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Journal of Drug Delivery Science and Technology 26 (2015) 17e23

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology


journal homepage: www.elsevier.com/locate/jddst

Original research

Improvement of the dissolution behavior of gliclazide, a slightly


soluble drug, using solid dispersions
Lauretta Maggi a, Andrea Canobbio a, *, Giovanna Bruni b, Giorgio Musitelli a,
Ubaldo Conte a
a
Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100, Pavia, Italy
b
C.S.G.I. e Department of Chemistry, Physico-Chemical Section, University of Pavia, Viale Taramelli 16, 27100, Pavia, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Gliclazide is a second generation sulphonylurea used in the treatment of type 2 diabetes characterized by
Received 12 December 2014 a low risk of hypoglycaemia and cardiovascular disorders. This drug shows poor water solubility,
Received in revised form particularly at low pH values, that may cause reduced and variable absorption after oral administration,
30 January 2015
above all in fasted state. To improve gliclazide dissolution behavior, different drug carrier systems were
Accepted 30 January 2015
prepared and tested using two different methods: co-mixing and co-milling. The samples produced were
Available online 31 January 2015
characterized by differential scanning calorimetry, powder X-ray diffraction, and scanning electron mi-
croscopy. Their dissolution rate was tested and compared to an immediate release commercial product.
Keywords:
Gliclazide
Several approaches were effective for a rapid and complete dissolution of this drug: co-milling with
Dissolution rate suitable hydrophilic carriers such as cross-linked swellable polymers or amorphous silica and co-milling
Solid dispersion with a small amount of sodium lauryl sulphate (10 mg). In the case of the highest dose (80 mg) both
Crosslinked polyvinylpyrrolidone approaches should be used at the same time to avoid saturation of the medium.
Co-milling © 2015 Elsevier B.V. All rights reserved.
Solubility

1. Introduction sulphonylureas, but a lower risk of hypoglycaemia and cardiovas-


cular disorders since it has a selective inhibitory activity towards
Type 2 diabetes mellitus, is a chronic metabolic disease char- pancreatic ATP-sensitive potassium (KATP) channels and a shorter
acterized by insufficient insulin secretion by pancreatic b-cell and/ half-life compared to others sulphonylureas [19]. Moreover it has
or diminished tissue responses to insulin; it is the most common unique antioxidant properties and other beneficial haemobio-
form of diabetes mellitus, accounting for approximately 90% of logical effects [23]. Gliclazide is available as oral tablets, 30 and
cases. An uncontrolled diabetes leads to several long-term com- 80 mg strength. This hypoglycemic agent is formulated both as
plications which include cardiovascular disorders, retinopathy, immediate release and as modified release formulation; the
nephropathy and peripheral neuropathy [2]. Currently, in addition severity of glycemia will determine the dosage and the kind of
to lifestyle modification, which remains the cornerstone of man- formulation, requiring adjustment to obtain the optimal response
agement of type 2 diabetes mellitus, metformin is the first-line oral at the lowest dosage. Gliclazide is an example of class II Biophar-
therapy. However its use is associated to several side effects like maceutical Classification System (BCS) compound, its oral
nausea, vomiting, diarrhea, abdominal pain (that occur in approx- bioavailability depends on the drug dissolution rate and solubility
imately 20% of patients) and rarely to serious lactic acidosis [18], in the gastrointestinal tract. Gliclazide shows poor water solubility
[20]. Sulphonylureas are an alternative for patients with contrain- (55 mg/ml) [1] and dissolution properties and this can give rise to
dication to metformin [8]. Gliclazide is a second generation sul- low and erratic bioavailability and poor dose-effect proportionality
phonylurea that is used in the treatment of patients with type 2 [11]. Moreover being gliclazide a weak acid (pKa 5.8) [22] its sol-
diabetes because it has similar efficacy compared to other ubility is lower in acid medium and this could be a problem in the
design of an immediate release oral dosage form because the entire
dose should be promptly released in very short times in the upper
part of the gastrointestinal tract. Therefore, the improvement of
 degli
* Corresponding author. Dipartimento di Scienze del Farmaco, Universita gliclazide dissolution behavior is an important issue for enhancing
Studi di Pavia, viale Taramelli 12, 27100, Pavia, Italy.
E-mail address: andrea.canobbio@unipv.it (A. Canobbio).
its bioavailability and therapeutic efficacy. Different methods have

http://dx.doi.org/10.1016/j.jddst.2015.01.002
1773-2247/© 2015 Elsevier B.V. All rights reserved.
18 L. Maggi et al. / Journal of Drug Delivery Science and Technology 26 (2015) 17e23

been proposed to improve the solubility and/or the dissolution rate modifications.
of poorly soluble drugs such as micronization [17], salt formation
[5], co-crystals [6], complexation [16] and solid dispersions 2. Materials and methods
[7,10,24] [21]. demonstrated an increase in gliclazide dissolution
rate, compared to gliclazide suspension and gliclazide alone, using 2.1. Materials
ordered binary and ternary mixture of the drug with water soluble
excipients. A significant enhancement of gliclazide dissolution rate Gliclazide was kindly donated by Labochim S.p.A. (Milan, Italy);
was also obtained using solid dispersion prepared with silica and crosslinked polyvinylpyrrolidone (PVPC) Polyplasdone® XL-10 was
polyvinypyrrolidone K30 [12], polyvinylpyrrolydone K90 [4] and from GAF corporation (New York, USA); sodium starch glycolate
PEG 6000 [3]. Several mechanisms were suggested for the (SSG) Primojel® from Elko (Milan, Italy); crosslinked carboxymethyl
improvement of the dissolution properties of insoluble drugs from cellulose (CMCC) Ac-Di-Sol® from FMC Europe (Brussel, Belgium);
solid dispersions, including particle size reduction of the drug, amorphous silica (AS) (Syloid® 72FP) from Grace Davison (Milan,
complete or partial transformation to the amorphous state, Italy); mannitol (M) (Pearlitol® 200SD) from Roquette-Italy (Cas-
reduction of aggregation and improved drug wettability [7]; [10]. sano Spinola, Italy); polyoxyethylene polyoxypropylene tri-block
Conventional methods for solid dispersion preparation include copolymer Poloxamer (PO) (Kolliphor P 407 Micro) from BASF
solvent evaporation, melt crystallization, hot-melt extrusion, (Ludwingshafe, Germany). All the chemicals were of reagent grade,
lyophilization; these methods are efficient, but they are charac- and all the materials were used as received. Some dosage forms
terized by several disadvantages [26]; [27]. In the melting method, available on the Italian market were also evaluated. Two immediate
water-soluble polymers which can solve drugs are limited, and the release (IR) formulations were Diabrezide® (80 mg gliclazide;
high process temperatures may adversely affect drug stability. Merck Serono S.p.A., Rome, Italy), gliclazide EG® (80 mg gliclazide;
Solvent evaporation methods have recently attracted considerable EG S.p.A., Milan, Italy). Five modified release (MR) formulations
attention, although they require organic solvents and are quite were: Diamicron® (30 mg gliclazide; Servier Italia S.p.A., Rome,
expensive processes [28]. Powders co-mixing and co-grinding is an Italy) Dramion® (30 mg gliclazide; I.F.B. Stroder S.r.l., Florence,
alternative solid dispersion generating method. Many authors have Italy), gliclazide EG® (30 mg gliclazide; EG S.p.A., Milan, Italy), gli-
demonstrated the efficacy of the co-grinding method for the clazide Mylan generics (gliclazide 30 mg; Mylan S.p.A., Milan, Italy).
enhancement of the dissolution rate of various poorly soluble drugs
such as danazolo, felodipine [29], nateglinide [13], aclofenac [15].
Co-grinding is an environmentally friendly and solvent-free 2.2. Methods
method, it avoids the thermal degradation of the drugs, it does
not require sophisticated equipments, it is industrially feasible and The particle size analysis was determined, by laser diffraction,
can be easily scaled-up. In this work, to enhance the dissolution Coulter LS 230 (CoulterCorp., Miami, FL, USA), on raw gliclazide and
behavior of gliclazide, some solid dispersions were prepared, in on a drug sample treated alone in the same conditions used for the
different drug to polymer ratios. The dissolution behavior of the co- production of the drug-carrier co-milled systems, to verify a
ground systems was evaluated and compared to that of the corre- possible particle size reduction.
sponding physical mixtures and to some commercial gliclazide Gliclazide solubility was determined in triplicate in over satu-
formulations, considered as references. Solid state characterization ration conditions by dispersing an excess of drug in volumetric
of drug-carrier systems was carried out by scanning electron mi- flasks at 21  C in distilled water. The suspensions were left under
croscopy (SEM), differential scanning calorimetry (DSC) and pow- constant magnetic stirring, 300 rpm, for 24 h. At 2, 4, 6 and 24 h, an
der X-ray diffraction (PXRD) to investigate possible drug aliquot of the liquid was filtered through a Millipore membrane
(pore size 0.45 mm), properly diluted and the drug concentration

Table 1
T50% ± Standard Deviations (S.D.) of gliclazide alone, gliclazide treated (T) and physical mixtures (PM) or co-milled (CM) drug-carrier systems in distilled water or HCl 0.1 N (*).

Dose Drug carrier system Method Code T50% (min) ± S.D.

30 mg Gliclazide e GLI 45 ± 6.3


Gliclazide treated T GLI T 160 ± 32
Gliclazide: Mannitol 1:8 PM GLI:M 1:8 >60
Gliclazide: Amorphous Silica 1:8 PM GLI:AS 1:8 18 ± 6.3
Gliclazide: Crosslinked Polyvinyl Pyrrolidone 1:8 PM GLI:PVPC 1:8 17.3 ± 0.57
Gliclazide: Mannitol 1:8 CM CM GLI:M 1:8 17 ± 7.4
Gliclazide: Amorphous Silica 1:8 CM CM GLI:AS 1:8 7.6 ± 1.5
Gliclazide: Crosslinked Polyvinyl Pyrrolidone 1:4 CM CM GLI:PVPC 1:4 13 ± 6.7
Gliclazide: Crosslinked Polyvinyl Pyrrolidone 1:6 CM CM GLI:PVPC 1:6 6.2 ± 1.1
Gliclazide: Crosslinked Polyvinyl Pyrrolidone 1:8 CM CM GLI:PVPC 1:8 4.6 ± 0.52
Gliclazide: Crosslinked Carbossy Methyl Cellulose 1:8 CM CM GLI:CMCC 1:8 5.8 ± 0.96
Gliclazide: Sodium Starch Glycolate 1:8 CM CM GLI:SSG1:8 12 ± 0.78
Gliclazide:Sodium Lauryl Sulphate CM CM GLI:SLS 2.2 ± 0.25
80 mg Gliclazide e GLI >60
Gliclazide: Mannitol 1:8 CM CM GLI:M 1:8 36 ± 10
Gliclazide: Amorphous Silica 1:8 CM CM GLI:AS 1:8 7.3 ± 1.7
Gliclazide: Crosslinked Polyvinyl Pyrrolidone 1:8 CM CM GLI:PVPC 1:8 11 ± 0.28
Gliclazide: Sodium Lauryl Sulphate CM CM GLI:SLS 3.7 ± 0.57
Gliclazide: Sodium Lauryl Sulphate: Crosslinked PolyvinylPyrrolidone 1:4 CM CM GLI:SLS:PVPC 1:4 13 ± 2.9
Gliclazide: Sodium Lauryl Sulphate: Crosslinked PolyvinylPyrrolidone 1:8 CM CM GLI:SLS:PVPC 1:8 14 ± 2.4
DIABREZIDE® e 35 ± 2.1
Gliclazide: Sodium Lauryl Sulphate: Crosslinked PolyvinylPyrrolidone 1:4 CM CM GLI:SLS:PVPC 1:4 5.8 ± 3.7*
Gliclazide: Sodium Lauryl Sulphate: Crosslinked PolyvinylPyrrolidone 1:8 CM CM GLI:SLS:PVPC 1:8 5.9 ± 0.82*
DIABREZIDE® e 47 ± 4.5*
L. Maggi et al. / Journal of Drug Delivery Science and Technology 26 (2015) 17e23 19

was assayed spectrophotometrically at 226 nm. Table 2


Co-ground solid dispersions were prepared in different drug to Gliclazide measured concentrations in distilled water, at 21  C ± Standard
Deviations (S.D.).
carrier ratios (1:4, 1:6, 1:8). Gliclazide and each superdisintegrant
or hydrophilic carrier were co-milled in a proper cylindrical Time (h) Drug concentration (mg/L) ± S.D.
container with 20 steel spheres (d ¼ 6.35 mm) for 30, 60, 90 or 2 42.7 ± 2.50
180 min, using a Turbula apparatus at 25 rpm; a sample of gliclazide 4 53.9 ± 2.95
alone (GLI T) was treated in the same conditions. The results ob- 6 54.6 ± 2.11
24 54.0 ± 3.73
tained after 90 min of treatment were reported, because no further
modification in the drug dissolution rate were detected after this
processing time. The corresponding physical mixtures were pre-
pared by simple blending the two components in the Turbula 3. Results and discussion
apparatus at 25 rpm without spheres for 90 min. The drug-carrier
systems prepared, and their codes, are reported in Table 1. Gliclazide showed a mean volume diameter of
The Gliclazide dissolution profiles were determined according 38.41 ± 30.64 mm; the calculated specific surface area was
to USP 31 Dissolution Test, in 1000 ml of distilled water or HCl 0.1 N, 11515 cm2/ml. By treating the drug alone in the same conditions
pH 1.0, at 37.0 ± 0.5  C, using the dissolution apparatus 2, paddle used for the co-milled drug carrier systems, did not modify its
(Erweka DTD6, Dusseldorf, Germany), at 100 rpm. An UVevis particle size, indeed GLI T mean volume diameter and calculated
spectrophotometer (Lambda 25, PerkineElmer, Monza, Italy) is specific surface area were comparable to that measured on the
connected to the dissolution apparatus with an automatic sampling untreated drug: 39.43 ± 25.50 mm and 13753 cm2/ml respectively.
device and a PC for data analysis. The time required for 50% of drug The dissolution profiles, in water, of several immediate release
to be released (t50%) was considered for comparing the dissolution or modified release gliclazide commercial forms, available on Ital-
results (Table 1). The difference of the dissolution curves was ian market, are depicted in Fig. 1.
evaluated using the f2 similarity factor: a value >50 indicates Table 2 summarizes the concentrations of gliclazide measured
similarity between two dissolution profiles [25]. in saturated condition, in distilled water. The amount of drug dis-
Thermal characterization was carried out by a DSC Q2000 solved in 2 h was 42.7 mg/l; the drug concentration slightly
apparatus interfaced with a TA 5000 data station (TA Instruments, increased after 4 h but then remained constant till 24 h, confirming
NewCastle, DE, USA). The DSC instrument was calibrated using it reached thermodynamic equilibrium in solution (about 54 mg/l).
ultrapure (99.999%) indium (melting point ¼ 156.6  C; Table 1 shows the t50% of gliclazide alone, physical mixtures and
DH ¼ 28.54 J g1) as standard. The calorimetric measurements were co-milled systems with the different excipients used in this study.
carried out in open standard aluminum pans under nitrogen flow T50% was used to compare the dissolution rate of the different
(45 mL min1) at 10 K min1. systems, but in some cases, drug released in one hour of test, was
PXRD measurements were performed by a D5005 Bruker even less than 50%. In Fig. 2 the dissolution profiles of the raw active
diffractometer (Karlsruhe, Germany) (CuKa radiation, material (GLI) and treated gliclazide (GLI T) are compared to
l(Ka1) ¼ 1.54056 Å; voltage of 40 kV and current of 40 mA) physical mixtures and co-milled systems containing mannitol or
equipped with a q-q vertical goniometer, Ni filter, monochromator amorphous silica. GLI T dissolved slower (t50% ¼ 160) than unpro-
and scintillator counter. The patterns were recorded at room tem- cessed drug (t50% ¼ 45). PXRD and DSC measurements revealed that
perature in step scan mode (step size: 0.020 , counting time: 3 s per the solid phase of the drug does not change as a consequence of the
step) in the 5 < 2q < 35 angular range. milling process. The single difference seen in the SEM micrographs
SEM measurements were performed using a Zeiss EVO MA10 is that the particles are more aggregated (Fig. 3a, b). Thus the
(Carl Zeiss, Oberkochen, Germany) on gold sputtered samples. dissolution behavior can be explained considering that, when the
drug is milled alone, the mechanical treatment may cause the

Fig. 2. Dissolution profiles of physical mixtures versus co-milled systems with


Fig. 1. Comparison of different gliclazide modified release (MR) and immediate release mannitol (M) or amorphous silica (AS), compared to raw or treated (T) gliclazide. Dose:
(IR) formulations available on the Italian market. 30 mg.
20 L. Maggi et al. / Journal of Drug Delivery Science and Technology 26 (2015) 17e23

Fig. 3. SEM micrographs of gliclazide (a), treated gliclazide (b), mannitol (c), CM GLI:M 1:8 (d), amorphous silica (e), CM GLI:AS 1:8 (f), PVPC (g) and CM GLI:PVPC 1:8 (h).
L. Maggi et al. / Journal of Drug Delivery Science and Technology 26 (2015) 17e23 21

Fig. 4. PXRD pattern of gliclazide (a), CM GLI:M 1:8 (b), mannitol (c), CM GLI:AS 1:8 (d) Fig. 7. PXRD pattern of gliclazide (a), CM GLI:PVPC 1:4 (b), CM GLI:PVPC 1:8 (c) and
and amorphous silica (e). PVPC (d).

formation of electrostatic charges on the particles surface that ex-


acerbates the agglomeration of hydrophobic particles resulting in a
decrease of the effective surface available for dissolution; this
behavior increases the wetting problems of the drug in aqueous
medium. The agglomeration of particles can be prevented just by
mixing the drug with suitable hydrophilic excipients like silica. Co-
milling with amorphous silica or mannitol determined a further
improvement of the dissolution rate compared to the correspond-
ing physical mixtures, demonstrating the advantages of a co-milled
formulation in terms of overcoming the wetting problems of gli-
clazide. The t50% values decreased from 18 min for the physical
mixture containing amorphous silica (GLI:AS 1:8) to less than 8 min
for the corresponding co-milled system (Table 1); in the case of
mannitol the physical mixture released less than 50% in 1 h of test,
while the CM GLI:M 1:8 showed a t50% of 17 min (Fig. 2). For poorly
soluble drugs, the dissolution rate is often higher from the co-
milled systems compared to the corresponding physical mixtures,
thanks to more intimately mix of the two components due to
Fig. 5. DSC curves of gliclazide (a), CM GLI:M 1:8 (b), mannitol (c), CM GLI:AS 1:8 (d) mechanical stress, as reported in a previous work [13,14].
and amorphous silica (e). Indeed, the SEM analysis of the co-milled CM GLI:M 1:8 sample
show that the mannitol particles seem crushed and the two com-
ponents appears in closer contact (Fig. 3ced). In the PXRD pattern
of the co-milled sample, the diffraction peaks of both components
are present indicating no-interaction and no-amorphization
occurred (Fig. 4). In the DSC curve of the same sample only one
peak is present at a temperature just below the mannitol melting
(Fig. 5). Its enthalpy change corresponds to the sum of the melting
enthalpies of mannitol and gliclazide corrected on the basis of the
mixture composition. It is likely that the melting of gliclazide takes
place early for the presence of the melted mannitol that surrounds
the drug particles. The SEM pictures of the CM GLI:AS 1:8 sample
show that the particles of gliclazide are covered by the tiny particles
of the amorphous silica (Fig. 3e, f). However, in this case, both PXRD
and DSC measurements agree with the hypothesis that the drug has
been amorphised for the presence of silica. Indeed, the melting
peak of gliclazide disappears in the DSC curve and its diffraction
effects are nearly absent in the PXRD pattern of both physical
mixture and co-milled samples (Figs. 4 and 5).
However no one of the two co-milled systems with hydrophilic
excipients was able to ensure a quantitative release of the drug dose
of 30 mg. To further enhance the interaction between the drug and
the dissolution medium, some co-milled systems containing the
superdisintegrant crosslinked polyvinylpyrrolidone, in different
Fig. 6. Gliclazide:crosslinked polyvinylpyrrolidone co-milled systems in different w:w w:w drug to polymer ratio, were prepared (1:4, 1:6, 1:8). The three
ratios compared to gliclazide alone. Dose: 30 mg.
22 L. Maggi et al. / Journal of Drug Delivery Science and Technology 26 (2015) 17e23

co-milled 1:8 is only the 25%. The same trend characterizes the
PXRD results: the intensity of the drug diffraction peaks is very low
in the patterns of the physical mixtures and even lower in those of
the co-milled systems (Fig. 7). Thus, these analyses allow to attri-
bute the increased drug dissolution rate also to another cause: the
partial amorphization of the drug.
The dissolution behavior of two other carriers, sodium starch
glicolate (SSG) and crosslinked carboxymethyl cellulose (CMCC)
was also investigated; in this case, only the highest drug:polymer
ratio, 1:8 (w:w), was evaluated. In both cases the carriers were
effective, although the dissolution profile were slightly slower than
that obtained from CM GLI:PVPC 1:8 (the f2 values were respec-
tively of 26.9 and 46.8) (Fig. 8). The CM GLI:CMCC 1:8 system
showed an initial improvement of the dissolution rate, comparable
to that of the system containing PVPC, but after 15 min the rate
decreased and the profile became quite flat, allowing the release of
roughly 75% of the dose in 1 h of test. On the other hand, the CM
GLI:SSG 1:8 formulation exhibited a slower dissolution rate
compared to the co-milled system containing CMCC (f2: 43.2), but
it released 90% of the dose in 60 min.
Fig. 8. Dissolution curves of gliclazide co-milled systems with PVPC, CMCC or SSG in
1:8 w:w drug:polymer ratio and co-milled system containing 10 mg of sodium lauryl These differences in the release profiles can be explained by the
sulfate, compared to gliclazide alone. Dose: 30 mg. different mechanisms of action of the three superdisintegrants.
When exposed to water, SSG and CMCC absorb water quickly and
swell a lot forming, particularly at high concentrations, a viscous gel
layer that could act as a barrier for drug diffusion and thus retarding
drug release. PVPC is characterized by a rigid porous structure, it
absorbs water by capillary action, without gelling, thus increasing
drug particles wettability without reducing drug diffusion.
To improve drug wettability the surfactant sodium lauryl sulfate
(SLS) was also evaluated. The Food and Drug Administration (FDA)
specifies the maximum amount of inactive ingredient for each
route/dosage form containing that ingredient; in the case of oral
tablets the maximum registered amount of SLS is 51,69 mg [9].
Indeed the CM GLI-SLS, containing 10 mg of sodium lauryl sulphate,
released 30 mg of gliclazide in less than 10 min (Fig. 8). We have
decided to use 10 mg in our formulation because the treatment
with gliclazide may involves many daily administrations.
All the co-milled systems were also evaluated on the higher
dosage of 80 mg, but, in this case, the saturation of the medium
occurred and none of the binary systems were able to release the
entire dose during the first 60 min of dissolution (Fig. 9). A ternary

Fig. 9. Gliclazide dissolution profiles from different co-milled systems, compared to


the drug alone. Dose: 80 mg.

systems allowed a significant improvement of dissolution proper-


ties of the drug, and this effect was more evident with increasing
the PVPC concentration in the system (Fig. 6) (similarity factor, f2,
reported in Supplementary Material). The highest dissolution rate
was exhibited by CM GLI:PVPC 1:8 which allowed the quantitative
release of the 30 mg dose in less than 30 min. As it can be seen in
Fig. 3g, h, the PVPC rounded particles cover the surface of all the
irregular sticks of the drug and it is reasonable to think that,
consequently, the agglomeration of drug particles in solution will
be significantly reduced, wetting will be facilitated and the hy-
drophilicity of the surface of the co-ground particles enhanced.
Both DSC and PXRD analyses indicate that the simple presence
of PVPC induces drug amorphization which is further accentuated
with milling. Indeed, the drug melting enthalpy in the physical
mixtures is lower than the value expected in the case of non-
interaction and even lower in the co-milled systems. In particular,
Fig. 10. Comparison of gliclazide dissolution curves obtained from the ternary co-
the enthalpy change of the drug melting peak in the DSC curve of
milled systems versus immediate release tablets Diabrezide® in distilled water or
the co-milled 1:4 is only the 57% of the expected value, while in the HCl 0.1 N pH 1.0 (*). Dose: 80 mg.
L. Maggi et al. / Journal of Drug Delivery Science and Technology 26 (2015) 17e23 23

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