Formulation and evaluation of new oxycodone extended release multiple unit pellet system

Abstract

The goal of the present study is to prepare a stable, multiple-unit, extended-release dosage form containing oxycodone pellets coated with aqueous ethylcellulose (EC) dispersion, Surelease E-7-19050. The application of 18% w/w of EC leads to the similar drug release with the hydrophobic, non-swelling, matrix reference product containing 20 mg of oxycodone. Increasing the compression force to 9 kN and including more than 50% w/w of oxycodone pellets into the formulation resulted in faster drug release, indicating the damaging to the EC film coating. The physical appearance of the final formulation, assay of oxycodone, moisture content, and dissolution data over the stability period showed that the multiple-unit pellet system (MUPS) is efficient for the production of highly stable product.

Full text

1OR
Coated pellets are frequently used for oral, controlled-release,
drug delivery. The recent trends indicate that multiparticulate
drug delivery systems are especially suitable for achieving
controlled- or delayed-release oral formulations with
low risk of dose dumping, exibility of blending to attain
dierent release patterns, as well as reproducible and short
gastric residence time (Dey et al., 2008). Controlled-release
drug delivery systems provide a uniform concentration at
absorption site, maintain plasma concentration within a
therapeutic range, reduce the frequency of administration,
and minimizes the side eects. It is also important to avoid
dose dumping after the oral administration of ER dosage
forms, especially for drugs that possess the characteristics of a
higher solubility, higher dose, or a fatal side eect (Uros et al.,
2014). Furthermore, an alcohol-induced dose dumping eect
in oral ER dosage forms has gained increased attention in the
recent years (Jedinger et al., 2014).
Compaction of multiparticulates, commonly called MUPS
(abbreviation for multiple-unit pellet system), is one of the
most recent and challenging technologies that combine
the advantages of both tablets and pellet-lled capsules in
one dosage form. The multiparticulates spread uniformly
throughout the gastrointestinal tract, resulting in less variable
bioavailability and a reduced risk of local irritation. Various
drug release proles can be obtained by simply mixing pellets
with dierent release characteristics or incompatible drugs
can be easily separated (Dashevsky et al., 2004).
Oxycodone hydrochloride is a semisynthetic opioid agonist
that provides eective relief for moderate to severe pain in
cancer and postoperative patients. The pharmacokinetic and
steady-state pharmacodynamic studies with immediate-
release (IR) oxycodone have shown it to be well tolerated,
with adverse eects similar to those of other opioids. The
bioavailability of oral oxycodone in humans is 60% (range: 50–
87%). The terminal elimination half-life is independent of dose,
with modest interindividual dierences (Fukui et al., 2017).
Ethylcellulose (EC) has been widely used as a barrier
membrane or binder to prepare pharmaceutical, oral,
Formulation and evaluation of new oxycodone extended
release multiple unit pellet system
Štefan Husár1,2 Miroslava Sýkorová1, Katarína Rumlová1,
Kamila Chomaničová1, Beáta Vladovičová2
The goal of the present study is to prepare a stable, multiple-unit, extended-release dosage form containing oxycodone pellets
coated with aqueous ethylcellulose (EC) dispersion, Surelease E-7-19050. The application of 18% w/w of EC leads to the similar
drug release with the hydrophobic, non-swelling, matrix reference product containing 20 mg of oxycodone. Increasing the
compression force to 9 kN and including more than 50% w/w of oxycodone pellets into the formulation resulted in faster drug
release, indicating the damaging to the EC lm coating. The physical appearance of the nal formulation, assay of oxycodone,
moisture content, and dissolution data over the stability period showed that the multiple-unit pellet system (MUPS) is ecient
for the production of highly stable product.
Opioids – Oxycodone - Dissolution – Extended release - Pellets Keywords
INTRODUCTION
© European Pharmaceutical Journal
EUROPEAN PHARMACEUTICAL JOURNAL
Abstract
Eur. Pharm. J. 2019, AoP.
ISSN 1338-6786 (online) and ISSN 2453-6725 (print version),
DOI: 10.2478/afpuc-2019-0019
Received 6 March, 2019, accepted 16 August, 2019
Original Paper
* E-mail: husar.stefan26@gmail.com
1Comenius University in Braslava,
Faculty of Pharmacy, Department
of Pharmaceucal chemistry, Slovak Republic
2Saneca Pharmaceucals a.s.,
Hlohovec, Slovak Republic
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Formulaon and evaluaon of new oxycodone extended release mulple unit pellet system Husár Š. et al.
Eur. Pharm. J. 2019, AoP
32
modied-release dosage forms. The aqueous dispersion of
EC, for example, Surelease, has been used to manufacture
modied-release multiparticulates for lling into capsules
and single-unit tablets or soft-gel capsules through lm-
coating applications. In addition, the use of aqueous EC
dispersion as a release retardant binder for the manufacture
of inert matrices has been reported. Surelease® enhanced
the compaction characteristics of the drug, and the drug
was released from those inert porous matrices by diusion
(Rajabi-Siahboomi & Farrell, 2008).
MATERIALS AND METHODS
Materials
The materials used in this study were oxycodone hydrochloride
(Saneca Pharmaceuticals, Slovakia), sugar spheres with
adiameter of 355–425 µm (Hanns G. Werner, Germany), talc
(Luzenac, China), hypromellose (HPMC, Methocel E5, Dow
Chemicals, GB), polysorbate 80 (Centralchem, Slovakia),
Surelease clear E-7-19050 (Colorcon, USA), microcrystalline
cellulose (Comprecel M102, Mingtai, China), silica dioxide
(Grace GmbH, GB), and magnesium stearate (Faci SPA, Italia).
METHODS
Preparation of opiate pellets
The spraying of water dispersion method was chosen to
prepare the opioid analgesic pellets. The required quantities
of hypromellose and polysorbate 80 were dispersed in water,
puried to prepare binding suspension, and mixed until clear
solution is achieved. Oxycodone HCl powder was then added
to the dispersion and mixed for another 45 min. The required
quantity of Talc was added at the end of oxycodone dispersion
preparation and mixed for 20 min. Required amount of sugar
spheres with a diameter of 355–425 µm was loaded into
a uidized bed coater Glatt GPCG-2 equipped with a 3.0-L
Wurster container, air distribution plate type A,and lter bags
with a porosity of below 20 μm (Glatt GmbH, Germany) and
preheated to aproduct temperature of 34–36°C. The layering
conditions were given as follows: batch size, 400 g; inlet air
temperature, 45°C; product temperature, 33°C; air ow, 120
m3/h; nozzle diameter, 1.2 mm; atomizing air pressure, 1.5 bar;
spray rate, 5 g/min; nal drying at 40°C for 20 min.
Coating of drug-layered pellets
The oxycodone drug-layered pellets were coated with aqueous
water dispersion of Surelease E-7-19050 (15% w/w solid
content) using the uidized bed coater Glatt GPCG-2 (Glatt
GmbH, Germany) and preheated to aproduct temperature
of 36–48°C. Three dierent quantities of Surelease E-7-19050
were applied onto oxycodone pellets (formulations F1–F3,
Table 1). The layering conditions were given as follows: batch
size, 400 g; inlet air temperature, 50°C; product temperature,
35°C; air ow, 140 m3/h; nozzle diameter, 1.2 mm; atomizing
air pressure, 1.5 bar; spray rate, 8 g/min; nal drying at 45°C
for 30 min.
Compression of coated pellets
The composition of MUPS tablets F1–F3 is presented in Table
1. Coated pellets were mixed in a slow speed blender RV1
(Kovymont, Slovakia) for 15 min at 13 rpm with dierent
amounts of microcrystalline cellulose (Comprecel M102).
Table 1. Formulation of oxycodone MUPS tablets F1–F3 (weights in mg/tablet)
Process step Material Formulation code
F1 F2 F3
Oxycodone drug
layered
pellets
Oxycodone hydrochloride 20.0 20.0 20.0
Hypromellose (Methocel E5) 1.2 1.2 1.2
Polysorbate 80 1.2 1.2 1.2
Talc 0.5 0.5 0.5
Sugar spheres with a diameter of 355–425
µm 50.0 50.0 50.0
Release modifying
polymer Surelease clear E-7-19050*11.7*
(7.3 mg EC) 21.0*
(13.1 mg EC) 30.4*
(19.0 mg EC)
Compression into
MUPS
Microcrystalline cellulose (Comprecel M102) 124.1 137.5 150.8
Magnesium stearate 2.2 2.4 2.6
Silica dioxide 1.1 1.2 1.3
MUPS tablet weight in mg 212.0 235.0 258.0
* Surelease clear E-7-19050 contains 62.4% w/w of EC.
EC, ethylcellulose.
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Formulaon and evaluaon of new oxycodone extended release mulple unit pellet system Husár Š. et al.
Eur. Pharm. J. 2019, AoP
32
After that 1.0% of magnesium stearate and 0.5% of silica
dioxide were added as a lubricant/glidant (Table 2) and
mixed in the slow speed blender RV1 for 5 min at 13 rpm. The
tablets were compressed on arotary tablet press Pressima
AX8 (IMA Pharma, Italy) with dierent compression forces;
the composition and tablet weight of formulations F1–F6
are presented in Tables 1 and 2. The hardness of tablets was
tested using a hardness tester Sotax Tester 8M (Sotax AG,
Switzerland), and the disintegration of 6 MUPS tablets in water
(temperature 35–39°C) was performed using a disintegration
tester Sotax DT2 (Sotax AG, Switzerland). The friability of 6.5g
of MUPS tablets was tested using a Sotax friability tester
(Sotax AG, Switzerland) and evaluated after 100 rotations of
the drum. The physical characteristics of MUPS fromulations
F1–F6 are reported in Table 3.
In vitro dissolution study
The drug release from the coated and compressed pellets
was investigated using apaddle apparatus Sotax AT7 Smart
(Sotax AG, Switzerland) in 900 mL of 0.1N HCl at 75 rpm at
37±0.5°C, n = 6. Samples were withdrawn at predetermined
time points (sample volume: 1.5 mL) and measured using
UV spectrophotometer (Cary 50 UV-VIS spectrophotometer,
Agilent technologies) at 230 nm.
Tablets bulk stability testing
The nal formulation of oxycodone MUPS tablets was set
for stability study in double PE bags with a dessicant placed
between them and closed in a nontransparent plastic
container for 3 months at a relative temperature (RT) and
relative humidity (RH) conditions in 3 dierent stability
chambers SC-12 Plus (REMI Laboratory Instruments, India):
25°C/60%, 30°C/65%, and 40°C/75%. After each month,
dissolution, appearance, assay, and LOD (halogen analyser
Mettler Toledo HF63, 10 min at 105°C, 5-g samples of crushed
tablets) were performed and evaluated.
RESULTS AND DISCUSSION
Compaction of multiparticulates, commonly called MUPS, is
one of the most recent and challenging technologies that
combine the advantages of both tablets and pellet-lled
capsules in one dosage form. Ideally, the compacted pellets
should not fuse into a nondisintegrating matrix during
compression and should disintegrate rapidly into individual
pellets in gastrointestinal uids. Importantly, the drug release
should not be aected by the compaction process and the
polymer coating must be able to resist to the compression
force; it can deform, but it should not rupture (Bhad et al.,
2010). Most studies on the compression of pellets with
EC revealed damage to the coating layer with a loss of the
extended-release properties. The mechanical properties of
the particular Surelease E-7-19050 polymer coating were
determined in order to investigate its suitability for the
coating of oxycodone pellets, which are intended to be
compressed into tablets.
Figure 1 shows drug release proles of MUPS compressed
using oxycodone coated pellets with dierent concentration
of retarding agent Surelease E-7-19050: 10% w/w (referring to
the active oxycodone pellets, see composition in Table 1) of
EC (EC, Formulation F1), 18% w/w of EC (F2), and 26% w/w of
EC (F3). The formulations F1–F3 were compressed at the same
main compression force of 4.5 kN. The dissolution proles
are compared with the commercially available reference
Table 2. Formulation of oxycodone MUPS tablets F4–F6 (weights in mg/tablet)
Process step Material Formulation code
F4 F5 F6
Oxycodone drug
layered pellets
Oxycodone hydrochloride 20.0 20.0 20.0
Hypromellose (Methocel E5) 1.2 1.2 1.2
Polysorbate 80 1.2 1.2 1.2
Talc 0.5 0.5 0.5
Sugar spheres with a diameter of 355–425
µm 50.0 50.0 50.0
Release modifying
polymer Surelease clear E-7-19050*21.0*
(13.1 mg EC) 21.0*
(13.1 mg EC) 21.0*
(13.1 mg EC)
Compression into
MUPS
Microcrystalline cellulose
(Comprecel M102) 214.4 91.3 38.1
Magnesium stearate 3.1 1.9 1.3
Silica dioxide 1.6 0.9 0.7
MUPS tablet weight in mg 313.0 188.0 134.0
* Surelease clear E-7-19050 contains 62.4% w/w of EC.
EC, ethylcellulose.
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Formulaon and evaluaon of new oxycodone extended release mulple unit pellet system Husár Š. et al.
Eur. Pharm. J. 2019, AoP
54
product, Targin® (Mundipharma, Austria), containing 20 mg
of oxycodone hydrochloride in a hydrophobic, non-swellable
matrix tablets. As it can be seen, the release decreased with
increasing EC content and the similar dissolution prole
(similarity factor f2 = 84) was achieved with formulation F2
containing 18% w/w of EC (Surelease E-7-19050). Following
this observation, the eect of ller/pellet content was further
investigated with this concentration of EC.
Three formulations, F4, F5, and F6 (containing 18% w/w of
EC, see composition in Table 2), were prepared with dierent
oxycodone pellet content, 30%, 50% and 70% w/w, mixed
with extragranular excipients and compressed at the same
main compression force of 4.5 kN. The oxycodone release
from compressed pellets was signicantly faster compared
with that from the original pellets coated with 18% of EC
as shown in Figure 2. This could be explained by the weak
mechanical properties of EC lms, which ruptured during
compression. It has been reported that plastically deforming
excipients are more eective in protecting the coated pellets
during compression; therefore, the microcrystalline cellulose
(Comprecel M102) was selected to provide a better protective
eect to the oxycodone-coated pellets. Figure 2 shows that
increasing the protective excipient to 70% w/w (30% pellet
content, formulation F4) minimized the damage to the
compressed drug pellets, with the f2 between compressed
and uncompressed pellets being 61. Values for f2 (similarity
factor) between 50 and 100 indicate that the two proles are
similar (Vetchý et al., 2014). Compressing coated pellets with
30% of protective excipient (formulation F6) resulted in the
loss of their extended-release properties. This is explained
by the lower yield pressure of the MCC ller that absorbs
the energy of compaction and preferentially deforms under
pressure, thus protecting the pellets. A higher level of the
cushioning excipient also reduces the number of oxycodone
Table 3. Physical characteristics of oxycodone MUPS tablets F1–F6
Formulation
code
Average weight [mg],
n = 20
Hardness [N],
n = 10
Friability
[25 rpm, 4 min, %], n = 3
Disintegration [s],
n = 6
F1 212.2 ± 2.9 51 ± 5.4 0.51 ± 0.08 31 ± 5.8
F2 235.2 ± 2.7 52 ± 6.3 0.47 ± 0.10 24 ± 7.5
F3 258.8 ± 3.6 54 ± 5.8 0.56 ± 0.06 42 ± 4.2
F4 313.0 ± 2.4 76 ± 5.0 0.50 ± 0.07 35 ± 2.8
F5 188.6 ± 2.2 41 ± 4.2 0.35 ± 0.06 161 ± 12.1
F6 134.7 ± 2.9 43 ± 3.6 0.28 ± 0.04 987 ± 9.9
F4 (3 kN) 313.6 ± 3.8 38 ± 4.1 0.91 ± 0.06 24 ± 1.8
F4 (6 kN) 314.2 ± 2.1 54 ± 3.0 0.65 ± 0.02 124 ± 8.2
F4 (9 kN) 313.4 ± 1.2 78 ± 2.6 0.04 ± 0.01 997 ± 13.4
Figure 1. Inuence of Ethyl celullose content on oxycodone drug release from MUPS tablets F1-F3
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Formulaon and evaluaon of new oxycodone extended release mulple unit pellet system Husár Š. et al.
Eur. Pharm. J. 2019, AoP
54
pellets coming in direct contact with each other or with the
punch surface during the compression cycle, which can cause
pellets to rupture (Al-Hashimi et al., 2018).
Figure 3 shows drug release prole of MUPS compressed
at dierent compression forces using 30% w/w oxycodone
pellets content in the formulation. Increasing compression
force resulted in faster drug release, indicating the damaging
to the EC lm coating. The f2 values for tablets compressed at
a compression force of 3 and 6 kN were 71 and 62, respectively,
compared with the matrix reference tablets, Targin. Increasing
the tablet compression force to 9 kN leads to MUPS tablets of
greater strength; however, an increase in tablet disintegration
time to more than 15 min was also observed (Table 3). Higher
disintegration time could be attributed to a lower penetration
of the disintegration test media into the tablet because of the
creation of undesirable matrix structure.
Figure 2. Inuence of proportion of coated pellets on oxycodone drug release from MUPS tablets F4-F6
Figure 3. Inuence of compression force on oxycodone drug release from MUPS tablets containing 30% w/w proportion of coated pellets
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Formulaon and evaluaon of new oxycodone extended release mulple unit pellet system Husár Š. et al.
Eur. Pharm. J. 2019, AoP
76
MUPS tablets of the formulation F4 (18% EC, 30% oxycodone
pellets content) compressed at 6 kN were set for the stability
for 3 months in three dierent stability chambers. The
appearance of MUPS tablets were found to be unchanged
even at the end of 3 months in all stability conditions except
40°C/75%RH, where the color of tablets becomes slightly
yellowish, which is negligible. The color change might be
related to the excipients, as after 3 months at 40°C/75%RH,
the assay of oxycodone was found 97.2%, which is close
to the initial value (Table 4). The LOD value was increased
slightly from its initial value in all stability conditions (Table
4). No signicant change in the assay of oxycodone was
observed from the storage conditions (Table 4), which reects
that the formulated MUPS tablets are stable. In each month,
the dissolution of oxycodone MUPS tablets was performed
for the samples stored in three dierent conditions. The t50%,
t80%, Q8, release rate constant (k), and diusion exponent (n)
at dierent time intervals showed no major dierence over
the stability period (Table 4). The calculation was performed
based on the following equations:
t50% = (0.5/k)1/n
t80% = (0.8/k)1/n
where kis the release rate constant and n is the diusion
exponent. The values of kand n were determined graphically
from the following equation (Siepmann & Peppas, 2001):
Qt /Q∞ = k.tn
where Qt /Q∞ is the fraction of drug released at time t,
log (Qt /Q∞) = log k + n.log t.
To study release kinetics, a graph is plotted between log
cummulative percentage of drug release (log (Qt /Q∞)) versus
log time (log t).
CONCLUSION
Oxycodone pellets coated with aqueous EC dispersion
(Surelease E-7-19050) were incorporated into a multiple-
unit pellet system providing consistent drug release proles.
Inclusion of 70% cushioning plastically deforming excipient
microcrystalline cellulose (Comprecel M102) into the MUPS
tablets and application of compression force between 3
and 6 kN resulted in similar dissolution of active substance
in comparison with reference matrix tablets. The physical
and chemical parameters of the oxycodone MUPS tablets
were found consistent over the stability period. The results
generated in this study showed that the selected excipients
and manufacturing process is suitable to design a new, stable,
oxycodone, MUPS, extended-release formulation.
ACKNOWLEDGMENT
The study was supported by the Ministry of Education,
Science, Research and Sport of the Slovak Republic within
project No. Req-00357-0001 „Research and development of
active pharmaceuticals ingredients by stereoselective processes
including development of nished dosage forms.“
Table 4. Stability data* of oxycodone MUPS tablets at dierent time intervals in three dierent conditions (formulation F4)
Parameters Initial 25°C/60% RH 30°C/65% RH 40°C/75% RH
1M 2M 3M 1M 2M 3M 1M 2M 3M
Assay % 98.7 98.4 98.0 97.7 98.2 98.4 98.0 97.4 97.0 97.2
Appearance
(white to o-
white, round,
biconvex tablets)
Comply Comply Comply Comply Comply Comply Comply Comply Comply Slightly
yellowish
Loss on drying % 2.8 3.5 3.8 3.8 3.8 3.8 3.9 4.0 4.2 4.4
Q8 85.91 84.24 84.65 82.17 82.01 82.53 79.85 83.08 81.24 78.66
t50% 2.14 1.98 2.02 1.89 2.01 2.14 1.80 1.99 1.96 1.78
t80% 6.30 6.14 6.28 6.02 6.24 6.34 5.98 6.27 6.24 5.90
r20.995 0.990 0.997 0.989 0.991 0.994 0.994 0.984 0.986 0.994
k2.362 2.512 2.378 2.156 2.318 2.305 2.224 1.214 1.105 1.064
n0.656 0.641 0.652 0.671 0.661 0.663 0.658 0.726 0.741 0.735
*Q8 indicates percentage of oxycodone drug release at 8 h; t50%, time required for 50% drug release; t80%, time required for 80% drug
release; r2, correlation coecient; k, release rate constant; n, diusion exponent; M, month.
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Formulaon and evaluaon of new oxycodone extended release mulple unit pellet system Husár Š. et al.
Eur. Pharm. J. 2019, AoP
76
References
[1] Dey NS, Majumdar S, Rao MEB. Multiparticulate drug delivery
systems for controlled release. Trop J Pharm Res. 2008; 7: 1067-
1075.
[2] Uros K, Sasa B, Igor L et al. Determining the polymer threshold
amount for achieving robust drug release from HPMC and HPC
matrix tablets containing a high dose BCS class 1 model drug: in
vitro and in vivo studies. AAPS PharmSciTech. 2014; 16: 398-406.
[3] Jedinger N, Khinast J, Roblegg E et al. The design of controlled
release formulations resistant to alcohol induced dose
dumping-a review. Eur J Pharm Biopharm. 2014; 87: 217-226.
[4] Dashevsky A, Koller K, Bodmeier R. Compression of pellets coated
with various aqueous polymer dispersions. Int J Pharm. 2004;
279: 19-26.
[5] Fukui S, Yano H, Yada S, Mikkaichi T, Minami H. Design and
evaluation of an extended release matrix tablet formulation,
the combination of Hypromellose acetate succinate and
hydroxypropylcellulose. Asian J Pharm Sci. 2017; 12: 149-156.
[6] Rajabi SAR, Farrel TP. Aqueous polymeric coatings for
pharmaceutical dosage forms. Eds McGinity J.W. and Feton LA;
2008.
[7] Bhad ME, Abdul S, Jaiswal SB, Chandewar AV, Jain JM, Sakarkar M.
Int J PharmTechRes. 2010; 2: 847-855.
[8] Vetchý D, Kopecká M, Vetchá M, Franc A. Modely in vitro-in vivo
vo vývoji liečiv. Chem Listy. 2014; 108: 32-39.
[9] Al-Hashimi N, Begg N, Alany RG, Hassanin H, Elshaer A. Oral
modied release multiple unit particulate systems: Compressed
pellets, microparticles and nanoparticles. Pharmaceutics. 2018;
10 (1-23).
[10] Siepmann J., Peppas NA. Modeling of drug release from delivery
systems based on hydroxypropyl methylcellulose (HPMC). Adv
Drug Delivery Rev. 2001; 48: 139-157.
Unauthentifiziert | Heruntergeladen 01.01.20 14:00 UTC