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Preparation and evaluation of novel multi-channel orally disintegrating tablets
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Preparation and evaluation of novel multi-channel orally disintegrating tablets Jiaojiao Yu , Xiaosong Shan , Shichao Chen , Xinli Sun , Pengjin Song , Ruidong Zhao , Liandong Hu PII: DOI: Reference:
S0928-0987(19)30381-1 https://doi.org/10.1016/j.ejps.2019.105108 PHASCI 105108
To appear in:
European Journal of Pharmaceutical Sciences
Received date: Revised date: Accepted date:
2 April 2019 28 August 2019 13 October 2019
Please cite this article as: Jiaojiao Yu , Xiaosong Shan , Shichao Chen , Xinli Sun , Pengjin Song , Ruidong Zhao , Liandong Hu , Preparation and evaluation of novel multichannel orally disintegrating tablets, European Journal of Pharmaceutical Sciences (2019), doi: https://doi.org/10.1016/j.ejps.2019.105108
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Preparation and evaluation of novel multi-channel orally disintegrating tablets Jiaojiao Yua,b , Xiaosong Shanb , Shichao Chenc,b , Xinli Sunc,b , Pengjin Songa , Ruidong Zhaoa , Liandong Hua,b,* a
School of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of
Hebei Province, Hebei University, Baoding, China. b
Affiliated Hospital of Hebei University, Baoding, China.
c
College of Medicine, Hebei University, Baoding, China.
*
Corresponding author: Liandong Hu: [email protected]
Abstract In this study, novel orally disintegrating tablets (ODTs) with multi-channel structure were designed to provide a rapid disintegration and subsequently drug dissolution. The ODTs were prepared using conventional wet compression through perforating channels with a special multi-channel mold. A modified sieve method was used in disintegration test as a quick screening tool during formulation evaluation. Moreover, physical properties, in vitro and in vivo disintegration time, dissolution rate and mouthfeel were also evaluated. The results demonstrated that developed multi-channel ODTs had good physical parameters, in vitro/in vivo correlation (IVIVC) of disintegration time and acceptable mouthfeel and dissolution. It also revealed that the presence of channels could accelerate the disintegration of ODTs because the channels could shorten the distance of water penetration and increased the specific surface area, resulting in a significant reduction in disintegration time. Above all, the introduction of novel multi-channel ODTs provided an alternative preparation method for ODTs and achieved good disintegration characteristics. Keywords: Orally disintegrating tablets, Multi-channel, Disintegration, Mouthfeel
1. Introduction Since the introduction of ODTs into the market in the 1980s, it has become one 2
of the most attractive oral drug delivery systems and has received much attention over the years (Quinten et al., 2012; Wagh et al., 2011). A lot of ODTs have already been commercially available (Aparna et al., 2018; Cilurzo et al., 2018; Reiner et al., 2010; Strickley et al., 2008; Vikas et al., 2006). As a kind of solid immediate preparation, ODTs can disintegrate and disperse with no water or only a small amount of water. When placed upon the tongue, it can disintegrate rapidly in the presence of saliva in a few seconds to 3 minutes. ODTs provide several advantages over traditional tablets: (1) It is convenient to take for patients with dysphagia, particularly for geriatric (Varia et al., 2007) and pediatric populations (Nagaraju et al., 2013) to improve patient compliance (Refaat et al., 2016; Stoltenberg and Breitkreutz, 2011). (2) The bioavailability of the drug can be improved, thereby improving drug absorption (Anup et al., 2018; Elwerfalli et al., 2016; Klingmann et al., 2013; Spomer et al., 2012). (3) The first-pass metabolism is avoided, with pregastric absorption in buccal and pharyngeal, resulting in improved drug efficacy (Clarke et al., 2003). There are several technologies that have been used to produce ODTs such as freeze-drying method, molding method, direct compression method, spray drying method, phase transformation method and so on (Fu et al., 2004; Shukla et al., 2009). The ODTs produced by freeze-drying process usually has very light with highly porous structures and rapid disintegration. However, the manufacturing process is relatively expensive, and the formulation is not stable at higher temperature and humidity (Rojas and Kumar, 2012, Batchelor et al., 2014). The ODTs produced by molding method using water-soluble components can rapidly disintegrate, but the mechanical strength of tablets is low (Heinemann et al., 2013; Wagh et al., 2011). From the pharmaceutical manufacturer's point of view, direct compression is the simplest and cost-effective preparation method of ODTs, which is suitable for drugs with good solubility, powder flowability and compressibility (Ved et al., 2011). But this technique often requires more disintegrants or effervescent agents. In the phase transformation method, the ODTs are compressed by low compression forces to keep porosity of the tablets followed by treatment using humidity or heat to imcrease mechanical properties. However, the use of humidity or heat treatment can decrease the stability to water-sensitive or heat-sensitive drugs.(Desai and Prabhakar, 2015). In addition, the bitterness and irritancy of the some drugs may affect the patient's acceptance (Anderson et al., 2005; Hu et al., 2013; Xu et al., 2008). In 3
order to solve the above problems of ODTs, we designed a novel multi-channel ODTs that were prepared by wet compression technology. Multiple channels formed in the ODTs allow water to quickly penetrate into the core and accelerate disintegration. Previously, caplets with perforated channels were prepared by fused deposition modelling (FDM) 3D printing technique, and the effect of channel width and length on drug release was investigated. The results demonstrated that the presence of the channel accelerated drug release (Sadia et al., 2018). However, due to the toxic side effects of materials, there are few printed materials that can be applied to the 3D printing technology field of preparation, and the high production costs further limits its application. In this study, the multi-channel ODTs were prepared by conventional wet compression with various excipients and dextromethorphan hydrobromide (DMB) as a model drug. The formulation was screened by a modified disintegration method. The quality control parameters such as diameter, thickness, weight difference, hardness and dissolution tests were evaluated. Simultaneously, in vitro and in vivo disintegration and the mouthfeel of ODTs were also performed. In addition, the effects of fillers and disintegrants on disintegration and dissolution were discussed and disintegration mechanism was also explored.
2. Materials and methods 2.1. Materials DMB as the model drug was purchased from Dingkang Pharmaceutical Co., Ltd. (Shanghai, China). Crospovidone (PVPP), carboxymethyl starch sodium (CMS-Na) and low-substituted hydroxypropyl cellulose (L-HPC) were purchased from Sunhere Pharmaceutical Excipients Co., Ltd. (Anhui, China). Glucose was purchased from Kemiou Chemical Reagent Co., Ltd. (Tianjin, China). Mannitol was purchased from Huadong Reagent Factory (Tianjin, China). Lactose was purchased from Shuangxuan Microbe Culture Medium Products Factory (Beijing, China). Aspartame was obtained from Shaoxing Yamei Biochemical Co., Ltd. (Zhejiang, China). All other chemicals and reagents were of analytical grade. 2.2. Methods 2.2.1. Preparation of multi-channel ODTs In this study, the multi-channel DMB-ODTs were manufactured by wet 4
compression method with a special mold. Before study, the disintegrants and fillers were separately milled and sieved through an 80 mesh screen. All ingredients of the ODT formulations were weighed and mixed thoroughly with water as a binder. The mixture was then transferred into a round mold (10.10 mm diameter) and compressed using a tablet press (TDP-5, Shanghai, China). Based on the preliminary studies, the compression force was chosen to 8-10 KN to achieve a thickness of about 4.12 mm. Nine channels were designed and the size of each channel was about 1.80 mm (Fig. 1). The prepared multi-channel ODTs were packed after drying at 40 ℃for 5 h. The detailed composition of ODTs was presented in Table 1.
Fig. 1. Multi-channel DMB-ODTs manufactured by wet compression method with a special mold. Table 1 Composition of ODT formulations. Ingredients (mg) DMB Glucose Mannitol Lactose PVPP CMS-Na L-HPC Aspartame Total Weight
F1
F2
F3
15 15 15 270 270 270 9 9 9 6 6 6 300 300 300
F4
Formulation Code F5 F6 F7 F8
15 15 270 270 9 9 6 6 300 300
15 15 15 270 204 204 66 66 9 9 9 6 6 6 300 300 300
F9
F10 F11 F12
15 204 66 9 6 300
15 135 135 9 6 300
15 135 135 9 6 300
15 135 135 9 6 300
2.2.2. Physical evaluation of multi-channel ODTs The diameter, thickness and channel size of ODTs were measured using digital 5
vernier caliper with sensitivity of 0.02 mm (Shanghai, China). The average weight and weight difference of ODTs were determined using an electronic balance (FA1104N, Shanghai, China). The hardness was conducted by a hardness tester (PYC-A, Shanghai, China). A moisture analyzer (MB23, Ohaus Corporation, Shanghai, China) equipped with a halogen dryer unit and a balance was used to measure the moisture content of ODTs. For moisture study, ten tablets were heated at 105 ℃using infrared heating component until the sample weight was constant, the weight before and after heating was recorded. 2.2.3. Modified sieve method with shaker In order to better evaluate the disintegration behavior, a modified sieve method for disintegration test was proposed. In the sieve method, the stainless steel sieve (2 mm diameter) was placed on a beaker, and purified water was added with 1cm level higher than the mesh. The beaker was constantly shaken at 100 r/min with a constant temperature reciprocating bath shaker (ZD-85A, Jiangsu, China). The ODTs were dropped on the sieve, and the time was measured. The apparatus was shown in Fig. 2. Tablets without channels were also prepared based on the Table 1 with the same weight, and the disintegration time was measured by the same method.
Fig. 2. Device diagram of modified sieve method for disintegration test. (A) Front view; (B) Top view; (C) Overall structure; (D) Sieve bottom.
2.2.4. In vivo disintegration time and mouthfeel assessment The in vivo disintegration study and mouthfeel assessment were performed by 6
keeping the ODTs under the tongue. Five healthy volunteers were enrolled in the study. Each test was repeated in triplicate with each test interval of 15 minutes. The rough mouthfeel of ODTs were evaluated using a 5-point scale: (1) no roughness and no bitterness; (2) slight roughness and no bitterness; (3) roughness and no bitterness; (4) appreciable roughness and bitterness; (5) strong roughness and appreciable bitterness. At the same time, in vivo disintegration time of each ODT was measured with a stopwatch. The ODTs were placed under the tongue without biting the tablet. The time was recorded immediately when the last noticeable particle was disintegrated. 2.2.5. Dissolution study In vitro dissolution study was carried out in accordance with Chinese Pharmacopoeia (2015 edition) at 50 rpm using a dissolution tester (ZRS-8G, Tianjin, China). Dissolution test was performed using 250 mL of water as dissolution medium at 37±0.5 ℃. At predetermined time intervals, samples were withdrawn and filtered through a 0.45 μm filter for analysis with an UV spectroscopy spectrophotometer (T6, Beijing, China) at 278 nm.
3. Results and discussion 3.1. Formulation screening The fillers were used to increase the weight and volume of tablets and could be classified into water-soluble fillers and water-insoluble fillers. Water-soluble fillers mainly included carbohydrates such as lactose, glucose and mannitol et al, the water-insoluble fillers mainly included starch, microcrystalline cellulose, inorganic salts and so on. From the preliminary studies, both water-soluble fillers and water-insoluble fillers could produce intact ODTs. However, given to excessive water-insoluble excipients in ODT formulations would cause rough mouthfeel (such as grittiness), glucose, mannitol and lactose were selected as fillers for further study. To evaluate the impact of the type and amount of disintegrants on the disintegration properties of ODTs, different disintegrants (PVPP, CMS-Na and L-HPC), and disintegrant amount (1%, 3% and 5%) were screened. The results showed disintegrants had an important impact on the disintegration time. The formulations containing PVPP demonstrated
the
most rapid
disintegration within 60 s. The ODTs with L-HPC disintegrated between 60-120 s and formulations containing CMS-Na disintegrated between 120-240 s. This might be related to the rapid capillary activity and swelling ability of PVPP (Anderson et al., 2005), while L-HPC and CMS-Na tended to form gels in the ODTs and the 7
disintegration time was extended. In addition, the effect of PVPP content on disintegration time was further investigated and the results illustrated that the disintegration time decreased when the content of PVPP increased from 1% to 5%. Given to PVPP was insoluble in water, the more the disintegrant content was, the more gritty feeling there will be. Moreover, when the PVPP content increased from 3% to 5%, there was no difference in disintegration time. Therefore, 3% PVPP was chosen as the best disintegrant content (F1, F4, F7 and F10) for further study. Fig. 3 indicated the images of entire disintegration process of F1, F4, F7 and F10. It could be seen that the disintegration of ODTs was also influenced by fillers. The disintegration time of F1 (glucose as filler), F4 (mannitol as filler), F7 (mannitol:lactose=3:1
as
filler)
was
53
s,
44
s,
16
s,
and
F10
(mannitol:lactose=1:1 as filler) was 9 s.
Fig. 3. The images of entire disintegration process of F1, F4, F7 and F10.
3.2. Disintegration method screening In order to better investigate the influence of disintegrants on the disintegration time of ODTs, a new modified sieve method was developed. In this sieve method with shaker, the stainless steel screen (2 mm mesh inner diameter) was used and the horizontal rotation of reciprocating shaker was 100 r/min, the method was simple and reproducible. It could not only acquire disintegration time of ODTs, but also provide adequate IVIVC in the study. 3.3. IVIVC of disintegration time In this study, the IVIVC of disintegration time was measured and the results were shown in Fig. 4. In vitro disintegration time was shorter than in vivo (oral) 8
disintegration time, due to differences in penetration rate between purified water and saliva. A good correlation (R 2=0.993) was found between in vitro and in vivo disintegration times. These results indicate that our modified sieve method with shaker may be available as a disintegration test for multi-channel ODTs.
Fig. 4. Relation between in vitro/in vivo correlation (IVIVC) of disintegration time.
3.4. Physical evaluation of multi-channel ODTs The characterization results of ODTs were presented in Table 2. In all cases, the average disintegration time of ODTs was less than 60 s, the weight difference was less than 5%, the hardness was about 9-10 N, and the moisture content was within 0.5%. The results of in vitro dissolution indicated that the dissolution rate of ODTs could reach 80% within 3 min. We compared the disintegration time of multi-channel ODTs and tablets without channels. It could be seen that the disintegration time of the multi-channel ODTs was much shorter than that of tablets without channels with the same formulation. The disintegration time of tablets without channels for F1, F4, F7 and F10 were 92±3 s, 74±3 s, 34±2 s and 26±2 s while the disintegration time of ODTs were 53±3 s, 44±3 s, 16±2 s and 9±2 s. The presence of the channels significantly accelerated the disintegration of ODTs.
9
Table 2 Evaluation results of multi-channel ODTs. Evaluation results In vitro disintegratio n time (s, n=6) In vivo disintegratio n time (s, n=18) Diameter (mm, n=10) Thickness (mm, n=10) Channel size (mm, n=10) Weight difference (mg, n=20) Hardness (N, n=6) Moisture content (%, n=3) In vitro dissolution
Formulation Code F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12
53.2±3.2
268.5±5. 1
160.8±5. 1
44.0±3.4
221.8±5. 0
131.8±4. 3
16.0±2.4
80.2±4.5
48.3±3.5
9.3±1.9
46.5±3.7
28.2±2.7
103.8±8. 4
496.2±8. 8
295.7±8. 7
81.3±7.4
413.5±8. 7
244.7±8. 6
36.2±4.3
150.2±8. 5
93.2±7.9
19.2±3.1
87.2±7.5
56.3±5.2
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
308.7±4. 3
304.7±4. 1
308.7±4. 3
302.7±4. 7
305.7±3. 9
302.7±4. 7
301.9±3. 2
300.9±4. 2
301.9±3. 2
302.0±4. 6
307.0±4. 0
302.0±4. 6
9.4±2.0
9.4±1.4
9.3±1.6
9.3±1.2
9.4±1.4
9.4±1.2
9.3±1.3
9.4±1.8
9.4±1.5
9.3±1.6
9.4±1.6
9.4±1.8
0.4±0.1
0.4±0.1
0.3±0.1
0.3±0.1
0.4±0.1
0.3±0.1
0.3±0.1
0.3±0.1
0.2±0.1
0.4±0.1
0.4±0.1
0.4±0.1
93.3±0.6
92.3±0.4
92.9±0.5
95.5±0.5
94.7±0.5
95.3±0.7
96.7±0.7
96.5±0.6
96.6±0.2
98.4±0.6
98.3±0.2
98.1±0.3
10
(%, n=3)
11
3.5. Mouthfeel The mouthfeel results revealed that the average scores were all less than 3 (Table 3), and the volunteers showed good response and acceptable mouthfeel without complain of numbness. Appropriate content of aspartame and flavor could improve mouthfeel. The water-soluble mannitol provided a creamy and sweet taste when the ODTs disintegrated, which could improve the mouthfeel very well. Table 3 The degree of acceptability of ODTs. Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
Volunteer No. (n=5) No.1 No.2 2.00±0.00 3.00±0.00 2.33±0.58 3.33±0.58 2.33±0.58 3.00±0.00 1.33±0.58 3.00±0.00 1.67±0.58 3.00±0.00 1.33±0.58 3.00±0.00 1.00±0.00 2.67±0.58 1.33±0.58 2.33±0.58 1.00±0.00 2.33±0.58 1.00±0.00 2.00±0.00 1.00±0.00 2.00±0.00 1.00±0.00 2.00±0.00
No.3 2.67±0.58 3.00±0.00 3.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 1.33±0.58 1.67±0.58 1.67±0.58
No.4 2.67±0.58 2.33±0.58 2.33±0.58 1.67±0.58 2.00±0.00 2.00±0.00 1.33±0.58 2.00±0.00 2.00±0.00 1.00±0.00 1.00±0.00 1.00±0.00
No.5 3.00±0.00 3.00±0.00 3.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 1.67±0.58 2.00±0.00 1.67±0.58
Average Scores 2.67±0.49 2.80±0.56 2.73±0.46 2.00±0.65 2.13±0.52 2.07±0.59 1.80±0.68 1.93±0.46 1.87±0.52 1.40±0.51 1.63±0.52 1.47±0.52
3.6. Disintegration mechanism of multi-channel ODTs In this paper, the influence of channel structure on the disintegration of ODTs was investigated and
the disintegration mechanism was illustrated. The
disintegration depended on three main factors: the effective surface area, water penetration distance, as well as the porosity of ODTs. The three factors mentioned above mutually improved the disintegration of ODTs. As conventional ODTs without channels, water penetrated into the total outer surface and then came into the core gradually, this process would last for tens of seconds to a few minutes. Compared with ODTs without channels, the multi-channel structure increased specific surface area. The increase in specific surface area increased the water contact area and thus contributed to disintegration. More importantly, this multi-channel structural design made channels through the entire core. The distance of water penetration from the surface into the core was significantly shortened, thereby significantly accelerating tablet disintegration. This was the remarkable advantage of multi-channel ODTs. 12
In the section 3.4, we did the comparative study to show the important role of multi-channel structure on the disintegration acceleration. The disintegration time of the multi-channel ODTs was much shorter than that of tablets without channels with the same formulation. The results demonstrated that the presence of the channels significantly accelerated the disintegration of ODTs. With the multi-channel structure, ODTs could be prepared with less disintegrants to reduce the cost and increase the mouthfeel. Furthermore, porosity of was also helpful in increasing the disintegration rate. The total three-dimensional structure of different ODTs with same channels was similar, but the different porosity resulted in the different disintegration rate among formulations. Porosity referred to tiny channels inside ODTs in our study, including the intra-particle porosity and inter-particle porosity. The ODTs prepared with different excipients resulted in different porosity. The inter -particle porosity may even have a more significant effect on the disintegration process. Porosity structure in ODTs promoted water penetration into these pores, thus multi-channel ODTs with higher porosity may have greater disintegration rate. In fact, the disintegration mechanism of multi-channel ODTs was very complicated. The number, diameter and arrangement of channels directly changed the distance between the channels. Therefore, the effect of the number, diameter and arrangement of channels on the disintegration behavior of ODTs deserved in -depth evaluation in future studies.
4. Conclusion In this study, the novel multi-channel ODTs were successfully prepared using conventional wet compression method with a special multi-channel mold. The resulting ODTs significantly accelerated the disintegration and drug dissolution due to the multi-channel nature. A modified sieve method with shaker for disintegration test was developed for formulation optimization and this test was simple and reproducible for the evaluation of multi-channel ODTs. ODTs optimized by this method showed good physical parameters and IVIVC of disintegration time. The fillers used in this experiment effectively improved the rough mouthfeel as well as volunteer compliance. The current study provided a highly acceptable method for the development of multi-channel ODTs, especially for children, the elderly, and patients with dysphagia.
Declaration of interest 13
The authors report no declarations of interest.
Acknowledgments This work was supported by the fund of the Top Young Talents Program of Hebei Province, the Scientific Research Project of Hebei Provincial High School (No. ZD2016136), the Post-graduate’s Innovation Fund Project of Hebei University (No. hbu2019ss080) and Key Research and Development Plan of Hebei Province (No. 19272701D).
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microcapsules of berberine hydrochloride. Aaps Pharmscitech 14, 29-37. Klingmann, V., Spomer, N., Lerch, C., Stoltenberg, I., Fromke, C., Bosse, H.M., Breitkreutz, J., Meissner, T., 2013. Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children. J Pediatr-Us 163, 1728-U1283. Nagaraju, T., Gowthami, R., Rajashekar, M., Sandeep, S., Mallesham, M., Sathish, D., Kumar, Y.S., 2013. Comprehensive review on oral disintegrating films. Curr Drug Deliv 10, 96-108. Quinten, T., Andrews, G.P., De Beer, T., Saerens, L., Bouquet, W., Jones, D.S., Hornsby, P., Remon, J.P., Vervaet, C., 2012. Preparation and evaluation of sustained-release matrix tablets based on metoprolol and an acrylic carrier using injection moulding. Aaps Pharmscitech 13, 1197-1211. Refaat, A., Sokar, M., Ismail, F., Boraei, N., 2016. A dual strategy to improve psychotic patients' compliance using sustained release quetiapine oral disintegrating tablets. Acta Pharmaceut 66, 515-531. Reiner, V., Giarratana, N., Monti, N.C., Breitenbach, A., Klaffenbach, P., 2010. Rapidfilm (R): an innovative pharmaceutical form designed to improve patient compliance. Int J Pharmaceut 393, 55-60. Rojas, J., Kumar, V., 2012. Effect of polymorphic form on the functional properties of cellulose: a comparative study. Carbohyd Polym 87, 2223-2230. Sadia, M., Arafat, B., Ahmed, W., Forbes, R.T., Alhnan, M.A., 2018. Channelled tablets: an innovative approach to accelerating drug release from 3D printed tablets. J Control Release 269, 355-363. Shukla, D., Chakraborty, S., Singh, S., Mishra, B., 2009. Mouth dissolving tablets II: an overview of evaluation techniques original papers. Scientia Pharmaceutica 77, 465-482. Spomer, N., Klingmann, V., Stoltenberg, I., Lerch, C., Meissner, T., Breitkreutz, J., 2012. Acceptance of uncoated mini-tablets in young children: results from a prospective exploratory cross-over study. Arch Dis Child 97, 283-286. Stoltenberg, I., Breitkreutz, J., 2011. Orally disintegrating mini-tablets (ODMTs)-a novel solid oral dosage form for paediatric use. Eur J Pharm Biopharm 78, 462-469. Strickley, R.G., Iwata, Q., Wili, S., Dahl, T.C., 2008. Pediatric drugs- a review of commercially available oral formulations. J Pharm Sci-Us 97, 1731-1774. Varia, I., Venkataraman, S., Hellegers, C., Gersing, K., Doraiswamy, P.M., 2007. Effect of mirtazapine orally disintegrating tablets on health-related quality of life in elderly depressed patients with comorbid medical disorders: a pilot study. Psychopharmacol Bull 40, 47-56. Ved, P., Saurabh, M., Shiv Kumar, Y., Vikas, J., 2011. Fast disintegrating tablets: opportunity in drug delivery system. Journal of Advanced Pharmaceutical Technology & Research 2, 223-235. Vikas, A.P.D., Bhavesh, H.K.M.S., Moe, D.V., Khankari, R.K., 2006. Drug delivery: fast-dissolve systems. Wagh, M.A., Dilip, K.P., Salunkhe, K.S., Chavan, N.V., Daga, V.R., 2011. Techniques used in orally disintegrating drug delivery system. International Journal of Drug Delivery, 98-107. Xu, J., Bovet, L.L., Zhao, K., 2008. Taste masking microspheres for orally disintegrating 15
tablets. Int J Pharmaceut 359, 63-69.
16
Preparation and evaluation of novel multi-channel orally disintegrating tablets Jiaojiao Yu , Xiaosong Shan , Shichao Chen , Xinli Sun , Pengjin Song , Ruidong Zhao , Liandong Hu PII: DOI: Reference:
S0928-0987(19)30381-1 https://doi.org/10.1016/j.ejps.2019.105108 PHASCI 105108
To appear in:
European Journal of Pharmaceutical Sciences
Received date: Revised date: Accepted date:
2 April 2019 28 August 2019 13 October 2019
Please cite this article as: Jiaojiao Yu , Xiaosong Shan , Shichao Chen , Xinli Sun , Pengjin Song , Ruidong Zhao , Liandong Hu , Preparation and evaluation of novel multichannel orally disintegrating tablets, European Journal of Pharmaceutical Sciences (2019), doi: https://doi.org/10.1016/j.ejps.2019.105108
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Graphical Abstract：
1
Preparation and evaluation of novel multi-channel orally disintegrating tablets Jiaojiao Yua,b , Xiaosong Shanb , Shichao Chenc,b , Xinli Sunc,b , Pengjin Songa , Ruidong Zhaoa , Liandong Hua,b,* a
School of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of
Hebei Province, Hebei University, Baoding, China. b
Affiliated Hospital of Hebei University, Baoding, China.
c
College of Medicine, Hebei University, Baoding, China.
*
Corresponding author: Liandong Hu: [email protected]
Abstract In this study, novel orally disintegrating tablets (ODTs) with multi-channel structure were designed to provide a rapid disintegration and subsequently drug dissolution. The ODTs were prepared using conventional wet compression through perforating channels with a special multi-channel mold. A modified sieve method was used in disintegration test as a quick screening tool during formulation evaluation. Moreover, physical properties, in vitro and in vivo disintegration time, dissolution rate and mouthfeel were also evaluated. The results demonstrated that developed multi-channel ODTs had good physical parameters, in vitro/in vivo correlation (IVIVC) of disintegration time and acceptable mouthfeel and dissolution. It also revealed that the presence of channels could accelerate the disintegration of ODTs because the channels could shorten the distance of water penetration and increased the specific surface area, resulting in a significant reduction in disintegration time. Above all, the introduction of novel multi-channel ODTs provided an alternative preparation method for ODTs and achieved good disintegration characteristics. Keywords: Orally disintegrating tablets, Multi-channel, Disintegration, Mouthfeel
1. Introduction Since the introduction of ODTs into the market in the 1980s, it has become one 2
of the most attractive oral drug delivery systems and has received much attention over the years (Quinten et al., 2012; Wagh et al., 2011). A lot of ODTs have already been commercially available (Aparna et al., 2018; Cilurzo et al., 2018; Reiner et al., 2010; Strickley et al., 2008; Vikas et al., 2006). As a kind of solid immediate preparation, ODTs can disintegrate and disperse with no water or only a small amount of water. When placed upon the tongue, it can disintegrate rapidly in the presence of saliva in a few seconds to 3 minutes. ODTs provide several advantages over traditional tablets: (1) It is convenient to take for patients with dysphagia, particularly for geriatric (Varia et al., 2007) and pediatric populations (Nagaraju et al., 2013) to improve patient compliance (Refaat et al., 2016; Stoltenberg and Breitkreutz, 2011). (2) The bioavailability of the drug can be improved, thereby improving drug absorption (Anup et al., 2018; Elwerfalli et al., 2016; Klingmann et al., 2013; Spomer et al., 2012). (3) The first-pass metabolism is avoided, with pregastric absorption in buccal and pharyngeal, resulting in improved drug efficacy (Clarke et al., 2003). There are several technologies that have been used to produce ODTs such as freeze-drying method, molding method, direct compression method, spray drying method, phase transformation method and so on (Fu et al., 2004; Shukla et al., 2009). The ODTs produced by freeze-drying process usually has very light with highly porous structures and rapid disintegration. However, the manufacturing process is relatively expensive, and the formulation is not stable at higher temperature and humidity (Rojas and Kumar, 2012, Batchelor et al., 2014). The ODTs produced by molding method using water-soluble components can rapidly disintegrate, but the mechanical strength of tablets is low (Heinemann et al., 2013; Wagh et al., 2011). From the pharmaceutical manufacturer's point of view, direct compression is the simplest and cost-effective preparation method of ODTs, which is suitable for drugs with good solubility, powder flowability and compressibility (Ved et al., 2011). But this technique often requires more disintegrants or effervescent agents. In the phase transformation method, the ODTs are compressed by low compression forces to keep porosity of the tablets followed by treatment using humidity or heat to imcrease mechanical properties. However, the use of humidity or heat treatment can decrease the stability to water-sensitive or heat-sensitive drugs.(Desai and Prabhakar, 2015). In addition, the bitterness and irritancy of the some drugs may affect the patient's acceptance (Anderson et al., 2005; Hu et al., 2013; Xu et al., 2008). In 3
order to solve the above problems of ODTs, we designed a novel multi-channel ODTs that were prepared by wet compression technology. Multiple channels formed in the ODTs allow water to quickly penetrate into the core and accelerate disintegration. Previously, caplets with perforated channels were prepared by fused deposition modelling (FDM) 3D printing technique, and the effect of channel width and length on drug release was investigated. The results demonstrated that the presence of the channel accelerated drug release (Sadia et al., 2018). However, due to the toxic side effects of materials, there are few printed materials that can be applied to the 3D printing technology field of preparation, and the high production costs further limits its application. In this study, the multi-channel ODTs were prepared by conventional wet compression with various excipients and dextromethorphan hydrobromide (DMB) as a model drug. The formulation was screened by a modified disintegration method. The quality control parameters such as diameter, thickness, weight difference, hardness and dissolution tests were evaluated. Simultaneously, in vitro and in vivo disintegration and the mouthfeel of ODTs were also performed. In addition, the effects of fillers and disintegrants on disintegration and dissolution were discussed and disintegration mechanism was also explored.
2. Materials and methods 2.1. Materials DMB as the model drug was purchased from Dingkang Pharmaceutical Co., Ltd. (Shanghai, China). Crospovidone (PVPP), carboxymethyl starch sodium (CMS-Na) and low-substituted hydroxypropyl cellulose (L-HPC) were purchased from Sunhere Pharmaceutical Excipients Co., Ltd. (Anhui, China). Glucose was purchased from Kemiou Chemical Reagent Co., Ltd. (Tianjin, China). Mannitol was purchased from Huadong Reagent Factory (Tianjin, China). Lactose was purchased from Shuangxuan Microbe Culture Medium Products Factory (Beijing, China). Aspartame was obtained from Shaoxing Yamei Biochemical Co., Ltd. (Zhejiang, China). All other chemicals and reagents were of analytical grade. 2.2. Methods 2.2.1. Preparation of multi-channel ODTs In this study, the multi-channel DMB-ODTs were manufactured by wet 4
compression method with a special mold. Before study, the disintegrants and fillers were separately milled and sieved through an 80 mesh screen. All ingredients of the ODT formulations were weighed and mixed thoroughly with water as a binder. The mixture was then transferred into a round mold (10.10 mm diameter) and compressed using a tablet press (TDP-5, Shanghai, China). Based on the preliminary studies, the compression force was chosen to 8-10 KN to achieve a thickness of about 4.12 mm. Nine channels were designed and the size of each channel was about 1.80 mm (Fig. 1). The prepared multi-channel ODTs were packed after drying at 40 ℃for 5 h. The detailed composition of ODTs was presented in Table 1.
Fig. 1. Multi-channel DMB-ODTs manufactured by wet compression method with a special mold. Table 1 Composition of ODT formulations. Ingredients (mg) DMB Glucose Mannitol Lactose PVPP CMS-Na L-HPC Aspartame Total Weight
F1
F2
F3
15 15 15 270 270 270 9 9 9 6 6 6 300 300 300
F4
Formulation Code F5 F6 F7 F8
15 15 270 270 9 9 6 6 300 300
15 15 15 270 204 204 66 66 9 9 9 6 6 6 300 300 300
F9
F10 F11 F12
15 204 66 9 6 300
15 135 135 9 6 300
15 135 135 9 6 300
15 135 135 9 6 300
2.2.2. Physical evaluation of multi-channel ODTs The diameter, thickness and channel size of ODTs were measured using digital 5
vernier caliper with sensitivity of 0.02 mm (Shanghai, China). The average weight and weight difference of ODTs were determined using an electronic balance (FA1104N, Shanghai, China). The hardness was conducted by a hardness tester (PYC-A, Shanghai, China). A moisture analyzer (MB23, Ohaus Corporation, Shanghai, China) equipped with a halogen dryer unit and a balance was used to measure the moisture content of ODTs. For moisture study, ten tablets were heated at 105 ℃using infrared heating component until the sample weight was constant, the weight before and after heating was recorded. 2.2.3. Modified sieve method with shaker In order to better evaluate the disintegration behavior, a modified sieve method for disintegration test was proposed. In the sieve method, the stainless steel sieve (2 mm diameter) was placed on a beaker, and purified water was added with 1cm level higher than the mesh. The beaker was constantly shaken at 100 r/min with a constant temperature reciprocating bath shaker (ZD-85A, Jiangsu, China). The ODTs were dropped on the sieve, and the time was measured. The apparatus was shown in Fig. 2. Tablets without channels were also prepared based on the Table 1 with the same weight, and the disintegration time was measured by the same method.
Fig. 2. Device diagram of modified sieve method for disintegration test. (A) Front view; (B) Top view; (C) Overall structure; (D) Sieve bottom.
2.2.4. In vivo disintegration time and mouthfeel assessment The in vivo disintegration study and mouthfeel assessment were performed by 6
keeping the ODTs under the tongue. Five healthy volunteers were enrolled in the study. Each test was repeated in triplicate with each test interval of 15 minutes. The rough mouthfeel of ODTs were evaluated using a 5-point scale: (1) no roughness and no bitterness; (2) slight roughness and no bitterness; (3) roughness and no bitterness; (4) appreciable roughness and bitterness; (5) strong roughness and appreciable bitterness. At the same time, in vivo disintegration time of each ODT was measured with a stopwatch. The ODTs were placed under the tongue without biting the tablet. The time was recorded immediately when the last noticeable particle was disintegrated. 2.2.5. Dissolution study In vitro dissolution study was carried out in accordance with Chinese Pharmacopoeia (2015 edition) at 50 rpm using a dissolution tester (ZRS-8G, Tianjin, China). Dissolution test was performed using 250 mL of water as dissolution medium at 37±0.5 ℃. At predetermined time intervals, samples were withdrawn and filtered through a 0.45 μm filter for analysis with an UV spectroscopy spectrophotometer (T6, Beijing, China) at 278 nm.
3. Results and discussion 3.1. Formulation screening The fillers were used to increase the weight and volume of tablets and could be classified into water-soluble fillers and water-insoluble fillers. Water-soluble fillers mainly included carbohydrates such as lactose, glucose and mannitol et al, the water-insoluble fillers mainly included starch, microcrystalline cellulose, inorganic salts and so on. From the preliminary studies, both water-soluble fillers and water-insoluble fillers could produce intact ODTs. However, given to excessive water-insoluble excipients in ODT formulations would cause rough mouthfeel (such as grittiness), glucose, mannitol and lactose were selected as fillers for further study. To evaluate the impact of the type and amount of disintegrants on the disintegration properties of ODTs, different disintegrants (PVPP, CMS-Na and L-HPC), and disintegrant amount (1%, 3% and 5%) were screened. The results showed disintegrants had an important impact on the disintegration time. The formulations containing PVPP demonstrated
the
most rapid
disintegration within 60 s. The ODTs with L-HPC disintegrated between 60-120 s and formulations containing CMS-Na disintegrated between 120-240 s. This might be related to the rapid capillary activity and swelling ability of PVPP (Anderson et al., 2005), while L-HPC and CMS-Na tended to form gels in the ODTs and the 7
disintegration time was extended. In addition, the effect of PVPP content on disintegration time was further investigated and the results illustrated that the disintegration time decreased when the content of PVPP increased from 1% to 5%. Given to PVPP was insoluble in water, the more the disintegrant content was, the more gritty feeling there will be. Moreover, when the PVPP content increased from 3% to 5%, there was no difference in disintegration time. Therefore, 3% PVPP was chosen as the best disintegrant content (F1, F4, F7 and F10) for further study. Fig. 3 indicated the images of entire disintegration process of F1, F4, F7 and F10. It could be seen that the disintegration of ODTs was also influenced by fillers. The disintegration time of F1 (glucose as filler), F4 (mannitol as filler), F7 (mannitol:lactose=3:1
as
filler)
was
53
s,
44
s,
16
s,
and
F10
(mannitol:lactose=1:1 as filler) was 9 s.
Fig. 3. The images of entire disintegration process of F1, F4, F7 and F10.
3.2. Disintegration method screening In order to better investigate the influence of disintegrants on the disintegration time of ODTs, a new modified sieve method was developed. In this sieve method with shaker, the stainless steel screen (2 mm mesh inner diameter) was used and the horizontal rotation of reciprocating shaker was 100 r/min, the method was simple and reproducible. It could not only acquire disintegration time of ODTs, but also provide adequate IVIVC in the study. 3.3. IVIVC of disintegration time In this study, the IVIVC of disintegration time was measured and the results were shown in Fig. 4. In vitro disintegration time was shorter than in vivo (oral) 8
disintegration time, due to differences in penetration rate between purified water and saliva. A good correlation (R 2=0.993) was found between in vitro and in vivo disintegration times. These results indicate that our modified sieve method with shaker may be available as a disintegration test for multi-channel ODTs.
Fig. 4. Relation between in vitro/in vivo correlation (IVIVC) of disintegration time.
3.4. Physical evaluation of multi-channel ODTs The characterization results of ODTs were presented in Table 2. In all cases, the average disintegration time of ODTs was less than 60 s, the weight difference was less than 5%, the hardness was about 9-10 N, and the moisture content was within 0.5%. The results of in vitro dissolution indicated that the dissolution rate of ODTs could reach 80% within 3 min. We compared the disintegration time of multi-channel ODTs and tablets without channels. It could be seen that the disintegration time of the multi-channel ODTs was much shorter than that of tablets without channels with the same formulation. The disintegration time of tablets without channels for F1, F4, F7 and F10 were 92±3 s, 74±3 s, 34±2 s and 26±2 s while the disintegration time of ODTs were 53±3 s, 44±3 s, 16±2 s and 9±2 s. The presence of the channels significantly accelerated the disintegration of ODTs.
9
Table 2 Evaluation results of multi-channel ODTs. Evaluation results In vitro disintegratio n time (s, n=6) In vivo disintegratio n time (s, n=18) Diameter (mm, n=10) Thickness (mm, n=10) Channel size (mm, n=10) Weight difference (mg, n=20) Hardness (N, n=6) Moisture content (%, n=3) In vitro dissolution
Formulation Code F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12
53.2±3.2
268.5±5. 1
160.8±5. 1
44.0±3.4
221.8±5. 0
131.8±4. 3
16.0±2.4
80.2±4.5
48.3±3.5
9.3±1.9
46.5±3.7
28.2±2.7
103.8±8. 4
496.2±8. 8
295.7±8. 7
81.3±7.4
413.5±8. 7
244.7±8. 6
36.2±4.3
150.2±8. 5
93.2±7.9
19.2±3.1
87.2±7.5
56.3±5.2
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
10.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
4.1±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
1.8±0.0
308.7±4. 3
304.7±4. 1
308.7±4. 3
302.7±4. 7
305.7±3. 9
302.7±4. 7
301.9±3. 2
300.9±4. 2
301.9±3. 2
302.0±4. 6
307.0±4. 0
302.0±4. 6
9.4±2.0
9.4±1.4
9.3±1.6
9.3±1.2
9.4±1.4
9.4±1.2
9.3±1.3
9.4±1.8
9.4±1.5
9.3±1.6
9.4±1.6
9.4±1.8
0.4±0.1
0.4±0.1
0.3±0.1
0.3±0.1
0.4±0.1
0.3±0.1
0.3±0.1
0.3±0.1
0.2±0.1
0.4±0.1
0.4±0.1
0.4±0.1
93.3±0.6
92.3±0.4
92.9±0.5
95.5±0.5
94.7±0.5
95.3±0.7
96.7±0.7
96.5±0.6
96.6±0.2
98.4±0.6
98.3±0.2
98.1±0.3
10
(%, n=3)
11
3.5. Mouthfeel The mouthfeel results revealed that the average scores were all less than 3 (Table 3), and the volunteers showed good response and acceptable mouthfeel without complain of numbness. Appropriate content of aspartame and flavor could improve mouthfeel. The water-soluble mannitol provided a creamy and sweet taste when the ODTs disintegrated, which could improve the mouthfeel very well. Table 3 The degree of acceptability of ODTs. Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
Volunteer No. (n=5) No.1 No.2 2.00±0.00 3.00±0.00 2.33±0.58 3.33±0.58 2.33±0.58 3.00±0.00 1.33±0.58 3.00±0.00 1.67±0.58 3.00±0.00 1.33±0.58 3.00±0.00 1.00±0.00 2.67±0.58 1.33±0.58 2.33±0.58 1.00±0.00 2.33±0.58 1.00±0.00 2.00±0.00 1.00±0.00 2.00±0.00 1.00±0.00 2.00±0.00
No.3 2.67±0.58 3.00±0.00 3.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 1.33±0.58 1.67±0.58 1.67±0.58
No.4 2.67±0.58 2.33±0.58 2.33±0.58 1.67±0.58 2.00±0.00 2.00±0.00 1.33±0.58 2.00±0.00 2.00±0.00 1.00±0.00 1.00±0.00 1.00±0.00
No.5 3.00±0.00 3.00±0.00 3.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 2.00±0.00 1.67±0.58 2.00±0.00 1.67±0.58
Average Scores 2.67±0.49 2.80±0.56 2.73±0.46 2.00±0.65 2.13±0.52 2.07±0.59 1.80±0.68 1.93±0.46 1.87±0.52 1.40±0.51 1.63±0.52 1.47±0.52
3.6. Disintegration mechanism of multi-channel ODTs In this paper, the influence of channel structure on the disintegration of ODTs was investigated and
the disintegration mechanism was illustrated. The
disintegration depended on three main factors: the effective surface area, water penetration distance, as well as the porosity of ODTs. The three factors mentioned above mutually improved the disintegration of ODTs. As conventional ODTs without channels, water penetrated into the total outer surface and then came into the core gradually, this process would last for tens of seconds to a few minutes. Compared with ODTs without channels, the multi-channel structure increased specific surface area. The increase in specific surface area increased the water contact area and thus contributed to disintegration. More importantly, this multi-channel structural design made channels through the entire core. The distance of water penetration from the surface into the core was significantly shortened, thereby significantly accelerating tablet disintegration. This was the remarkable advantage of multi-channel ODTs. 12
In the section 3.4, we did the comparative study to show the important role of multi-channel structure on the disintegration acceleration. The disintegration time of the multi-channel ODTs was much shorter than that of tablets without channels with the same formulation. The results demonstrated that the presence of the channels significantly accelerated the disintegration of ODTs. With the multi-channel structure, ODTs could be prepared with less disintegrants to reduce the cost and increase the mouthfeel. Furthermore, porosity of was also helpful in increasing the disintegration rate. The total three-dimensional structure of different ODTs with same channels was similar, but the different porosity resulted in the different disintegration rate among formulations. Porosity referred to tiny channels inside ODTs in our study, including the intra-particle porosity and inter-particle porosity. The ODTs prepared with different excipients resulted in different porosity. The inter -particle porosity may even have a more significant effect on the disintegration process. Porosity structure in ODTs promoted water penetration into these pores, thus multi-channel ODTs with higher porosity may have greater disintegration rate. In fact, the disintegration mechanism of multi-channel ODTs was very complicated. The number, diameter and arrangement of channels directly changed the distance between the channels. Therefore, the effect of the number, diameter and arrangement of channels on the disintegration behavior of ODTs deserved in -depth evaluation in future studies.
4. Conclusion In this study, the novel multi-channel ODTs were successfully prepared using conventional wet compression method with a special multi-channel mold. The resulting ODTs significantly accelerated the disintegration and drug dissolution due to the multi-channel nature. A modified sieve method with shaker for disintegration test was developed for formulation optimization and this test was simple and reproducible for the evaluation of multi-channel ODTs. ODTs optimized by this method showed good physical parameters and IVIVC of disintegration time. The fillers used in this experiment effectively improved the rough mouthfeel as well as volunteer compliance. The current study provided a highly acceptable method for the development of multi-channel ODTs, especially for children, the elderly, and patients with dysphagia.
Declaration of interest 13
The authors report no declarations of interest.
Acknowledgments This work was supported by the fund of the Top Young Talents Program of Hebei Province, the Scientific Research Project of Hebei Provincial High School (No. ZD2016136), the Post-graduate’s Innovation Fund Project of Hebei University (No. hbu2019ss080) and Key Research and Development Plan of Hebei Province (No. 19272701D).
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