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Optimization and characterization of novel sustained release supermicro-pellet based dry suspensions that load dexibuprofen
Journal Pre-proof Optimization and characterization of novel sustained release supermicro-pellet based dry suspensions that load dexibuprofen Ya-Nan Xia, Xiang-Hui Li, Jie-Hong Xu, Li-Qing Chen, Atef Mohammed Qasem Ahmed, Dingyun Cao, Huan-Huan Du, Yibin Deng, Qing-Ri Cao PII:
S1773-2247(19)31257-2
DOI:
https://doi.org/10.1016/j.jddst.2019.101420
Reference:
JDDST 101420
To appear in:
Journal of Drug Delivery Science and Technology
Received Date: 24 August 2019 Revised Date:
27 October 2019
Accepted Date: 25 November 2019
Please cite this article as: Y.-N. Xia, X.-H. Li, J.-H. Xu, L.-Q. Chen, A.M. Qasem Ahmed, D. Cao, H.H. Du, Y. Deng, Q.-R. Cao, Optimization and characterization of novel sustained release supermicropellet based dry suspensions that load dexibuprofen, Journal of Drug Delivery Science and Technology (2019), doi: https://doi.org/10.1016/j.jddst.2019.101420. 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.
Super-mini core
100
Drug layer SR coating layer
Release rate (%)
80 60
SR pellets (PVPK30) SR pellets (Poloxamer188)
40
Drug-layered pellets (PVPK30) Drug-layered pellets (Poloxamer188)
20 0
SR pellet
0
0.5
1
2 4 Time(h)
Suspending agents Diluent granules
Sedimentation rate (Hu/H)
1
8
12
24
0.8 0.6 F1
0.4
F2 F3
0.2
F4 F5
SR dry suspension
0 1
2
3 Time(min)
4
5
1
Optimization and characterization of novel sustained release supermicro-pellet
2
based dry suspensions that load dexibuprofen
3 4
Ya-Nan Xiaa,1, Xiang-Hui Lib,1, Jie-Hong Xua, Li-Qing Chena, Atef Mohammed
5
Qasem Ahmeda, Dingyun Caoc, Huan-Huan Dua, Yibin Denga, Qing-Ri Caoa,*
6 7
a
8
Republic of China
9
b
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People’s
Jilin Armed Police Corps Hospital, Pharmacy Department, Jilin province, Changchun
10
130052, People’s Republic of China
11
c
12
People’s Republic of China
Suzhou No3 high school sino-us course center, Jiangsu Province, Suzhou 215001,
13 14 15
Corresponding authors:
16
*
Qing-Ri Cao, E-mail: [email protected], Tel: 86-13862012952.
17 18
1
These authors contributed equally to this work.
19 20
1
21
ABSTRACT
22
Traditional dosage forms of dexibuprofen extremely limit their clinical applications
23
because of the bitter taste and the frequent drug administration caused by the relatively
24
short half-life of the drug. This study aims to design novel sustained release (SR)
25
supermicro-pellet based dry suspensions that load dexibuprofen, and also optimize the
26
formulations in terms of morphology, release rate, flowability, and physicochemical
27
stability of dosage forms. Drug-loaded pellets were prepared by using a bottom spray
28
fluid bed coating technique using microcrystalline cellulose supermicro-pellets as the core
29
and PVP K30 or Poloxamer 188 as the binder. The drug-loaded pellets were further
30
coated with Kollicoat SR 30D to form SR pellets. The optimal SR dry suspensions are
31
composed of SR pellets, diluent granules, and suspending agents. PVP K30- and
32
Poloxamer 188-based SR pellets release the drug molecules in a SR manner over 8 h and
33
show a high release profile for Poloxamer 188-based pellets. The drug release profile is
34
not affected by the rotation speed of the paddle but shows a distinct pH-responsive
35
behavior. The physical property of dexibuprofen has been changed during the
36
preparation process. The SR dry suspensions (F5, with high amount of xanthan gum in
37
suspending agents and low amount of poloxamer 188 in diluent granules) show high
38
physical stability with the sedimentation rate of 0.8 (Hu/H) within 5 min and good
39
flowability with the angle of repose (θ) at 27°. Low content variations were observed with
40
a value of A+1.80SD ≤15, and no significant change was found in the drug content
41
under high humidity and strong light. In conclusion, novel SR supermicro-pellet based
42
dry suspensions have been successfully prepared, and the optimal formulation shows
43
excellent SR, good flowability, content uniformity, and physicochemical stability.
44 45
Keywords: Dexibuprofen; Sustained release; Supermicro-pellet; Dry suspension;
46
Optimization
47
2
48
1. Introduction
49
Dexibuprofen is the S (+)-isomer of ibuprofen that was launched in Austria in 1994 [1].
50
Numerous studies have shown that the S (+) ibuprofen is more effective against analgesic
51
and anti-inflammatory effects and in reducing acute gastric damage than its racemate
52
[2,3]. The activity of dexibuprofen is 160 and 1.6 times of its left-handed and racemic
53
forms [4-7]. Therefore, research on dexibuprofen formulations became popular in
54
medicine and pharmacy fields.
55
Currently, the formulations of dexibuprofen on the market are mainly capsules, oral
56
liquid suspensions, suppositories, and tablets [8]. The elimination half-life of
57
dexibuprofen is 1.6–4.2 hours, thereby requiring frequent drug administration. This
58
phenomenon often leads to fluctuations in blood drug concentration and adverse effects
59
[9]. Thus, the development of dexibuprofen sustained-release (SR) preparations can help
60
reduce the peak and valley fluctuation of blood drug concentration, reduce the drug
61
administration frequency, and improve patient compliance [10, 11]. To the best of our
62
knowledge, only a few studies have been performed on dexibuprofen’s SR dosage forms.
63
Manjanna et al. investigated novel dexibuprofen SR microbeads prepared with
64
alginate and showed good SR performance after being further coated with guar gum
65
(1% w/v) and chitosan (1%w/v) [9]. Kim et al. prepared dexibuprofen dry elixir (DDE)
66
and coated DDE (CDDE) with Eudragit RS as the coating material [12]. In contrast to
67
dexibuprofen powder, the dissolution rate and bioavailability of DDE were improved.
68
In particular, CDDE can delay the dissolution of dexibuprofen without reducing
69
bioavailability. However, the preparation processeses of the dexibuprofen SR
70
microbeads and coated dexibuprofen dry elixir are complicated and may have
71
technical difficulties for continuous production.
72
As a multiple-unit preparation, sustained-release pellets have the following advantages.
73
Firstly, the contact area between the drug and gastrointestinal tract increases after oral
74
administration, thereby avoiding the stimulation of gastric mucosa caused by the high
75
concentration of local drugs [13, 14]. Secondly, defects in individual units do not affect
76
the whole preparation [15]. The individual difference of pellets is reduced, affording
77
stable bioavailability in vivo. Thirdly, the small particle size of the pellets ensures that
78
they are not easily affected by gastric emptying, thereby resulting in stable drug release
79
for well controlling its blood–drug concentration [16, 17]. Lastly, there is a low incidence
80
of adverse reactions for sustained-release dexibuprofen pellets, and the bitter taste is
81
masked [15, 18-20]. 3
82
Dry suspension is a new dosage form in which a poorly soluble drug and a suitable
83
auxiliary material are made into a powder or a granule that can be dispersed into a
84
suspension for oral administration by shaking with water [21]. Dry suspensions have the
85
advantages of solid preparations (granules) such as convenient to carry and transport and
86
good stability. Moreover, dry suspensions can be administered easily, especially suitable
87
for patients such as children and the elderly who have difficulty in swallowing [22-24].
88
Kollicoat SR 30D, as one of most well known coating materials, has been widely used
89
for SR pellets or tablets [1, 25, 26]. However, core pellet with a diameter larger than 300
90
µm causes remarkable size growth by drug layering and Kollicoat SR coating, thereby
91
resulting in possible content non-uniformity when mixing with other powder type
92
excipients. In contrast, formulating with supermicro-sized pellet (100-300 µm) may
93
guarantee the content uniformity of dry suspension, whereas it needs high experienced
94
coating technique to avoid the aggregation of pellet during the coating process [27]. In
95
addition, the taste-masking effect of bitter dexibuprofen can also be achieved through this
96
approach.
97
In this study, novel SR supermicro-pellet based dry suspensions that load
98
dexibuprofen were studied, and the formulations were also optimized in terms of
99
morphology, release rate, flowability, and physicochemical stability of the obtained
100
dosage forms. The drug-loaded and Kollicoat SR 30D-coated pellets were prepared by a
101
bottom spray fluid bed coating technique using microcrystalline cellulose
102
supermicro-pellet as the core and PVP K30 (or Poloxamer 188) as the binder. The
103
effects of the binder on the drug release of SR pellets were investigated. The effect of
104
various dissolution conditions on drug release was evaluated as well. In addition,
105
physicochemical characterizations of SR pellets were conducted to verify the
106
molecular changes of drug in pellets. Finally, the SR dry suspensions composed of SR
107
pellets, diluent granules, and suspending agents were optimized on the basis of
108
sedimentation rate, angle of repose, content uniformity, and stress test.
109 110
2. Materials and methods
111
2.1. Materials
112
Dexibuprofen (C102-1412017M) was purchased from Hubei Baike Hengdi
113
Pharmaceutical Co., Ltd. (Hubei, China). Blank pellet core (14I2) was purchased from
114
Asahi Kasei Corp (Japan). Polyvinylpyrrolidone K-30 (PVP-K30, 20110924) was
115
provided by Beijing Fengli Jingqi Co., Ltd. (Beijing, China). 4
Poloxamer 188,
116
Kollicoat SR 30D and hydroxypropyl methyl cellulose were purchased from BASF
117
(Germany). Starch, xanthan gum and silicon dioxide were obtained from Anhui
118
Shanhe Pharmaceutical Accessories Co., Ltd. (Anhui, China). Talc powder was
119
provided by Guangxi Longsheng Huamei Co., Ltd. (Guangxi, China). Anhydrous
120
citric acid, phosphoric acid, hydrochloric acid, potassium dihydrogen phosphate,
121
sodium hydroxide, sodium benzoate, sucralose and sucrose were purchased from
122
Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Sodium citrate was
123
purchased from Hunan huari pharmaceutical Co., Ltd. (Hunan, China). Triethyl citrate
124
was purchased from Aladdin (Shanghai, China). Flavor was purchased from Symrise
125
Co., Ltd. (Shanghai, China). Acetonitrile was purchased from Honeywell Trading
126
Shanghai Co., Ltd. (Shanghai, China). Acetic acid was purchased from CHINASUN
127
Specialty Products Co., Ltd. (Jiangsu, China). Ethanol was purchased from Shanghai
128
lingfeng Chemical Reagent Co., Ltd. (Shanghai, China).
129
2.2. Preparation of dexibuprofen sustained-release pellets
130
2.2.1. Drug-loading layer
131
The binder PVP K30 (or Poloxamer 188) was dissolved in anhydrous ethanol by
132
gentle stirring. The dexibuprofen was added to the binder solution while stirring.
133
Drug-loaded pellets were prepared by loading a drug–binder solution on micro-pellet
134
cores with particle sizes of 100–300 µm in a fluidized bed coater (Mini-XYT,
135
Shenzhen, China) via the bottom spray technique. The coating parameters were as
136
follows: inlet temperature, 38–42 °C; product temperature, 28–31 °C; atomization
137
pressure, 0.05–0.07 MPa; spray rate, 1.0–1.5 ml/min; and final drying at 37 °C for 30
138
min.
139
2.2.2. Sustained-release layer
140
Talc was added to some portion of water and homogenized by a high-pressure shear
141
homogenizer for 10 min. Triethyl citrate and Kollicoat SR 30D were added to the
142
remaining water while stirring. The talc suspension was added to the Kollicoat SR
143
30D dispersion to obtain SR coating suspension after thoroughly mixing. The
144
drug-loaded pellets were coated with the upper SR coating suspension in a fluidized
145
bed coater. The inlet and product temperature were set at 35 °C and 28–30 °C, and the
146
spray rate and atomization pressure were 0.5–0.7 ml/min and 0.05–0.07 MPa,
147
respectively. The fan rolling speed was 600 rpm/min. The coated pellets were dried at
148
37 °C for 30 min and further incubated at 60 °C for 5 h. Finally, the sustained-release
149
pellets were stored in desiccators at ambient temperature. Table 1 summarizes the 5
150
compositions of two different sustained-release pellets that load dexibuprofen.
151
2.3. Preparation of dexibuprofen sustained-release dry suspensions
152
2.3.1. Preparation of diluent granules
153
Poloxamer 188 was dissolved in distilled water to form an aqueous solution.
154
Sucrose, sodium citrate, anhydrous citric acid, and sodium benzoate were mixed
155
together. Then, poloxamer 188 aqueous solution was added dropwise to the powder
156
mixture by grinding. The resulting wet mass passed through a 20-mesh sieve and the
157
generated particles were dried at 60 °C for 2 h to obtain diluent granules. Table 2
158
summarizes the compositions of three different diluent granules.
159
2.3.2. Preparation of dry suspensions
160
Starch, xanthan gum, talc, flavor, silicon dioxide, and sucrose were weighted and
161
thoroughly mixed. Then, the resulting powder were mixed with the drug-loaded SR
162
pellets and diluent granules and further blended for 10 min. Table 3 shows five
163
different formulation compositions of SR micro-pellet-based dry suspensions.
164
2.4. Surface morphology
165
The surface morphologies of blank micro-pellet core, drug-loaded pellets, and SR
166
pellets were imaged using a digital camera and a scanning electron microscope (SEM,
167
ZEISS EVO18). For SEM images, the samples were placed on a double-sided
168
adhesive tape attached to an aluminum stub and then sputter-coated with
169
gold/palladium beam for 2 min. Furthermore, the appearance of dexibuprofen
170
sustained-release dry suspensions was imaged using a digital camera.
171
2.5. Drug release
172
According to the Chinese Pharmacopoeia 2015 Edition of the “Dexibuprofen
173
capsule” dissolution test method, the dissolution rate of the drug-layered pellets and
174
their sustained-release coated forms were investigated. Each sample (100 mg) was
175
accurately weighed and placed in the dissolution basket. The temperature of
176
dissolution medium was set at 37 ± 0.5 °C. At 0.5, 1, 2, 4, 8, 12, and 24 h, 2.5 ml of
177
each medium was taken and diluted by adding phosphate buffer solution with the
178
same volume. Then, each sample was centrifuged at 10,000 rpm for 10 min. A total of
179
20 µl of the supernatant solution was injected to HPLC according to the content
180
analysis of chromatographic method for dexibuprofen. The effects of stirring speed
181
(50, 100, and 150 rpm) of basket and pH (1.2, 4.5, 6.8, 7.4, and water) of the
182
dissolution medium on drug release were also investigated.
183
2.6. HPLC analysis of dexibuprofen 6
184
Drug analysis was conducted according to the method of Chinese Pharmacopoeia
185
2015 using a 5C18-MS-II (5 µm, 4.6 mm × 250 mm) column on a high-performance
186
liquid chromatography (HPLC, LC-15C, SHIMADZU, Japan). The column
187
temperature remained at 35 °C. The mobile phase consisted of 35% acetonitrile and
188
65% phosphate buffer (pH 7.6) (v/v). The injection volume was 20 µl, and the flow
189
rate was 1.0 ml/min. The detection wavelength was set at 280 nm.
190
2.7. Differential scanning calorimetry (DSC)
191
The DSC of dexibuprofen (pure drug), blank pellet core, PVP K30, Poloxamer 188,
192
drug-loaded pellets (with PVP K30), and drug-loaded pellets (with Poloxamer 188)
193
were measured using a differential scanning calorimeter (Model 2010, TA Instruments,
194
USA). The empty aluminum clamp pan was used as the reference material, and 3 mg
195
of each sample was placed in the other aluminum pot. The samples were heated from
196
10 °C to 250 °C at a scanning speed of 10 °C/min under the nitrogen atmosphere.
197
2.8. Sedimentation rate
198
Three grams of dry suspension was dispersed in distilled water contained in 50 ml
199
glass tube, followed by thoroughly shaking. The initial height (H) was recorded, and
200
the sediment height (Hu) at 1, 2, 3, 4, and 5 min were recorded separately. Then, the
201
sedimentation volume ratio F (Hu/H) was calculated by measuring the ratio of Hu to
202
H. The sedimentation rate curve was plotted by taking the sedimentation volume ratio
203
F (Hu/H) as the ordinate and time T as the abscissa.
204
2.9. Angle of repose (Flowability)
205
Approximately 20 grams of dexibuprofen micro-pellet-based dry suspensions were
206
taken, and the angle of repose was measured according to Chinese Pharmacopoeia
207
2015.
208
2.10.
Content uniformity
209
The drug content uniformity of dry suspensions (F5) was determined. Ten samples
210
(0.11 g for each sample) of each formulation were randomly selected and separately
211
placed in 25 ml volumetric flasks. Methanol at 15 ml was added and vortexed to fully
212
dissolve the drug. Then, methanol was added to the marking line. After shaking for 5
213
min, the suspension was centrifuged at 10,000 rpm for 10 min. Finally, the drug
214
content of the supernatant was determined using the HPLC method as described
215
above.
216
2.11.
217
Stress test
The stability of dexibuprofen sustained-release dry suspension were investigated 7
218
under stress conditions, such as high temperature 60 °C, high humidity (25 °C,
219
relative humidity 92.5 %), and strong light (4500±500) Lx, for 10 days. The samples
220
were individually taken after 5 and 10 days. The drug content and related substances
221
in dexibuprofen sustained-release dry suspensions were analyzed by a HPLC system.
222
2.12.
Statistical analysis
223
Data were presented as mean ± standard deviation (S.D.), and their statistical
224
significance of difference was examined using SPSS 16.0. P-values less than 0.05
225
were considered statistically significant. (*p<0.05, **p<0.01, ***p<0.001).
226 227
3. Results and discussion
228
3.1. Surface morphology
229
This study developed novel dexibuprofen SR supermicro-pellet based dry
230
suspensions. Aggregates of mini-pellets commonly appeared during the fluid-bed
231
coating process, and this phenomenon was fully overcome by modulating the
232
parameters of the coating process. Dexibuprofen was loaded onto the microcrystalline
233
cellulose supermicro-pellet cores using PVP K30 or Poloxamer 188 as the binder,
234
followed by coating with Kollicoat SR 30D as the sustained-release coating polymer.
235
Two types of SR pellets were prepared (Table 1). The reason of adding enough talc in
236
SR coating layer is to avoid the aggregation of pellets during the coating process. If
237
talc was less than this level, we could not get the uniform SR pellets. The dry
238
suspensions were obtained by mixing SR pellets, diluent granules, and suspending
239
agents. The formulation compositions of various diluent granules and dry suspensions
240
for optimization are also listed in Table 2. Fig. 1 shows that after drug layering and
241
SR coating, the SR pellets are still spherical in shape showing similar morphology to
242
the pellet core. As shown in Fig.2, the distinct drug and SR layers could be observed
243
from the cross section of the pellets.
244
3.2. Drug release
245
In this study, the SR characteristics of dexibuprofen SR pellets were evaluated at
246
different release conditions. Firstly, the effects of two different binders on the release
247
of dexibuprofen were investigated. As shown in Fig. 3, two drug-layered pellets had a
248
dissolution rate of more than 90% within 30 min, and the SR effect was not apparent.
249
In fact, no significant difference was observed in the SR effect of PVPK30- and
250
Poloxamer188-based pellets. On the contrary, the coated SR pellets showed sustained
251
release over 8 h. Moreover, the release rate of Poloxamer188-based SR pellets was 8
252
higher than that of PVPK30-based SR pellets, and a significant difference between the
253
two formulations was observed within the first 4 h. This result may be due to the
254
solubilization effect of Poloxamer 188. The solubilization of Poloxamer 188 on drug
255
is based on the decrease of surface tension and drug wettability.
256
The effect of stirring rate on drug release from SR pellets was investigated (Fig. 4).
257
The stirring rate did not remarkably affect the release rate of SR pellets for PVPK30-
258
and Poloxamer188-based SR pellets. In addition, the release of dexibuprofen SR
259
pellets was also investigated in buffer solutions with different pH values. In Fig. 5, the
260
drug release from SR pellets increased with increasing pH. However, the release rate
261
of SR pellets did not significantly differ at pH 6.8 and pH 7.4. This finding may be
262
attributed to the pH-dependent solubility of drug in various dissolution media. The
263
previous study illustrated that low pH values limited drug solubility, and drug release
264
increased with increasing pH [5].
265
3.3. DSC
266
The DSC pattern of pure drug, drug-free core, binders, and drug-layered pellets are
267
shown in Fig. 6. The endothermic peak at 50 °C refers to the melting point peak of
268
dexibuprofen. Another endothermic peak was observed at 210 °C, which corresponds
269
to the evaporation of dexibuprofen. Our data were basically consistent with those of
270
the previous study, which showed that the onset of the endothermic peak of
271
dexibuprofen was at 47.25 °C, thereby reaching a peak at 56.51 °C. The enthalpy was
272
210.40 J/g [28]. No significant peaks for the pellet core and PVP K30 appeared at
273
50 °C and 210 °C, respectively. The drug-layered pellets showed a melting point peak
274
at 50 °C and an obvious endothermic peak at 260 °C. The shifting of endothermic
275
peak from 210 °C to 260 °C might be due to the change of the physical property of
276
dexibuprofen during the preparation process [29].
277
3.4. Sedimentation rate
278
The sedimentation rate of the five types of SR dry suspensions were evaluated by
279
measuring the ratio of Hu to H. In Fig. 7, the sedimentation rates of F1 and F3 were
280
relatively fast, whereas those of F2, F4, and F5 were relatively slow. This result might
281
be attributed to the amount of xanthan gum in suspending agents and poloxamer in
282
diluent granules. The sedimentation rate gradually decreased as the amount of xanthan
283
gum increased (F1, F4, and F5). Undoubtedly, the suspending properties of SR dry
284
suspensions were remarkably affected by the amount xanthan gum. In addition, the
285
amount of Poloxamer 188 was also related to the sedimentation rate of the 9
286
suspensions, and low levels of Poloxamer 188 led to high stability of the suspensions
287
(F1, F2, and F3). This phenomenon may be due to the fact that the surfactant has no
288
positive effects for the suspending properties of xanthan gum. Khan et al. found that
289
the viscosity of xanthan gum could decrease with the increase of surfactant
290
concentration. When the concentration of sodium dodecyl sulfate increased from 0
291
mM to 5 mM, the viscosity of xanthan gum solution remarkably decreased [30].
292
3.5. Angle of repose (Flowability)
293
The flowability of SR dry suspensions was investigated by measuring the angle of
294
repose. Low angle of repose corresponds to high flowability for the granules. When the
295
angle of repose (θ) is ≤ 40°, flowability is satisfied with the requirements in the
296
production process. When the angle of repose (θ) is ≤ 30°, the granules shows excellent
297
flowability. In Fig. 8, all formulations (F1, F2, F3, F4, and F5) showed good flowability
298
since all the angle of repose (θ) is less than 31°. Especially, the angle of repose (θ) was
299
even lower than 28° for F1 and F5, which showed extremely good flowability. Overall,
300
SR dry suspensions, which were composed of SR pellets, diluent granules, and
301
suspending agents, were suitable for the filling and packing process.
302
3.6. Content uniformity
303
The uniformity of drug content was determined for the formulation F5 based on the
304
results of sedimentation rate and angle of repose. In Table 4, the formulation F5 had
305
A+1.80SD≤15.0, and the sample showed relatively high content uniformity.
306
3.7. Stress test
307
The stress stability of F5 formulation were evaluated under high temperature
308
(60 °C), high humidity (92.5% RH), and strong light (4500 Lx) for 5 and 10 days,
309
respectively. The changes of related substances were measured by HPLC. In Table 5,
310
the content of related substances significantly increased within 10 days at a high
311
temperature of 60 °C. However, almost no change was observed under high humidity
312
(RH 92.5%) and strong light (4500 Lx). Therefore, our findings suggested that SR dry
313
suspensions should be stored in a cool place to ensure stability.
314 315
4. Conclusion
316
In this study, novel SR supermicro-pellet based dry suspensions composed of SR
317
pellets, diluent granules, and suspending agents were successfully prepared and
318
characterized. PVP K30- and Poloxamer 188-based SR pellets released the drug
319
molecules as a SR manner over 8 h. The drug release was stable and not affected by the 10
320
rotation speed of the paddle. The DSC result showed that the physical property of
321
dexibuprofen has been changed during the preparation process. The optimal
322
formulation F5 with high amount of xanthan gum in suspending agents and low amount
323
of poloxamer 188 showed low sedimentation rate and good flowability, content
324
uniformity, and chemical stability under various storage conditions. The SR dry
325
suspensions should be kept in a cool dry place to ensure stability.
326 327 328 329
Acknowledgements This work was partially supported by the project funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions, China.
330 331 332
Conflict of interest No potential conflicts of interest were disclosed.
333 334
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335 336
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381 382
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Novel compaction techniques with pellet-containing granules, Eur. J. Pharm.
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Biopharm. 75 (3) (2010) 436-442.
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Q.R. Cao, Positively charged surface-modified solid lipid nanoparticles promote 12
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the intestinal transport of docetaxel through multifunctional mechanisms in rats,
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dry emulsion and dry suspension using octenyl succinic anhydride starch as
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emulsifying agent and solid carrier. Int. J. Pharm. 498 (1-2) (2016) 347-354.
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oral dry suspension using taste masked Ornidazole particles prepared using
404
Kollicoat(®) Smartseal 30 D, Drug Dev. Ind. Pharm. 39 (7) (2013) 1091-1097.
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[23] Y. Du, Y. Zhai, J. Zhang, C. Wu, C. Luo, J. Sun, Z. He, Development and
406
evaluation of taste-masked dry suspension of cefuroxime axetil for enhancement
407
of oral bioavailability, Asian J. Pharm. Sci. 8 (5) (2013) 287–294.
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[24] M.R. Rao, R.C. Bhingole, Nanosponge-based pediatric-controlled release dry
409
suspension of Gabapentin for reconstitution, Drug Dev. Ind. Pharm.
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(2015) 2029-2036.
41 (12)
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[25] G. Zoubari, R. Ali, A. Dashevskiy, Water-insoluble polymers as binders for pellet
412
drug layering: Effect on drug release and performance upon compression, Int. J.
413
Pharm. 569 (2019) :118520. doi: 10.1016/j.ijpharm.2019.118520. Epub 2019 Jul
414
27.
415
[26] F. Eisenächer, G. Garbacz, K. Mäder, Physiological relevant in vitro evaluation of
416
polymer
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417
Biopharm.88(3)(2014) 778-786.
floating
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Pharm.
418
[27] J.Y. Liu, X.X. Zhang, H.Y. Huang, B.J. Lee, J.H. Cui, Q.R. Cao, Esomeprazole
419
magnesium enteric-coated pellet-based tablets with high acid tolerance and good
420
compressibility, J. Pharm. Invest. 48(2018) 341-350.
421
[28] B.M. El-Houssieny, E.Z. El-Dein, H.M. El-Messiry, Enhancement of solubility 13
422
of dexibuprofen applying mixed hydrotropic solubilization technique, Drug
423
Discov. Ther. 8 (4) (2014) 178-184.
424
[29] S.A. Botha, A.P. Lotter, Compatibility study between atenolol and tablet
425
excipient using differential scanning calorimetery, Drug Dev. Ind. Pharm. 16 (12)
426
(2008) 1945-1954.
427 428
[30] S.Y. Khan, M. Yusuf, N. Sardar, Studies on rheological behavior of xanthan gum solutions in presence of additives, PEDJP. 2017-2017.
429
14
430
FIGURE LEGENDS
431
Fig. 1. Surface morphology of pellet core, drug-loaded pellets, and sustained-release
432
pellets. (A) PVP K30 as a binder, (B) Poloxamer 188 as a binder, (a) core pellets, (b)
433
drug-layered pellet, and (c) SR coated pellets
434
Fig. 2. Cross section images of pellet core, drug-loaded pellets, and sustained-release
435
pellets. (A) PVP K30 as a binder, (B) Poloxamer 188 as a binder, (a) core pellets, (b)
436
drug-layered pellet, and (c) SR coated pellets
437
Fig. 3. Release profiles of drug-layered and SR pellets at pH 7.4 phosphate buffer
438
saline solution.
439
Fig. 4. Effect of rotation speed on drug release from SR pellets.
440
Fig. 5. Effect of pH on the release of drug release from SR pellets
441
Fig. 6. DSC curves of pure drug, drug-free core, binders, and drug-layered pellets
442
Fig. 7. Sedimentation rate of five different SR dry suspensions
443
Fig. 8. Angle of repose of five different SR dry suspensions.
444
15
445
TABLE LEGENDS
446 447
Table 1 Formulation compositions of sustained-release pellets
448
Table 2 Formulation compositions of three different diluent granules
449
Table 3 Formulation compositions of SR dry suspensions
450
Table 4 Drug content uniformity of optimal SR dry suspensions (F5)
451
Table 5 Stress stability of optimal SR dry suspensions (F5)
452
16
Table 1 Type Pellet core Drug-layered pellets
Sustainedrelease pellets
SR1
SR2
MCC Drug PVP K30
80g 36g 1g
Ethanol
100ml
Kollicoat SR 30D Triethyl citrate Talc Water
MCC Drug Poloxamer 188 Ethanol Water
80g 36g 1g 95ml 5ml
20g
Kollicoat SR 30D
20g
1g 8g 100ml
Triethyl citrate Talc Water
1g 8g 100ml
1
Table 2 Ingredient
DG1 (mg)
DG2 (mg)
DG3 (mg)
Poloxamer 188
125
75
175
Sucrose
34418
34468
34368
Sodium citrate
965
965
965
Anhydrous citric acid
1290
1290
1290
Sodium benzoate
500
500
500
Sucralose
200
200
200
Purified Water
1764
1764
1764
2
Table 3 Ingredient (g) Sustained-release pellets
F1
F2
F3
F4
F5
2.6484
2.647
2.6437
2.6396
2.645
Diluent granules
17.033 (DG1)
17.033 (DG2)
17.033 (DG3)
17.033 (DG1)
17.033 (DG1)
Starch
1.567
1.567
1.567
1.567
1.567
Xanthan gum
0.1205
0.1705
0.1705
0.1705
0.2205
Talc
0.2275
0.2275
0.2275
0.2275
0.2275
Flavor
0.1705
0.1705
0.1705
0.1705
0.1705
Silicon dioxide
0.2275
0.2275
0.2275
0.2275
0.2275
Sucrose
0.7295
0.6795
0.6795
0.6795
0.6295
3
Table 4 F5
Drug content* (mg)
1
0.04
2
0.06
3
0.06
4
0.05
5
0.05
6
0.05
7
0.05
8
0.05
9
0.04
SD
Average
Labelled amount
0.0067
0.05
0.046
10 0.05 * Drug content per mg sample
4
X=Average/ Labelled A=|100-X| A+1.80SD amount *100
109
9
9.01
Table 5 Related substances/% Formulation
RH 92.5%
60 ℃
4500 Lx
0d 5d
10d
5d
10d
5d
10d
F5（Sample 1）
0.03
0.99
2.41
0.04
0.02
0.12
0.04
F5（Sample 2）
0.04
0.86
3.91
0.04
0.02
0.03
0.05
F5（Sample 3）
0.04
0.87
2.87
0.04
0.11
0.03
0.04
5
Fig.1
1
Fig.2
2
100
Release rate (%)
80 60 SR pellets (PVPK30)
40
SR pellets (Poloxamer188) Drug-layered pellets (PVPK30)
20 Drug-layered pellets (Poloxamer188)
0 0
0.5
1
2
4
Time(h)
Fig.3
3
8
12
24
100 80
Release rate (%)
50RPM(PVPK30) 100RPM(PVPK30)
60
150RPM(PVPK30)
40
50RPM(Poloxamer188) 100RPM(Poloxamer188)
20
150RPM(Poloxamer188)
0 0
0.5
1
2
4
Time (h)
Fig.4
4
8
12
24
100
Release rate（%）
80 60 Water
40
pH1.2 pH4.5
20
pH6.8 pH7.4
0 0
0.5
1
2
4
Time (h)
Fig.5
5
8
12
24
Drug-layered pellets (with Poloxamer 188) Drug-layered pellets (with PVP K30) Poloxamer 188 PVP K30 Drug-free core Drug
50
100
150
200
250
300
350
T(centigrade)
Fig.6
6
400
450
500
1 0.9
Sedimentation rate (Hu/H
0.8 0.7 0.6
F1
0.5
F2
0.4
F3
0.3
F4 F5
0.2 0.1 0 1
2
3
Time(min) Fig.7
7
4
5
32.0
Angle of repose(θ)
31.0 30.0 29.0 28.0 27.0 26.0 25.0 24.0 F1
F2
F3
Formulation code Fig.8
8
F4
F5
Declaration of interest The authors declare no conflict of interest.
S1773-2247(19)31257-2
DOI:
https://doi.org/10.1016/j.jddst.2019.101420
Reference:
JDDST 101420
To appear in:
Journal of Drug Delivery Science and Technology
Received Date: 24 August 2019 Revised Date:
27 October 2019
Accepted Date: 25 November 2019
Please cite this article as: Y.-N. Xia, X.-H. Li, J.-H. Xu, L.-Q. Chen, A.M. Qasem Ahmed, D. Cao, H.H. Du, Y. Deng, Q.-R. Cao, Optimization and characterization of novel sustained release supermicropellet based dry suspensions that load dexibuprofen, Journal of Drug Delivery Science and Technology (2019), doi: https://doi.org/10.1016/j.jddst.2019.101420. 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.
Super-mini core
100
Drug layer SR coating layer
Release rate (%)
80 60
SR pellets (PVPK30) SR pellets (Poloxamer188)
40
Drug-layered pellets (PVPK30) Drug-layered pellets (Poloxamer188)
20 0
SR pellet
0
0.5
1
2 4 Time(h)
Suspending agents Diluent granules
Sedimentation rate (Hu/H)
1
8
12
24
0.8 0.6 F1
0.4
F2 F3
0.2
F4 F5
SR dry suspension
0 1
2
3 Time(min)
4
5
1
Optimization and characterization of novel sustained release supermicro-pellet
2
based dry suspensions that load dexibuprofen
3 4
Ya-Nan Xiaa,1, Xiang-Hui Lib,1, Jie-Hong Xua, Li-Qing Chena, Atef Mohammed
5
Qasem Ahmeda, Dingyun Caoc, Huan-Huan Dua, Yibin Denga, Qing-Ri Caoa,*
6 7
a
8
Republic of China
9
b
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People’s
Jilin Armed Police Corps Hospital, Pharmacy Department, Jilin province, Changchun
10
130052, People’s Republic of China
11
c
12
People’s Republic of China
Suzhou No3 high school sino-us course center, Jiangsu Province, Suzhou 215001,
13 14 15
Corresponding authors:
16
*
Qing-Ri Cao, E-mail: [email protected], Tel: 86-13862012952.
17 18
1
These authors contributed equally to this work.
19 20
1
21
ABSTRACT
22
Traditional dosage forms of dexibuprofen extremely limit their clinical applications
23
because of the bitter taste and the frequent drug administration caused by the relatively
24
short half-life of the drug. This study aims to design novel sustained release (SR)
25
supermicro-pellet based dry suspensions that load dexibuprofen, and also optimize the
26
formulations in terms of morphology, release rate, flowability, and physicochemical
27
stability of dosage forms. Drug-loaded pellets were prepared by using a bottom spray
28
fluid bed coating technique using microcrystalline cellulose supermicro-pellets as the core
29
and PVP K30 or Poloxamer 188 as the binder. The drug-loaded pellets were further
30
coated with Kollicoat SR 30D to form SR pellets. The optimal SR dry suspensions are
31
composed of SR pellets, diluent granules, and suspending agents. PVP K30- and
32
Poloxamer 188-based SR pellets release the drug molecules in a SR manner over 8 h and
33
show a high release profile for Poloxamer 188-based pellets. The drug release profile is
34
not affected by the rotation speed of the paddle but shows a distinct pH-responsive
35
behavior. The physical property of dexibuprofen has been changed during the
36
preparation process. The SR dry suspensions (F5, with high amount of xanthan gum in
37
suspending agents and low amount of poloxamer 188 in diluent granules) show high
38
physical stability with the sedimentation rate of 0.8 (Hu/H) within 5 min and good
39
flowability with the angle of repose (θ) at 27°. Low content variations were observed with
40
a value of A+1.80SD ≤15, and no significant change was found in the drug content
41
under high humidity and strong light. In conclusion, novel SR supermicro-pellet based
42
dry suspensions have been successfully prepared, and the optimal formulation shows
43
excellent SR, good flowability, content uniformity, and physicochemical stability.
44 45
Keywords: Dexibuprofen; Sustained release; Supermicro-pellet; Dry suspension;
46
Optimization
47
2
48
1. Introduction
49
Dexibuprofen is the S (+)-isomer of ibuprofen that was launched in Austria in 1994 [1].
50
Numerous studies have shown that the S (+) ibuprofen is more effective against analgesic
51
and anti-inflammatory effects and in reducing acute gastric damage than its racemate
52
[2,3]. The activity of dexibuprofen is 160 and 1.6 times of its left-handed and racemic
53
forms [4-7]. Therefore, research on dexibuprofen formulations became popular in
54
medicine and pharmacy fields.
55
Currently, the formulations of dexibuprofen on the market are mainly capsules, oral
56
liquid suspensions, suppositories, and tablets [8]. The elimination half-life of
57
dexibuprofen is 1.6–4.2 hours, thereby requiring frequent drug administration. This
58
phenomenon often leads to fluctuations in blood drug concentration and adverse effects
59
[9]. Thus, the development of dexibuprofen sustained-release (SR) preparations can help
60
reduce the peak and valley fluctuation of blood drug concentration, reduce the drug
61
administration frequency, and improve patient compliance [10, 11]. To the best of our
62
knowledge, only a few studies have been performed on dexibuprofen’s SR dosage forms.
63
Manjanna et al. investigated novel dexibuprofen SR microbeads prepared with
64
alginate and showed good SR performance after being further coated with guar gum
65
(1% w/v) and chitosan (1%w/v) [9]. Kim et al. prepared dexibuprofen dry elixir (DDE)
66
and coated DDE (CDDE) with Eudragit RS as the coating material [12]. In contrast to
67
dexibuprofen powder, the dissolution rate and bioavailability of DDE were improved.
68
In particular, CDDE can delay the dissolution of dexibuprofen without reducing
69
bioavailability. However, the preparation processeses of the dexibuprofen SR
70
microbeads and coated dexibuprofen dry elixir are complicated and may have
71
technical difficulties for continuous production.
72
As a multiple-unit preparation, sustained-release pellets have the following advantages.
73
Firstly, the contact area between the drug and gastrointestinal tract increases after oral
74
administration, thereby avoiding the stimulation of gastric mucosa caused by the high
75
concentration of local drugs [13, 14]. Secondly, defects in individual units do not affect
76
the whole preparation [15]. The individual difference of pellets is reduced, affording
77
stable bioavailability in vivo. Thirdly, the small particle size of the pellets ensures that
78
they are not easily affected by gastric emptying, thereby resulting in stable drug release
79
for well controlling its blood–drug concentration [16, 17]. Lastly, there is a low incidence
80
of adverse reactions for sustained-release dexibuprofen pellets, and the bitter taste is
81
masked [15, 18-20]. 3
82
Dry suspension is a new dosage form in which a poorly soluble drug and a suitable
83
auxiliary material are made into a powder or a granule that can be dispersed into a
84
suspension for oral administration by shaking with water [21]. Dry suspensions have the
85
advantages of solid preparations (granules) such as convenient to carry and transport and
86
good stability. Moreover, dry suspensions can be administered easily, especially suitable
87
for patients such as children and the elderly who have difficulty in swallowing [22-24].
88
Kollicoat SR 30D, as one of most well known coating materials, has been widely used
89
for SR pellets or tablets [1, 25, 26]. However, core pellet with a diameter larger than 300
90
µm causes remarkable size growth by drug layering and Kollicoat SR coating, thereby
91
resulting in possible content non-uniformity when mixing with other powder type
92
excipients. In contrast, formulating with supermicro-sized pellet (100-300 µm) may
93
guarantee the content uniformity of dry suspension, whereas it needs high experienced
94
coating technique to avoid the aggregation of pellet during the coating process [27]. In
95
addition, the taste-masking effect of bitter dexibuprofen can also be achieved through this
96
approach.
97
In this study, novel SR supermicro-pellet based dry suspensions that load
98
dexibuprofen were studied, and the formulations were also optimized in terms of
99
morphology, release rate, flowability, and physicochemical stability of the obtained
100
dosage forms. The drug-loaded and Kollicoat SR 30D-coated pellets were prepared by a
101
bottom spray fluid bed coating technique using microcrystalline cellulose
102
supermicro-pellet as the core and PVP K30 (or Poloxamer 188) as the binder. The
103
effects of the binder on the drug release of SR pellets were investigated. The effect of
104
various dissolution conditions on drug release was evaluated as well. In addition,
105
physicochemical characterizations of SR pellets were conducted to verify the
106
molecular changes of drug in pellets. Finally, the SR dry suspensions composed of SR
107
pellets, diluent granules, and suspending agents were optimized on the basis of
108
sedimentation rate, angle of repose, content uniformity, and stress test.
109 110
2. Materials and methods
111
2.1. Materials
112
Dexibuprofen (C102-1412017M) was purchased from Hubei Baike Hengdi
113
Pharmaceutical Co., Ltd. (Hubei, China). Blank pellet core (14I2) was purchased from
114
Asahi Kasei Corp (Japan). Polyvinylpyrrolidone K-30 (PVP-K30, 20110924) was
115
provided by Beijing Fengli Jingqi Co., Ltd. (Beijing, China). 4
Poloxamer 188,
116
Kollicoat SR 30D and hydroxypropyl methyl cellulose were purchased from BASF
117
(Germany). Starch, xanthan gum and silicon dioxide were obtained from Anhui
118
Shanhe Pharmaceutical Accessories Co., Ltd. (Anhui, China). Talc powder was
119
provided by Guangxi Longsheng Huamei Co., Ltd. (Guangxi, China). Anhydrous
120
citric acid, phosphoric acid, hydrochloric acid, potassium dihydrogen phosphate,
121
sodium hydroxide, sodium benzoate, sucralose and sucrose were purchased from
122
Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Sodium citrate was
123
purchased from Hunan huari pharmaceutical Co., Ltd. (Hunan, China). Triethyl citrate
124
was purchased from Aladdin (Shanghai, China). Flavor was purchased from Symrise
125
Co., Ltd. (Shanghai, China). Acetonitrile was purchased from Honeywell Trading
126
Shanghai Co., Ltd. (Shanghai, China). Acetic acid was purchased from CHINASUN
127
Specialty Products Co., Ltd. (Jiangsu, China). Ethanol was purchased from Shanghai
128
lingfeng Chemical Reagent Co., Ltd. (Shanghai, China).
129
2.2. Preparation of dexibuprofen sustained-release pellets
130
2.2.1. Drug-loading layer
131
The binder PVP K30 (or Poloxamer 188) was dissolved in anhydrous ethanol by
132
gentle stirring. The dexibuprofen was added to the binder solution while stirring.
133
Drug-loaded pellets were prepared by loading a drug–binder solution on micro-pellet
134
cores with particle sizes of 100–300 µm in a fluidized bed coater (Mini-XYT,
135
Shenzhen, China) via the bottom spray technique. The coating parameters were as
136
follows: inlet temperature, 38–42 °C; product temperature, 28–31 °C; atomization
137
pressure, 0.05–0.07 MPa; spray rate, 1.0–1.5 ml/min; and final drying at 37 °C for 30
138
min.
139
2.2.2. Sustained-release layer
140
Talc was added to some portion of water and homogenized by a high-pressure shear
141
homogenizer for 10 min. Triethyl citrate and Kollicoat SR 30D were added to the
142
remaining water while stirring. The talc suspension was added to the Kollicoat SR
143
30D dispersion to obtain SR coating suspension after thoroughly mixing. The
144
drug-loaded pellets were coated with the upper SR coating suspension in a fluidized
145
bed coater. The inlet and product temperature were set at 35 °C and 28–30 °C, and the
146
spray rate and atomization pressure were 0.5–0.7 ml/min and 0.05–0.07 MPa,
147
respectively. The fan rolling speed was 600 rpm/min. The coated pellets were dried at
148
37 °C for 30 min and further incubated at 60 °C for 5 h. Finally, the sustained-release
149
pellets were stored in desiccators at ambient temperature. Table 1 summarizes the 5
150
compositions of two different sustained-release pellets that load dexibuprofen.
151
2.3. Preparation of dexibuprofen sustained-release dry suspensions
152
2.3.1. Preparation of diluent granules
153
Poloxamer 188 was dissolved in distilled water to form an aqueous solution.
154
Sucrose, sodium citrate, anhydrous citric acid, and sodium benzoate were mixed
155
together. Then, poloxamer 188 aqueous solution was added dropwise to the powder
156
mixture by grinding. The resulting wet mass passed through a 20-mesh sieve and the
157
generated particles were dried at 60 °C for 2 h to obtain diluent granules. Table 2
158
summarizes the compositions of three different diluent granules.
159
2.3.2. Preparation of dry suspensions
160
Starch, xanthan gum, talc, flavor, silicon dioxide, and sucrose were weighted and
161
thoroughly mixed. Then, the resulting powder were mixed with the drug-loaded SR
162
pellets and diluent granules and further blended for 10 min. Table 3 shows five
163
different formulation compositions of SR micro-pellet-based dry suspensions.
164
2.4. Surface morphology
165
The surface morphologies of blank micro-pellet core, drug-loaded pellets, and SR
166
pellets were imaged using a digital camera and a scanning electron microscope (SEM,
167
ZEISS EVO18). For SEM images, the samples were placed on a double-sided
168
adhesive tape attached to an aluminum stub and then sputter-coated with
169
gold/palladium beam for 2 min. Furthermore, the appearance of dexibuprofen
170
sustained-release dry suspensions was imaged using a digital camera.
171
2.5. Drug release
172
According to the Chinese Pharmacopoeia 2015 Edition of the “Dexibuprofen
173
capsule” dissolution test method, the dissolution rate of the drug-layered pellets and
174
their sustained-release coated forms were investigated. Each sample (100 mg) was
175
accurately weighed and placed in the dissolution basket. The temperature of
176
dissolution medium was set at 37 ± 0.5 °C. At 0.5, 1, 2, 4, 8, 12, and 24 h, 2.5 ml of
177
each medium was taken and diluted by adding phosphate buffer solution with the
178
same volume. Then, each sample was centrifuged at 10,000 rpm for 10 min. A total of
179
20 µl of the supernatant solution was injected to HPLC according to the content
180
analysis of chromatographic method for dexibuprofen. The effects of stirring speed
181
(50, 100, and 150 rpm) of basket and pH (1.2, 4.5, 6.8, 7.4, and water) of the
182
dissolution medium on drug release were also investigated.
183
2.6. HPLC analysis of dexibuprofen 6
184
Drug analysis was conducted according to the method of Chinese Pharmacopoeia
185
2015 using a 5C18-MS-II (5 µm, 4.6 mm × 250 mm) column on a high-performance
186
liquid chromatography (HPLC, LC-15C, SHIMADZU, Japan). The column
187
temperature remained at 35 °C. The mobile phase consisted of 35% acetonitrile and
188
65% phosphate buffer (pH 7.6) (v/v). The injection volume was 20 µl, and the flow
189
rate was 1.0 ml/min. The detection wavelength was set at 280 nm.
190
2.7. Differential scanning calorimetry (DSC)
191
The DSC of dexibuprofen (pure drug), blank pellet core, PVP K30, Poloxamer 188,
192
drug-loaded pellets (with PVP K30), and drug-loaded pellets (with Poloxamer 188)
193
were measured using a differential scanning calorimeter (Model 2010, TA Instruments,
194
USA). The empty aluminum clamp pan was used as the reference material, and 3 mg
195
of each sample was placed in the other aluminum pot. The samples were heated from
196
10 °C to 250 °C at a scanning speed of 10 °C/min under the nitrogen atmosphere.
197
2.8. Sedimentation rate
198
Three grams of dry suspension was dispersed in distilled water contained in 50 ml
199
glass tube, followed by thoroughly shaking. The initial height (H) was recorded, and
200
the sediment height (Hu) at 1, 2, 3, 4, and 5 min were recorded separately. Then, the
201
sedimentation volume ratio F (Hu/H) was calculated by measuring the ratio of Hu to
202
H. The sedimentation rate curve was plotted by taking the sedimentation volume ratio
203
F (Hu/H) as the ordinate and time T as the abscissa.
204
2.9. Angle of repose (Flowability)
205
Approximately 20 grams of dexibuprofen micro-pellet-based dry suspensions were
206
taken, and the angle of repose was measured according to Chinese Pharmacopoeia
207
2015.
208
2.10.
Content uniformity
209
The drug content uniformity of dry suspensions (F5) was determined. Ten samples
210
(0.11 g for each sample) of each formulation were randomly selected and separately
211
placed in 25 ml volumetric flasks. Methanol at 15 ml was added and vortexed to fully
212
dissolve the drug. Then, methanol was added to the marking line. After shaking for 5
213
min, the suspension was centrifuged at 10,000 rpm for 10 min. Finally, the drug
214
content of the supernatant was determined using the HPLC method as described
215
above.
216
2.11.
217
Stress test
The stability of dexibuprofen sustained-release dry suspension were investigated 7
218
under stress conditions, such as high temperature 60 °C, high humidity (25 °C,
219
relative humidity 92.5 %), and strong light (4500±500) Lx, for 10 days. The samples
220
were individually taken after 5 and 10 days. The drug content and related substances
221
in dexibuprofen sustained-release dry suspensions were analyzed by a HPLC system.
222
2.12.
Statistical analysis
223
Data were presented as mean ± standard deviation (S.D.), and their statistical
224
significance of difference was examined using SPSS 16.0. P-values less than 0.05
225
were considered statistically significant. (*p<0.05, **p<0.01, ***p<0.001).
226 227
3. Results and discussion
228
3.1. Surface morphology
229
This study developed novel dexibuprofen SR supermicro-pellet based dry
230
suspensions. Aggregates of mini-pellets commonly appeared during the fluid-bed
231
coating process, and this phenomenon was fully overcome by modulating the
232
parameters of the coating process. Dexibuprofen was loaded onto the microcrystalline
233
cellulose supermicro-pellet cores using PVP K30 or Poloxamer 188 as the binder,
234
followed by coating with Kollicoat SR 30D as the sustained-release coating polymer.
235
Two types of SR pellets were prepared (Table 1). The reason of adding enough talc in
236
SR coating layer is to avoid the aggregation of pellets during the coating process. If
237
talc was less than this level, we could not get the uniform SR pellets. The dry
238
suspensions were obtained by mixing SR pellets, diluent granules, and suspending
239
agents. The formulation compositions of various diluent granules and dry suspensions
240
for optimization are also listed in Table 2. Fig. 1 shows that after drug layering and
241
SR coating, the SR pellets are still spherical in shape showing similar morphology to
242
the pellet core. As shown in Fig.2, the distinct drug and SR layers could be observed
243
from the cross section of the pellets.
244
3.2. Drug release
245
In this study, the SR characteristics of dexibuprofen SR pellets were evaluated at
246
different release conditions. Firstly, the effects of two different binders on the release
247
of dexibuprofen were investigated. As shown in Fig. 3, two drug-layered pellets had a
248
dissolution rate of more than 90% within 30 min, and the SR effect was not apparent.
249
In fact, no significant difference was observed in the SR effect of PVPK30- and
250
Poloxamer188-based pellets. On the contrary, the coated SR pellets showed sustained
251
release over 8 h. Moreover, the release rate of Poloxamer188-based SR pellets was 8
252
higher than that of PVPK30-based SR pellets, and a significant difference between the
253
two formulations was observed within the first 4 h. This result may be due to the
254
solubilization effect of Poloxamer 188. The solubilization of Poloxamer 188 on drug
255
is based on the decrease of surface tension and drug wettability.
256
The effect of stirring rate on drug release from SR pellets was investigated (Fig. 4).
257
The stirring rate did not remarkably affect the release rate of SR pellets for PVPK30-
258
and Poloxamer188-based SR pellets. In addition, the release of dexibuprofen SR
259
pellets was also investigated in buffer solutions with different pH values. In Fig. 5, the
260
drug release from SR pellets increased with increasing pH. However, the release rate
261
of SR pellets did not significantly differ at pH 6.8 and pH 7.4. This finding may be
262
attributed to the pH-dependent solubility of drug in various dissolution media. The
263
previous study illustrated that low pH values limited drug solubility, and drug release
264
increased with increasing pH [5].
265
3.3. DSC
266
The DSC pattern of pure drug, drug-free core, binders, and drug-layered pellets are
267
shown in Fig. 6. The endothermic peak at 50 °C refers to the melting point peak of
268
dexibuprofen. Another endothermic peak was observed at 210 °C, which corresponds
269
to the evaporation of dexibuprofen. Our data were basically consistent with those of
270
the previous study, which showed that the onset of the endothermic peak of
271
dexibuprofen was at 47.25 °C, thereby reaching a peak at 56.51 °C. The enthalpy was
272
210.40 J/g [28]. No significant peaks for the pellet core and PVP K30 appeared at
273
50 °C and 210 °C, respectively. The drug-layered pellets showed a melting point peak
274
at 50 °C and an obvious endothermic peak at 260 °C. The shifting of endothermic
275
peak from 210 °C to 260 °C might be due to the change of the physical property of
276
dexibuprofen during the preparation process [29].
277
3.4. Sedimentation rate
278
The sedimentation rate of the five types of SR dry suspensions were evaluated by
279
measuring the ratio of Hu to H. In Fig. 7, the sedimentation rates of F1 and F3 were
280
relatively fast, whereas those of F2, F4, and F5 were relatively slow. This result might
281
be attributed to the amount of xanthan gum in suspending agents and poloxamer in
282
diluent granules. The sedimentation rate gradually decreased as the amount of xanthan
283
gum increased (F1, F4, and F5). Undoubtedly, the suspending properties of SR dry
284
suspensions were remarkably affected by the amount xanthan gum. In addition, the
285
amount of Poloxamer 188 was also related to the sedimentation rate of the 9
286
suspensions, and low levels of Poloxamer 188 led to high stability of the suspensions
287
(F1, F2, and F3). This phenomenon may be due to the fact that the surfactant has no
288
positive effects for the suspending properties of xanthan gum. Khan et al. found that
289
the viscosity of xanthan gum could decrease with the increase of surfactant
290
concentration. When the concentration of sodium dodecyl sulfate increased from 0
291
mM to 5 mM, the viscosity of xanthan gum solution remarkably decreased [30].
292
3.5. Angle of repose (Flowability)
293
The flowability of SR dry suspensions was investigated by measuring the angle of
294
repose. Low angle of repose corresponds to high flowability for the granules. When the
295
angle of repose (θ) is ≤ 40°, flowability is satisfied with the requirements in the
296
production process. When the angle of repose (θ) is ≤ 30°, the granules shows excellent
297
flowability. In Fig. 8, all formulations (F1, F2, F3, F4, and F5) showed good flowability
298
since all the angle of repose (θ) is less than 31°. Especially, the angle of repose (θ) was
299
even lower than 28° for F1 and F5, which showed extremely good flowability. Overall,
300
SR dry suspensions, which were composed of SR pellets, diluent granules, and
301
suspending agents, were suitable for the filling and packing process.
302
3.6. Content uniformity
303
The uniformity of drug content was determined for the formulation F5 based on the
304
results of sedimentation rate and angle of repose. In Table 4, the formulation F5 had
305
A+1.80SD≤15.0, and the sample showed relatively high content uniformity.
306
3.7. Stress test
307
The stress stability of F5 formulation were evaluated under high temperature
308
(60 °C), high humidity (92.5% RH), and strong light (4500 Lx) for 5 and 10 days,
309
respectively. The changes of related substances were measured by HPLC. In Table 5,
310
the content of related substances significantly increased within 10 days at a high
311
temperature of 60 °C. However, almost no change was observed under high humidity
312
(RH 92.5%) and strong light (4500 Lx). Therefore, our findings suggested that SR dry
313
suspensions should be stored in a cool place to ensure stability.
314 315
4. Conclusion
316
In this study, novel SR supermicro-pellet based dry suspensions composed of SR
317
pellets, diluent granules, and suspending agents were successfully prepared and
318
characterized. PVP K30- and Poloxamer 188-based SR pellets released the drug
319
molecules as a SR manner over 8 h. The drug release was stable and not affected by the 10
320
rotation speed of the paddle. The DSC result showed that the physical property of
321
dexibuprofen has been changed during the preparation process. The optimal
322
formulation F5 with high amount of xanthan gum in suspending agents and low amount
323
of poloxamer 188 showed low sedimentation rate and good flowability, content
324
uniformity, and chemical stability under various storage conditions. The SR dry
325
suspensions should be kept in a cool dry place to ensure stability.
326 327 328 329
Acknowledgements This work was partially supported by the project funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions, China.
330 331 332
Conflict of interest No potential conflicts of interest were disclosed.
333 334
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14
430
FIGURE LEGENDS
431
Fig. 1. Surface morphology of pellet core, drug-loaded pellets, and sustained-release
432
pellets. (A) PVP K30 as a binder, (B) Poloxamer 188 as a binder, (a) core pellets, (b)
433
drug-layered pellet, and (c) SR coated pellets
434
Fig. 2. Cross section images of pellet core, drug-loaded pellets, and sustained-release
435
pellets. (A) PVP K30 as a binder, (B) Poloxamer 188 as a binder, (a) core pellets, (b)
436
drug-layered pellet, and (c) SR coated pellets
437
Fig. 3. Release profiles of drug-layered and SR pellets at pH 7.4 phosphate buffer
438
saline solution.
439
Fig. 4. Effect of rotation speed on drug release from SR pellets.
440
Fig. 5. Effect of pH on the release of drug release from SR pellets
441
Fig. 6. DSC curves of pure drug, drug-free core, binders, and drug-layered pellets
442
Fig. 7. Sedimentation rate of five different SR dry suspensions
443
Fig. 8. Angle of repose of five different SR dry suspensions.
444
15
445
TABLE LEGENDS
446 447
Table 1 Formulation compositions of sustained-release pellets
448
Table 2 Formulation compositions of three different diluent granules
449
Table 3 Formulation compositions of SR dry suspensions
450
Table 4 Drug content uniformity of optimal SR dry suspensions (F5)
451
Table 5 Stress stability of optimal SR dry suspensions (F5)
452
16
Table 1 Type Pellet core Drug-layered pellets
Sustainedrelease pellets
SR1
SR2
MCC Drug PVP K30
80g 36g 1g
Ethanol
100ml
Kollicoat SR 30D Triethyl citrate Talc Water
MCC Drug Poloxamer 188 Ethanol Water
80g 36g 1g 95ml 5ml
20g
Kollicoat SR 30D
20g
1g 8g 100ml
Triethyl citrate Talc Water
1g 8g 100ml
1
Table 2 Ingredient
DG1 (mg)
DG2 (mg)
DG3 (mg)
Poloxamer 188
125
75
175
Sucrose
34418
34468
34368
Sodium citrate
965
965
965
Anhydrous citric acid
1290
1290
1290
Sodium benzoate
500
500
500
Sucralose
200
200
200
Purified Water
1764
1764
1764
2
Table 3 Ingredient (g) Sustained-release pellets
F1
F2
F3
F4
F5
2.6484
2.647
2.6437
2.6396
2.645
Diluent granules
17.033 (DG1)
17.033 (DG2)
17.033 (DG3)
17.033 (DG1)
17.033 (DG1)
Starch
1.567
1.567
1.567
1.567
1.567
Xanthan gum
0.1205
0.1705
0.1705
0.1705
0.2205
Talc
0.2275
0.2275
0.2275
0.2275
0.2275
Flavor
0.1705
0.1705
0.1705
0.1705
0.1705
Silicon dioxide
0.2275
0.2275
0.2275
0.2275
0.2275
Sucrose
0.7295
0.6795
0.6795
0.6795
0.6295
3
Table 4 F5
Drug content* (mg)
1
0.04
2
0.06
3
0.06
4
0.05
5
0.05
6
0.05
7
0.05
8
0.05
9
0.04
SD
Average
Labelled amount
0.0067
0.05
0.046
10 0.05 * Drug content per mg sample
4
X=Average/ Labelled A=|100-X| A+1.80SD amount *100
109
9
9.01
Table 5 Related substances/% Formulation
RH 92.5%
60 ℃
4500 Lx
0d 5d
10d
5d
10d
5d
10d
F5（Sample 1）
0.03
0.99
2.41
0.04
0.02
0.12
0.04
F5（Sample 2）
0.04
0.86
3.91
0.04
0.02
0.03
0.05
F5（Sample 3）
0.04
0.87
2.87
0.04
0.11
0.03
0.04
5
Fig.1
1
Fig.2
2
100
Release rate (%)
80 60 SR pellets (PVPK30)
40
SR pellets (Poloxamer188) Drug-layered pellets (PVPK30)
20 Drug-layered pellets (Poloxamer188)
0 0
0.5
1
2
4
Time(h)
Fig.3
3
8
12
24
100 80
Release rate (%)
50RPM(PVPK30) 100RPM(PVPK30)
60
150RPM(PVPK30)
40
50RPM(Poloxamer188) 100RPM(Poloxamer188)
20
150RPM(Poloxamer188)
0 0
0.5
1
2
4
Time (h)
Fig.4
4
8
12
24
100
Release rate（%）
80 60 Water
40
pH1.2 pH4.5
20
pH6.8 pH7.4
0 0
0.5
1
2
4
Time (h)
Fig.5
5
8
12
24
Drug-layered pellets (with Poloxamer 188) Drug-layered pellets (with PVP K30) Poloxamer 188 PVP K30 Drug-free core Drug
50
100
150
200
250
300
350
T(centigrade)
Fig.6
6
400
450
500
1 0.9
Sedimentation rate (Hu/H
0.8 0.7 0.6
F1
0.5
F2
0.4
F3
0.3
F4 F5
0.2 0.1 0 1
2
3
Time(min) Fig.7
7
4
5
32.0
Angle of repose(θ)
31.0 30.0 29.0 28.0 27.0 26.0 25.0 24.0 F1
F2
F3
Formulation code Fig.8
8
F4
F5
Declaration of interest The authors declare no conflict of interest.