Development and evaluation of novel innovative multi-channel aripiprazole orally disintegrating tablets

Journal Pre-proof Development and evaluation of novel innovative multi-channel aripiprazole orally disintegrating tablets Xiao Han, Xiaosong Shan, Yuxin Du, Saixi Pang, Liandong Hu PII:

S1773-2247(19)31113-X

DOI:

https://doi.org/10.1016/j.jddst.2019.101446

Reference:

JDDST 101446

To appear in:

Journal of Drug Delivery Science and Technology

Received Date: 1 August 2019 Revised Date:

25 November 2019

Accepted Date: 2 December 2019

Please cite this article as: X. Han, X. Shan, Y. Du, S. Pang, L. Hu, Development and evaluation of novel innovative multi-channel aripiprazole orally disintegrating tablets, Journal of Drug Delivery Science and Technology (2020), doi: https://doi.org/10.1016/j.jddst.2019.101446. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

Development and evaluation of novel innovative multi-channel

aripiprazole

orally

disintegrating

tablets Xiao Hana,b, Xiaosong Shanb, Yuxin Duc, Saixi Pangc, Liandong Hua,b* a

Key Laboratory of Pharmaceutical Quality Control of Hebei Province, School of Pharmaceutical Sciences, Hebei University, Baoding, China. b

Affiliated Hospital of Hebei University, Baoding, China.

c

Department of pharmacy, Bao Ding No.1 Hospital, Baoding, China.

*

Corresponding author: Liandong Hu: [email protected]

Keywords: orally disintegrating tablets; aripiprazole, multi-channel, disintegration, dissolution, mouthfeel

Abstract In this study, novel multi-channel orally disintegrating tablets (ODTs) containing aripiprazole were developed and evaluated to provide a rapid disintegration and subsequently drug dissolution. The ODTs were prepared using wet compression method with a special multi-channel mold, the type and amount of disintegrants were screened and optimized. Moreover, the characterization analysis, in vivo and in vitro disintegration time, dissolution study and taste of the ODTs were evaluated. The results showed that multi-channel ODT had a good characterization, fast in vitro / in vivo disintegration and dissolution. The results also showed that the multi-channel structure could effectively increase the contact area with water and shorten the penetration distance, thus accelerated the disintegration and drug release. In conclusion, the multi-channel ODT prepared by wet compression method can accelerate tablet disintegration, reduce production costs and improve patient compliance. 1. Introduction 1

For the majority of the methods of administration, the oral administration has been the most commonly accepted route due to its increased convenience and patient compliance [1]. However, it was difficult for some specific patients such as children, geriatric populations, the patients with chew dysfunction [2, 3] or the people with busy lives who can take drugs at anytime and anywhere [4]. Most of these problems could be solved by developing orally disintegrating tablet (ODT). ODT is a popular solid preparation which can rapidly disintegrate and disperse with saliva, or with a small volume of water in the oral cavity, or can dispersed directly in water to form a solution [5]. Compared with ordinary solid preparations, ODTs offer the advantages of quick disintegration, convenience and accuracy of dosing, high bioavailability and less irritation to digestive tract mucosa [6]. According to the Chinese Pharmacopoeia (ChP, 2015 edition), ODT is a dosage form that completely disintegrate in 3 minutes. Therefore, ODT can be used not only for those who have difficulty in swallowing, but also for those who need a quick and easy way to administration, even without water [7]. Furthermore, taste-masking is necessary for ODTs, in order to overcome the unpleasant taste, such as bitterness and gritty taste [8], sweeteners and flavors were added to prepare ODTs [9, 10]. Various methods were used for the preparation of ODTs, such as freeze drying method, molding method, spray drying method, direct compression technology, cotton candy technology, phase transition method and so on [11, 12]. Many pharmaceutical companies choose the direct compression technology, which is suitable for drugs with good solubility, flowability and compressibility of powders, with low cost and simple operation [13]. However, this technology often requires more disintegrants, which will affect the taste of ODT. In order to solve the problem of bitterness and gritty of ODTs, we proposed novel multi-channel ODTs [14]. By using traditional wet compression technology and adding a small amount of disintegrants, multi-channel ODTs were formed to accelerate disintegration and drug dissolution to a certain extent. The multiple multi-channel allowed ODTs to disintegrate quickly with a good taste. Schizophrenia is a common mental disorder characterized by abnormal thinking, 2

perception, behavior and emotions, as well as a decline in psychosocial functioning, seriously hamper the patients’ life and work [15-17]. The first generation of antipsychotic drugs include chlorpromazine, haloperidol and perphenazine, the second generation of antipsychotic agents are clozapine, olanzapine, risperidone, and aripiprazole [18]. Aripiprazole is more effective and popular in the treatment of schizophrenia, which can effectively alleviate the positive and negative symptoms, and cognitive dysfunctions of patients, significantly reduce the incidence of adverse reactions [19]. In this study, novel multi-channel ODTs were designed and developed with aripiprazole as a model drug using a wet compression technology, the multi-channel structure was formed in the ODTs to allow water to quickly penetrate into the core and accelerate disintegration. The formulation was optimized by different fillers and disintegrants, and the quality control parameters such as thickness, diameter, hardness, moisture content, weight variation and dissolution study were evaluated for the multi-channel aripiprazole ODTs, the in vitro and in vivo disintegration and the taste of the multi-channel ODTs and commercial ODTs were also assessed. In addition, the effects of multi-channel structure on disintegration and drug release were discussed and release mechanism were also explored. 2. Materials and methods 2.1 Materials Aripiprazole was purchased from Jiangsu Nhwa Pharmaceutical Co., Ltd (Jiangsu, 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). Lactose was purchased from Shuangxuan Microbe Culture Medium Products Factory (Beijing, China). Mannitol was purchased from Huadong Reagent Factory (Tianjin, China). Aspartame was purchased from Shaoxing Yamei Biochemical Co., Ltd. (Zhejiang, China). Strawberry flavor was purchased from Beijing Fengli Jingqiu Pharmaceutical Co., Ltd (Beijing, 3

China). All other chemicals and reagents were of analytical grade. Commercial aripiprazole ODT (5 mg) was purchased from Chinese market, and used as the reference in disintegration, dissolution and taste evaluation studies. 2.2 Methods 2.2.1

Preparation of multi-channel ODTs In this study, the multi-channel aripiprazole ODTs were prepared by a wet

compression method with a special mold. The fillers and disintegrants were separately screened by an 80-mesh sieve. All ingredients of the ODT formulations were homogeneously mixed with water as a binder, then the wet mixture was transferred into the die cavity model and compressed into multi-channel tablets (9 channels, seen in Fig. 1), the diameter of each channel is 1.8 mm. The prepared multi-channel aripiprazole ODTs were subsequently dried at 50 ℃ for more than 5 h. The ingredients of ODT formulations were shown in Table 1.

Fig. 1 Multi-channel aripiprazole ODTs manufactured by wet compression method Table 1 The composition of ODT formulations Series

Ingredients (mg) F1

F2

F3

F4

F5

F6

F7

F8

F9

Aripiprazole

5

5

5

5

5

5

5

5

5

Mannitol

210

210

210

206

206

206

201

201

201

Lactose

70

70

70

68

68

68

67

67

67

PVPP

3

CMS-Na L-HPC

9

15

3

9 3

15 9

4

15

Strawberry flavor

8

8

8

8

8

8

8

8

8

Aspartame

4

4

4

4

4

4

4

4

4

Total Weight

300

300

300

300

300

300

300

300

300

2.2.2

Characterization analysis of multi-channel ODTs The thickness and diameter of ODTs were measured by a vernier caliper

(Shanghai, China). The average weight and weight variation of ODTs were determined using an electronic balance (FA1104N, Shanghai, China). The hardness was conducted by a hardness tester (PYC-A, Shanghai, China). The moisture content of ODTs were measured using a moisture analyzer (MB23, Ohaus Corporation, Shanghai, China). 2.2.3

Disintegration study The disintegration test was performed in a beaker with 5 mL distilled water at

constant temperature, the multi-channel ODTs and commercial ODTs were put into the beaker respectively and the disintegration time was recorded. Meanwhile, the effect of water temperature(20°C, 37 °C and 50°C) on the disintegration of the ODTs were also measured, the water temperature of 37 °C was used to simulate the temperature of oral cavity, the water temperatures of 20 °C and 50 °C were used to simulate the temperature of cold water and warm water respectively. 2.2.4

Dissolution study The in vitro dissolution study was performed using a ZRS-8G dissolution

apparatus (Tianjin, China) and a temperature of 37±0.5°C. 250 ml of 0.l mol/L HCl containing 1% sodium dodecyl sulfate was used as dissolution medium with a paddle method at 100 rpm. Then 4ml of samples were collected at predetermined time intervals and filtered using 0.45µm filter and analyzed by an ultraviolet spectrophotometer at 250 nm. 2.2.5

Taste evaluation and in vivo disintegration time Taste evaluation and in vivo disintegration time of multi-channel ODTs and

commercial ODTs were measured. The ethics approval for in vivo study was 5

approved by the ethics committee of Affiliated Hospital of Hebei University (No. HDFY-LL-2019-107), and all volunteers provided written consent to participate in the study. Before the test, all the healthy volunteers gargled with purified water and then take one ODT on the tongue until it disintegrated, then spit it out and rinse the mouth with water. The taste of each ODT were measured according to the palatability evaluation parameters: (1) the mouth feel of ODT could be evaluated as gritty, acceptable or excellent; (2) the sweetness of ODT could be evaluated as bitter, moderate and sweet. Complete disintegration of ODT in volunteers' mouths without obvious particles was determined as the in vivo disintegration time. Each test was repeated in triplicate with each test interval of 15 minutes. 3. Results 3.1 Screening of formulations In this study, water-soluble fillers were used because they had good solubility in water and wouldn't cause rough mouthfeel (such as grittiness). The ingredients of ODT formulations was shown in Table 1. Mannitol, lactose, glucose and sucrose were usually used as water-soluble fillers in this study. Preliminary study showed mannitol was an excellent filler for preparing ODTs, it dissolved quickly in water. The tablets prepared by lactose had smooth surface and good compressibility. Sucrose had strong adhesiveness and hygroscopicity, and the tablets prepared by sucrose had higher hardness, resulted in the delay of disintegration or dissolution of tablets. Glucose had poor compressibility and generally required a large amount of binder. Therefore, the mass ratio of mannitol to lactose=3:1 was used as fillers for further study. Moreover, the impact of the type (PVPP, CMS-Na, L-HPC) and amount (1%, 3% and 5%) of disintegrants on the disintegrantion properties of ODTs were also evaluated. The disintegration time of multi-channel ODTs were shown in Figure 2. different disintegrants had different impact on the disintegration time. The formulation containing L-HPC and CMS-Na tended to form gels in the ODTs and extended the disintegration time, as the amount of L-HPC and CMS-Na increased from 1% to 5%, the disintegration time increased gradually. The formulation 6

containing PVPP showed the fastest disintegration rate, the disintegration time decreased when content of PVPP increased from 1% to 5%. the enhanced disintegration might be due to the capillary action and excellent hydration ability of PVPP [20]. In addition, we further investigated the effect of PVPP content on the insoluble residue after complete disintegration. The results in Fig. 3 showed that the insoluble residue increased gradually when PVPP content increased from 1% to 10%. PVPP was insoluble in water, and the increase of PVPP could cause a gritty feeling in the mouth, Therefore, 3% PVPP (F4) was selected as the best amount of disintegrant for further study.

Fig. 2 The disintegration time of different formulations of multi-channel aripiprazole ODTs

7

Fig. 3 The comparison of insoluble residues when PVPP content increased from 1% to 10%. 3.2 Characterization analysis of multi-channel ODTs The thickness, diameter and hardness of multi-channel ODTs were determined and the results were presented in Table 2, the mean thickness was 4.13 ± 0.02mm, and the mean diameter were 10.04 ± 0.04mm and the mean hardness was 13.50 ± 1.05N respectively. The average weight of multi-channel ODTs was 301.5 ± 1.58mg and the weight variation was within the range of 5%. In this study, the multi-channel ODTs were formed by a wet compression method. The moisture content after drying affected the hardness, friability and the flowability of powders of the ODTs. Consequently, in order to prepare high-quality ODTs, the moisture content of ODTs must be strictly controlled (0.70% ± 0.02).

8

Table 2 The test results of multi-channel aripiprazole ODTs (mean ± SD) Test projects

Results (F4)

Thickness (mm, n=6)

4.13 ± 0.02

Diameter (mm, n=6)

10.04 ± 0.04

Hardness (N, n=6)

13.50 ± 1.05

Moisture content (%, n=3)

0.70 ± 0.02

Weight variation (mg, n=20)

301.5 ± 1.58

In vitro disintegration time (s, n=6)

10.28±1.03

In vivo disintegration time (s, n=27)

23.77±3.28

3.3 Disintegration study Fig. 4 showed the disintegration process of multi-channel ODTs and commercial ODTs at 37 ℃, after complete disintegration the insoluble residue in multi-channel ODTs were less than that of commercial ODTs. It might be due to less water-insoluble disintegrants added in multi-channel aripiprazole ODTs. Fig. 5 showed the disintegration time of ODTs decreased with the increase of temperature, and the disintegration time of multi-channel ODTs at different temperatures (20°C, 37°C and 50°C) were all slightly shorter than those of the commercial ODTs.

Fig. 4 The disintegration process of (A) commercial aripiprazole ODTs and (B) multi-channel aripiprazole ODTs at 37℃.

9

Fig. 5 Disintegration time of multi-channel aripiprazole ODTs and commercial aripiprazole ODTs at different temperatures. 3.4 Dissolution study The in vitro dissolution results in Fig. 6 showed that multi-channel ODTs had similar in vitro dissolution characteristics as commercial ODTs, 80% of the aripiprazole dissolved in 5 min for multi-channel ODTs and commercial ODTs, and more than 95% of the aripiprazole dissolved in 20 min (Fig. 6). Due to multi-channel ODTs contained fewer disintegrants than those of commercial ODTs, it could effectively reduce the cost and improve the taste by reducing the content of disintegrants.

10

Fig. 6 The in vitro dissolution studies of aripiprazole in different ODT formulations. 3.5 Taste evaluation and in vivo disintegration time In this study, all the volunteers showed good acceptable palatability to multi-channel ODTs with an excellent mouthfeel. However, all the volunteers responded unpleasantly to commercial ODTs with a gritty mouthfeel and moderate-tasting. The in vivo disintegration time of multi-channel ODTs and commercial ODTs was 23.77±3.28s and 26.91± 2.68s respectively. The volunteers concluded that multi-channel ODTs were more palatable and disintegrate slightly faster than those of commercial ODTs and had no gritty feeling in the mouth. Moreover, although mannitol and lactose in the formulation provided a cool and sweet taste, the addition of aspartame and strawberry flavor could furtherly improve taste and increase volunteers’ acceptance. 3.6 Disintegration mechanism and physical model analysis In this study, the influence of channel structure on the disintegration of ODTs were investigated and the underlying mechanism of disintegration theory was illustrated. In general, incorporation of disintegrants was an established method to accelerate drug release from tablets. However, with the help of multi-channel structure, disintegrants worked more effectively by increasing water permeation into the inner of ODTs. The acceleration of disintegration of ODTs was attributed to shortening the water penetration distance and increasing the specific surface area 11

[21-23]. The Figure 7 showed the disintegration process of multi-channel ODTs and commercial ODTs without channels. Due to the swelling action of the disintegrants and the strong hydrophilicity of the fillers, the water could form a hydrophilic network with the surface of the ODTs, and then the water penetrated into the inner part on the surface of ODTs in all directions. The water penetration kinetics could follow a square-root of time behavior, the penetration distance was a function of time [24]. The penetration rate decreased with distance from the surface, when water contacted with multi-channel ODTs, water would penetrate into the outer surface and internal channels, the swelling action of the disintegrants further promoted the penetration of water, so both the substances on the outer surface of ODTs and the inner surface of the channels disintegrated and collapsed, then new surface appeared and disintegration was accelerated. While for a traditional or commercial tablet without the channels, the tablet disintegration happened layer by layer from outer surface to inner core, the permeation distance during disintegration was much longer than that of multi-channel structure. Therefore, the presence of the channels significantly shortened the distance of water penetration, thereby significantly accelerating tablet disintegration, this was the remarkable advantage of multi-channel ODTs.

12

Fig. 7 A simple physical model of the effect of channels on disintegration. Where R was the radius of ODTs, r was the radius of multi-channels, h was the thickness of ODTs. In the research of multi-channel ODTs, we realized the number, diameter and location of channels would change the distance between the channels. The effect of the number, diameter and location of channels on the disintegration behavior of ODTs should be investigated in the further study. 4. Conclusion In this study, multi-channel aripiprazole ODTs were developed using wet compression method. The optimum formulation was screened and the characterization and quality control of ODTs were studied. 3% PVPP and mannitol: lactose = 3:1 were used in the optimized formulation for the multi-channel ODTs. A series of studies confirmed that multi-channel aripiprazole ODTs had shorter disintegration time, faster dissolution and better palatability than commercial ODTs. The results demonstrated that multi-channel ODTs shorten the penetration distance of water, and thus increased the disintegration rate of ODTs and the multi-channel ODTs was suitable for further use in clinical practice. Declaration of Interest 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);

the

Hebei

University

College

Students

Innovation

and

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Author Statement Dear editor: I am very grateful for your rigorous work, and thanks for your invitation to revise my submission “Development and evaluation of a novel innovative multi-channel aripiprazole orally disintegrating tablets”. JDDST_2019_1070. We would like to express our sincere thanks to the reviewers for the constructive and positive comments. We have addressed the comments raised by the reviewers, and the amendments are highlighted in the revised manuscript. Point by point responses to the reviewers’ comments are listed below this letter. If you have any questions about the revision, please contact with me. I look forward to hearing from you soon. Sincerely, Liandong Hu [email protected]

Declaration of Interest The authors report no declarations of interest.