6 465.4 454.0 224.5 105.8 901.6 866.1 369.0 ND
8.1 6.5 3.4 0.9 0.4 8.4 2.8 1.2 ND
Ratio of total solid ingredients/solvent: solid/solvent = 1:10 (w/w). Solvent: ethanol/distilled water = 2:1(w/w).
formulated, and then their effects on the properties of ODFs were verified [10]. The morphologies of the MCC particles and the L-HPC particles are shown in Fig. 2. Silica particles are frequently added as a carrier for pharmaceutics, or as an anti-adhesive agent, a diluent, a glidant to improve flowability, and more, and these particles have an individualized small size and differing shapes (in the Fuji Silysia product catalog). The morphologies of the silica particles are shown in Fig. 3.
strength (MPa) was calculated as the fracture force divided by the crosssectional area of the film: Tensile strength (MPa) = fracture force (N)/cross-sectional area (mm2). The elastic modulus (MPa) and the elongation at break (%) were computed during the tensile test. 2.2.3.3. Disintegration time. We used the Petri dish method to determine the disintegration times [16]. The measurements were repeated three times using three film samples for each type of formulation. With this method, both the measurement of the disintegration time and the observation of the disintegrating behaviors can be performed during the tests.
3.1. The effect of insoluble particles (IPs) on the disintegration and mechanical properties of the unloaded ODFs 3.1.1. The effects of the polymer/MCC and L-HPC particles ratio The HPMC ODFs with added MCC (MPF20) and L-HPC (LH31) were prepared (based on the formulations in Table 2) and evaluated. These two IPs are very commonly used additives in the design of pharmaceutical tablets. The particle sizes of MPF20 and LH31 are approx. 17 μm (Table 1). The ratio of HPMC and each IP was in the range of 100:0 to 20:80 (Table 2). We attempted to design the ODFs with both high mechanical strength and a low disintegration time, even with the addition of IPs. We thus measured the tensile strength values and disintegration times to evaluate each of the designed ODFs. The disintegration times of the ODFs with the IPs (i.e., the MCC and L-HPC particles) are shown in Fig. 4. For the films without IPs, i.e., the HPMC films (100:0), the disintegration time was nearly 60 s. The addition of IPs reduced the disintegration time. The times were 42 s and 40 s for the films with MCC and L-HPC at the ratio of 80:20, respectively. The higher the amount of IPs was, the shorter the disintegration time became. The films for which the ratio of polymer/MCC and L-HPC was over 60:40 showed disintegration times > 30 s. In contrast, the films for which the ratio of polymer/IPs was under 40:60 showed the targeted disintegration time of approx. ≤30 s. At present, the quality control regarding the disintegration time of orally disintegrating formulations is recognized as “No specific guideline on quality available [17].” Therefore, ODF products should be
2.2.4. Morphological observation A scanning electron microscope (JSM-T6510LV; Japan Electron, Tokyo) was used to observe the particles. 3. Results and discussion ODFs are prepared from a water-soluble polymer. Among such polymers, HPMC, HPC, and PUL are considered suitable as film-formers because they have the advantages of being tasteless, odorless, and easily dissolved in water. HPMC, which is a nonionic water-soluble cellulose ether prepared from cellulose, does not interact with APIs and is the most frequently used as a film-forming polymer for the marketed ODFs [3,7]. We used HPMC as a film-forming polymer in the present study in the following sections. The three insoluble particles described below were added into the polymer solutions as a disintegration enhancer. Microcrystalline cellulose (MCC) is a representative filler and a disintegrant used for pharmaceutical solid-dosage forms. Low-substituted hydroxypropyl cellulose (L-HPC) is also a representative disintegrant used for pharmaceutical tablets, and it is water-insoluble. In our previous study, MCC as a filler and L-HPC as one of the film formers were Table 3 Formulation and characteristics of ODFs added silica particles. Code
No additives SY350 SY380 S1054 S0809
HPMC %
100 60 60 60 60
Silica % Sylysia 350
Sylysia 380
Sylospher C1054
Sylospher C0809
– 40 – – –
– – 40 – –
– – – 40 –
– – – – 40
Total %
Thickness μm
Weight mg
Tensile strength MPa
Elastic modulus MPa
Elongation %
100 100 100 100 100
30.4 40.9 38.6 31.3 34.4
23.0 24.8 17.0 20.9 18.0
66.1 32.6 15.5 31.1 23.9
864.6 467.3 464.6 675.2 586.9
8.1 9.0 3.9 5.2 4.9
Ratio of polymer/additives: HPMC/additive = 60/40 (w/w). Ratio of total solid ingredients/solvent: solid/solvent = 1:10 (w/w). Solvent: ethanol/distilled water = 2:1(w/w). 3
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Table 4 Formulation of films loaded with donepezil hydrochloride and added MCC particles. Content of donepezil hydrochloride
HPMC %
Microcrystallin cellulose MP102 %
Donepezil hydrochloride DH %
Total %
Thickness μm
Weight mg
Tensile strength MPa
Elastic modulus MPa
Elongation %
0% 13% 20% 26% 40%
60 52 48 44 36
40 35 32 30 24
– 13 20 26 40
100 100 100 100 100
84.2 101.0 111.3 117.2 ND
25.3 23.4 22.7 24.4 ND
5.6 6.3 5.2 4.7 ND
226.6 222.5 219.5 155.7 ND
2.6 2.4 2.4 3.2 ND
Ratio of polymer/additive: HPMC/MCC = 60/40. Ratio of total solid ingredients (except DH)/solvent: solid/solvent = 1:10 (w/w). Solvent: ethanol/distilled water = 2:1(w/w).
Fig. 2. Morphology observations of the insoluble particles (IPs). MCC particles. (a) PH-F20JP, (b) PH-101, and (c) PH-102. L-HPC particles: (d) LH-31, (e) LH-21, and (f) LH-11. Bars = 50 μm.
particles are usually added as pigments and opacifying agents. The study by Felton and McGinity [11] and references therein stated that the tensile properties of HPMC films were affected as a function of the titanium dioxide concentration. Our present findings are similar to the above described results regarding the influence of IPs on the mechanical properties of films. The addition of IPs decreased the tensile strength and shortened the disintegration times. Cilurtz et al. studied maltodextrin fast-dissolving films with an active drug and MCC (Avicel® PH 101, particle dia. 50 μm, in the Asahi Kasei Chemicals catalog). Based on their results, those authors suggested that the dispersion of MCC in the maltodextrin matrix caused the formation of a non-continuous film and originated the initial point of the break during the tensile stress testing [20]. The formation of polymer films is thought to be composed of an uninterrupted entanglement of coiled molecular chains, and the primary cause of instability of the coated film is the so-called internal stress in the film after it has dried [13]. It is thought that the addition of IPs to a polymer solution affects the formation of the entanglement of chains and contributes to the build-up of internal stress. The entanglement of the macromolecular chains in film is decreased by the addition of IPs, and this decreases the strength and promotes the film's disintegration under water.
developed based on the targeted disintegration time, i.e., < 30 s, in reference to the U. S. Food and Drug Administration (FDA) guidance [18]. The tensile strength values of the ODFs with IPs are also shown in Fig. 4. For the films without IPs, the tensile strength was > 60 MPa. The addition of IPs lowered the tensile strength. When the amount of IPs was increased, the tensile strength decreased. Table 2 provides the elastic modulus and elongation values with the tensile strength. The addition of IPs to the films also decreased the elastic modulus and the elongation along with the tensile strength, resulting in the higher brittleness of these films. For the ODFs with L-HPC with 20:80 as the ratio of polymer/IPs, the films’ tensile strength was not high enough to evaluate. In the case of the films for which the ratio of polymer/IPs was over 40:60, the strength could be maintained over the limit to ensure the ODF handling, i.e., 2 MPa [10]. During the tensile tests, we obtained the stress-strain curves, which provide information about the mechanical characteristics of the films. No stress-strain curve is provided herein due to a limitation of this article's length, but the curves of HPMC ODFs with or without IPs showed the same properties. This result suggested that the addition of IPs could change the strength but not the fracture characteristics [17,19]. In the pharmaceutical preparations research field, water-soluble polymers and the properties of free films made of those polymers have been well investigated as film-formers in formulations of film-coated tablets [11–13]. In a polymer solution and dispersion, some insoluble
3.1.2. The effect of the size of the IPs on the ODFs’ characteristics In their investigation of a film-coating system, Felton and McGinity 4
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Fig. 3. Morphology observations of the silica particles. (a) Sylysia 350, (b) Sylysia 380, (c) Sylospher C-1504, and (d) Sylospher C-0809. Bars = 10 μm.
(2002) [11] observed that films containing larger talc particles exhibited a higher modulus compared to films with smaller particles, and that the inclusion of more irregularly shaped particles in film-coating formulations resulted in greater increases in the elastic modulus of the polymer film compared to the inclusion of spherical particles. Here we added IPs (MCC and L-HPC) of different sizes to the film formulations and prepared and evaluated the films in order to investigate the effects of the IPs’ size on the ODF properties. The particle sizes of MCC and LHPC are shown in Table 1. As we noted above, the advantages and drawbacks of the addition of IPs can be determined, and our results demonstrated that the placebo ODFs prepared at an 80:20 ratio of polymer/IPs, did not show a suitable reduction in the disintegration time, and the placebo ODFs prepared at 40:60 could not maintain adequate strength. In this part of our study, the ratio of polymer/IPs for all films was kept at 60:40 (w/w). Fig. 5 illustrates the effects of the particle size of the IPs on the disintegration time and tensile strength of HPMC films. The disintegration time decreased with the increase in the particle size, and at the same time the tensile strength decreased. There was no significant
Fig. 5. The effect of the particle size of the IPs on the characteristics of the HPMC ODFs. The insoluble particles were MCC and L-HPC. The ratio of polymer/additive is shown in w/w as dry powder: HPMC/additives = 60:40 (w/w). Squares: Tensile strength on the first (left) vertical axis. Circles: Disintegration time on the second (right) vertical axis.
Fig. 4. The effects of the amount of additives on the characteristics of the HPMC ODFs. Insoluble particles: (a) MCC: MPF20, (b) L-HPC: LH31. The ratios of polymer/additive are shown in w/w as dry powder. Solvent: ethanol/distilled water = 2:1 (w/w). Bars: Tensile strength on the first (left) vertical axis. Circles: Disintegration time on the second (right) vertical axis.
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HPC (Fig. 4, Table 2), respectively. Compared to those results, the tensile strength of the films with silica particles were higher (from 32.6 to 15.5 MPa), as expected, because the sizes of the silica particles are smaller than those of L-HPC and MCC particles. The elastic modulus of the films with silica particles was not much different from those of the films with MCC and L-HPC. Compared to the elongation of the films with larger IPs, the elongation values of the films with silica particles were slightly higher. According to these results, when IPs are added to improve the characteristics of ODFs, we must consider the sizes of the particles more than their shapes. In the design of ODF formulations, the IP size must be considered critically important to the palatability of the ODFs.
difference between the effects of MCC and those of L-HPC. When the particle size is larger, the macromolecular chain entanglement density would be more decreased, and thus water can easily permeate the films, improving the disintegration. On the other hand, increasing the particle size lowered the tensile strength. We speculate that the reason for this is because the structure, which is kept sturdy with the entanglement of the molecular chains, was disturbed by the existence of the IPs. 3.1.3. The effects of silica IPs with different sizes and shapes on the ODFs’ characteristics Studies of the film-coated tablets indicated that larger particles of a pigment disrupted the interfacial bonding between the polymer and the tablet surface and that the shape of the pigment influenced the elastic modulus of the polymeric films [12]. The size and shape of IPs were also reported to affect the dissolution of a drug from coated tablets [11]. The larger the IPs in the polymer were, the more slowly the drug was released. Felton and Porter [12] stated that the mechanical strength was affected by the addition of IPs, but they did not focus on the impact of the addition of IPs on the film disintegration properties. To investigate the effect of the IPs’ size and shape on ODF properties, we chose silica particles. Silica is a useful additive in pharmaceutical solid-dosage formulations, with many applications; e.g., as an anticaking agent, a diluent, a carrier, and an agent that improves flowability. Different sizes and different shapes of silica particles are available (Fuji Silysia Chemical catalog). The silica particles used herein were clearly smaller than the L-HPC and MCC particles described in the previous section. We added four types of silica particles to the formulation to investigate their effects on the enhancement of disintegration properties. The SY350 and SY380 particles had irregular shapes, and the S1054 and S0809 particles were spherical (Fig. 3). SY350 and S1054 were smaller than SY380 and S0809, respectively (Table 1). Fig. 6 illustrates the characteristics of the films to which these silica particles were added. The addition of silica particles decreased the disintegration time from approx. 60 s to < 40 s. The disintegration times of the films with larger silica particles were slightly lower than those of the films with smaller silica particles. In contrast, the difference in the particle shapes, i.e., irregular or spherical, did not affect the disintegration times of the films (from approx. 38 s–21 s). Compared to the size of the particles, the shape of the silica particles had less effect on the film characteristics. The results in Fig. 6 and Table 3 demonstrated that the addition of silica particles also lowered the tensile strength from 60 MPa to approx. ≤30 MPa, and that the addition of silica particles (except for SY350) decreased both the elastic modulus and the elongation along with the tensile strength. We noted above in Section 3.1.1 that the tensile strength of the films with the polymer/IPs ratio of 60:40 showed a decrease in tensile strength to 14.2 and 22.1 MPa for the films added with both MCC and L-
3.2. The effect of IPs on the disintegration and mechanical properties of ODFs loaded with APIs 3.2.1. Preparing ODFs loaded with APIs (as preliminary experiments) We verified the effects of IPs on the properties of ODF as described above, and it had already been indicated that drug loading affects the disintegration and mechanical properties of ODFs. For example, in our previous studies, ibuprofen loaded into HPC films delayed the disintegration more than ascorbic acid and acetaminophen loading, depending on the properties of the APIs [16]. The impact of the loading of drug (poorly water-soluble) nanoparticles on the mechanical properties of strip films was also investigated [21]. The tensile strength and elastic modulus did not change significantly, but the elongation decreased dramatically with the increase in the amount of drug nanoparticle loading. Liew et al. (2018) [9] also investigated that the impact of the additions of mannitol and MCC (Avicel® PH 102, particle dia. 100 μm in the company catalog) at different ratios (from 3:4 to 0:1) on the properties of ODFs loaded with APIs. Their results also demonstrated that the increase in the content of MCC decreased the tensile strength and the elongation, and slightly decreased the bending flexibility. It was also reported that a decrease in the mannitol content and an increase in the MCC content reduced the disintegration time [9]. As preliminary experiments, we prepared ODFs loaded with APIs. Donepezil hydrochloride (DH), ibuprofen (IBP), famotidine (FAM), ascorbic acid (ASA) and acetaminophen (AAP) were used as model drugs loaded into HPMC ODFs. Our evaluation of these ODFs revealed that DH loaded on HPMC ODFs without IPs decreased the disintegration time from approx. 55 s–13 s, whereas IBP loaded increased the disintegration time from 55 s to 59 s. In the case of ODFs with IPs, the loading of DH, FAM, ASA, or AAP also decreased the disintegration time from approx. 27 s to 12–19 s, but IBP loading increased the disintegration time to 43 s. The loading of APIs thus affected the disintegration time of the films depending on the types of APIs, as expected. It seemed that the impacts of the above APIs on the disintegration properties were due to their water solubility. For example, IBP is “practically insoluble in water” and DH is “soluble in water” (Japanese Pharmacopeia 17th edition). Based on these findings, we next investigated the effect of IPs on the disintegration times of ODFs under the condition of loading with APIs. 3.2.2. The effects of IPs on the characteristics of ODFs loaded with DH As noted above, the loading of APIs affects the ODFs characteristics, and it could also be predicted that the addition of IPs would improve the disintegration times of loaded films. We used DH as a model API; IBP could not be used due to the possibility of its crystallization in the films. MCC (MP102) was used as the IP. Donepezil hydrochloride is a very useful active ingredient for medication used to treat Alzheimer's disease, but it is known to have a strongly bitter taste [22,23]. It has been prescribed in commercial ODTs and ODFs, e.g., Aricept® (Eisai Co., Tokyo) and Donepezil Hydrochloride OD film (Elmed Eisai Co., Tokyo). The ODTs and ODFs are provided at doses of 3 mg, 5 mg and 10 mg and are generally required by elderly patients. Therefore, DH is
Fig. 6. The effect of silica particles on the characteristics of the HPMC ODFs. The ratio of polymer/additive is shown in w/w as dry powder: HPMC/silica = 60:40 (w/w). The ratio of total solid ingredients and solvent: solid/solvent = 1:10 (w/w). Solvent: ethanol/distilled water = 2:1 (w/w). Bars: Tensile strength on the first (left) vertical axis. Circles: Disintegration time on the second (right) vertical axis. 6
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Fig. 7. The effect of IPs on the disintegration time of the HPMC ODFs loaded with donepezil hydrochloride (DH). The ratios of polymer/API are shown in w/w as dry powder. The ratio of polymer/additives is shown in w/w as dry powder: HPMC/MCC = 60:40 (w/w). MCC particles: # MP102.
indicating the brittleness of these films. The increase in the DH concentration did not markedly impact the tensile strength, elongation, or elastic modulus (Table 4). Taking all of these results together, it is apparent that also in the case of HPMC films loaded with DH, the addition of IPs, i.e., MCC particles, decreased the disintegration time. The larger size of IPs decreased the disintegration time more, but the addition of large IPs more markedly reduced the mechanical strength of the films.
one of the most suitable APIs for ODF preparations. Although we have already evaluated ODFs loaded with DH using an electronic taste-sensing system [24], this oral dosage form should be further tested to obtain a more appropriate formulation in the future. The effects of the IPs on the disintegration properties of ODFs loaded with DH are illustrated in Fig. 7. First, the effect of loading DH on the HPMC films was clear, and it decreased the disintegration time from approx. 55 s–40 s. The results also elucidated that the addition of IPs (polymer/MCC [MP102] = 60:40) decreased the disintegration times of HPMC films from 55 s to 26 s. We then evaluated the addition of MCC (MP102) particles at the ratio of 60:40 in HPMC films loaded with 13%–40% DH (Table 4). For the HPMC films loaded with DH at any ratio, the addition of MCC decreased the disintegration time from approx. 27 s–15 s. However, the 26% DH weakened the films so much that they could not be handled at the mechanical test, and the 40% DH disturbed the film forming. Fig. 8 summarizes our observations of HPMC films with added MCC (MP102) without loading DH, and with 26% loading. A crack could be seen around the edge of the films with 26% DH,
4. Conclusions We prepared orally disintegrating films (ODFs) from HPMC and added water-insoluble particles (IPs) to enhance the films’ disintegration properties. MCC, L-HPC, and silica as insoluble particles were added to the formulations of ODFs. Donepezil hydrochloride was loaded as a model API. The disintegration times were determined by means of the Petri dish method, and mechanical properties (i.e., the tensile strength, elastic modulus and elongation) were characterized with the use of a creep meter. The results can be summarized as follows:
Fig. 8. Observation of ODFs. HPMC film with MCC (polymer/MCC = 60/40). a: Unloaded. b: Loaded with 26% DH. 7
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(1) The addition of IPs decreased the disintegration time, but it lowered the tensile strength, depending on the ratio of IPs per the filmforming polymer. (2) The larger the size of the IPs was, the more that the disintegration time of the ODFs decreased. In contrast, the shape of the particles in the case of silica did not markedly influence the characteristics of the ODFs. (3) Although the addition of APIs also affected the disintegration properties of the ODFs, the addition of IPs decreased the disintegration times even in the cases of ODFs loaded with APIs.
[7]
[8]
[9] [10]
[11]
We observed that the addition of IPs shortened the disintegration time of ODFs without further additives, and when a suitable amount of IPs was added, the mechanical strength was not significantly weakened. ODFs formulated with IPs to improve the disintegration properties were thus successfully designed, and we were able to verify that this formulation concept allows the application of various APIs to ODFs.
[12] [13] [14] [15]
Funding [16]
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
[17]
Declaration of competing interest
[18]
The authors report that they have no conflicts of interest regarding this study.
[19]
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