Presented by Prof B Mishra Professor amp Former Head Department of Pharmaceutics Indian Institute of Technology Banaras Hindu University Varanasi 221 005 Components of Research Background ID: 728541
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Slide1
Pastillation Technology Based Design & Development of Oral Modified Release Multiparticulate Drug Delivery System
Presented by:Prof. B. MishraProfessor & Former Head,Department of Pharmaceutics,Indian Institute of Technology(Banaras Hindu University)Varanasi- 221 005Slide2
Components of Research
Background Lipid based multiparticulate drug delivery systemDoxofylline as potential anti-asthmatic agentExperimental workDevelopment of Immediate and controlled release pastillesDevelopment of pulsatile release pastillesIn vivo study2Slide3
Lipid based multiparticulate system
Nanoparticles
Granules
Microparticles
Pellets/Beads
3Slide4
Pastillation
Pastillation is a widely used technique in chemical, petrochemical and agrochemical industriesIt is used for the solidification of dusty hazardous powders of chemicals into pastilles (hemispherical solidified units of uniform size) which eases their handling. In this process, the drops of chemical substances in molten state are deposited on a cooled stainless steel surface for rapid solidification to generate pastilles of uniform dimensions.Depending on the size of the drops and the physical properties of the melt, the drops flatten to a certain extent. The solidified droplet, therefore, has the typical pastille-like shape. The production process can be easily carried out at large scale with the help of specially designed equipments called ‘Rotoformer’.4Slide5
Pastillation
equipment
5Slide6
Suitable for hygroscopic drug as the processing of the ingredients is absolutely free from use of water.
Environment friendly as involves no use of organic solvents.Pastilles are stable and highly uniform in shape.Pastilles can be produced in a wide range of sizes with diameters ranging from 1 to 30mm.Pastilles have higher bulk density and better packing properties than powders and therefore, ideal for handling, filling and packaging.The conversion of a bulk molten liquid directly into individual solidified units provides dust free working environment. Single step process involving one equipment (melting of lipid, mixing of drug and excipients followed by solidification).Reduced energy costs due to absence of number of processes of formulation.Ease of packaging as the pastilles of smaller dimension can be capsule filled while the larger ones can either be strip packed or filled directly in sachets/bottles.Why pastillation in DDS?
6Slide7
Components of Research
Background Lipid based multiparticulate drug delivery systemDoxofylline as potential anti-asthmatic agent
Experimental work
Development of immediate and controlled release pastilles
Development of pulsatile release pastilles
In vivo study
7Slide8
Chemical Name:
2-(7-theophyllinemethyl)-1,3 dioxolaneMolecular Formula: C11H14N4O4Formula weight: 266Melting Point: 144-145.5°CSolubility: Freely Soluble in chloroform and Dichloromethane soluble in acetone, sparingly soluble in water and ethyl acetateStorage: Store in cool, dark and dry place.
Doxofylline
Ist
Marketed product in India
Product:
DOXOBID (
Doxofylline
tablets 400mg)
Company:
Dr. Reddy’s Labs.
Label Claim:
Each uncoated tablet contains:
Doxofylline
400mg
Indication :
used as Bronchodilator in Asthma
& chronic obstructive pulmonary
disease(COPD)
Dose :
400mg IR is given 2-3 times daily
8Slide9
Absorption
Absorption Bioavailability : 62.6%Therapeutic Drug ConcentrationChronic Bronchitis : 8-20 µg/mlTime to peak concentration (tmax) : 1.19 hours
The steady state is reached within 6hrs : 9.43 µg/ml
Area under the curve, AUC : 69.5 hr×µg
/mlDistribution
Protein Binding :
48%
Distribution Half Life :
0.19 hr
Volume of distribution :
1 L/kg
Metabolism
Metabolism sites & kinetics: Liver >90%
Metabolites:
Hydroxyethyltheophylline
(inactive)
Excretion
Kidney: Less than 4% of an administered dose of
doxofylline
is excreted unchanged in the urine
Total Body Clearance: 444-806µg/ml
Elimination Half life: Parent compound – 7 to 10hrs
Pharmacokinetic profile
9Slide10
Objectives of the research work
PART ITo design a immediate and controlled release formulation of doxofylline using pastillation technology
PART II
To design a pulsatile release formulation of doxofylline using pastillation technology
PART III
To evaluate
pharmacokinetic behavior of
the
developed formulations in animal model
To explore pastillation to design a platform technology for the development of novel and unique modified release drug delivery system
10Slide11
In-house laboratory scale device for pastillation
TransformerGlass syringeNeedlePastillesCold plate
Ice tray
Shaft
Ceramic insulation
Heating coil
11Slide12
Operating parameters
Sl No.FactorsLow (-)High (+)
1.
Needle dimensions (X1)
16G
20G
2.
Dropping height (X
2
)
1 cm
3 cm
3.
Temperature of plate (X
3
)
4 °C
25 °C
Factorial design using MINITAB
®
12Slide13
Evaluating parameter
Contact angle measurementMethod of analysis (Photographic method)The photographs of the pastilles were taken from the horizontal side at their contact with the plate and the snaps were then proportionally magnified and processed using Adobe Photoshop® software. The angle of contact was determined manually and confirmed mathematically using the following equation:θ = 2tan−12h/dWhere h is the height of the drop from the plate and d is the diameter of the drop. Both of these dimensions can be measured from the photograph for calculating the contact angle.
13Slide14
Contact angle of pastilles
14Slide15
Formulation batches (for optimization)
Sl. No.BatchesX1X2
X3Avg. Contact angle (Y
1)
1.
A1
16G
1 cm
4 °C
121°
2.
A2
16G
1 cm
25 °C
110°
3.
A3
16G
3 cm
4 °C
100°
4.
A4
16G
3 cm
25 °C
80°
5.
A5
20G
1 cm
4 °C
120°
6.
A6
20G
1 cm
25 °C
115°
7.
A7
20G
3 cm
4 °C
95°
8.
A8
20G
3 cm
25 °C
85°
15Slide16
Effect of needle size and dropping height on contact angle
(A) Response Surface 3D plot (B) Contour plot16Slide17
Effect of temperature of plate and dropping height on contact angle
(A) Response Surface 3D plot (B) Contour plot17Slide18
Effect of needle size and temperature of plate on contact angle
(A) Response Surface 3D plot (B) Contour plot18Slide19
Flow property of pastilles based on their contact angle
Flow propertyContact AnglePoor60-85°Fair
85-105°Good
105-125°
19Slide20
Optimized parameters for highest achievable (desirable) contact
angle Sl No.Optimized parameters1.
Needle dimensions (X1
)
20 G
2.
Dropping height (X
2
)
1
cm
3.
Temperature of plate (X
3
)
4 °C
20Slide21
Formulation chart
Compositiong/batch
B-1
B-2
B-3
B-4
B-5
B-6
B-7
B-8
B-9
B-10
DOX
0.5
0.5
0.5
0.5
0.5
0.3
0.4
0.5
0.5
0.5
Stearic acid
2.0
2.0
2.0
2.0
2.0
2.0
1.7
1.7
1.7
Benefat
-
-
-
-
-
-
0.3
1.5
0.75
PEG 4000
2.0
-
0.3
-
-
0.3
0.3
-
-
-
PEG 6000
-
-
0.3
-
-
-
-
-
-
PEG 400
-
-
-
0.3
-
-
-
-
-
Colloidal
silicon
dioxide
75
Drug content Uniformity (%)
100.56 ± 0.93
98.89 ± 1.23
21Slide22
Evaluation
Drug content uniformity (20 ml water added to pastilles eq. to 10 mg drug and heated at 75°, sonicated, cooled and volume made upto 25 ml. 5 ml filtered and measured spectrophotometrically)Drug release study (USP Appt. II, 500 ml of 0.1 N HCl, 50 rpm, 37±0.5°C for 2 h followed by pH 6.8 phosphate buffer for next 22 h)Scanning electron microscopy (The morphological structure of the prepared pastilles was observed using scanning electron microscope (FEI Quantum 200E Instrument)Stability studies (pastilles packed in 30 ml HDPE bottles kept in 40°C/75%RH for 3 months storage conditions in stability chamber
(Narang Scientific Works Pvt. Ltd., New Delhi, India))
22Slide23
Analytical method
UV–VIS spectrophotometry (Hitachi U-1800)Standard curves of doxofylline were prepared in water, 0.1 N HCl (pH 1.2) and phosphate buffer solutions (pH 6.8) in the concentration range of 5–35 μg/ml.A UV visible spectrum of doxofylline showed a characteristic peak at 273 nm in all the solutions.The standard curve was plotted as drug concentration (μg/ ml) vs. absorbance plot. Curve fitting was done by linear regression analysis using Microsoft Excel program 23Slide24
Standard Curves of Doxofylline
24Slide25
Effect of pore former & type of buffer media on drug release
25Slide26
Effect of drug load on drug release
26Slide27
Effect of benefat (lipid pore former) concentration on drug release behavior
R2=0.98327Slide28
Scanning electron microscopy
Batch B1 (B) Batch B1 at higher magnification (C) Batch B10 (D) Batch B10 at higher magnification28Slide29
Drug release profiles of initial and 3 months stored samples
Drug content uniformity1M-98.66%2M- 97.12%3M-96.46%Stability study at 40°C/75%RH indicate stable formulation with no change in physical appearance, drug release and drug content29Slide30
Components
of ResearchBackground Drug delivery systemTherapeutic applicationExperimental workDevelopment of immediate, controlled and pulsatile release pastillesIn vivo animal study30Slide31
Formulation chart
Ingredients P-IP-IIP-IIIP-IV
P-VP-VI
DOX (mg)
500
500
500
500
500
500
PEG 4000 (mg)
2000
2000
2000
2000
2000
2000
Colloidal silicon dioxide (mg)
-
75
150
75
75
75
Enteric coat
1
(5 g
Eudragit
L100 55 and 0.25 g
triethyl
citrate (plasticizer)
& 2% talc in 100ml methanol
-
-
-
10 ± 5 %*
-
-
Enteric coat
2
(5 g
Eudragit
L100 55 and 0.5 g
triethyl
citrate (plasticizer)
& 2% talc in 100ml methanol
10 ± 5 %*
10 ± 5%*
Floating
layer
(1g HPMC K15M, 0.1 g
triethyl
citrate (plasticizer) in 100 ml IPA DCM
mixture (60:40 v/v). NaHCO
3
crushed and passed through #100 mesh & 2% talc was dispersed in the above solution
-
-
-
-
-
20 ± 5%#
* Amount of enteric coat applied was calculated in terms of percentage weight gain with respect to the weight of uncoated pastilles
# Amount of floating coat applied was calculated in terms of percentage weight gain with respect to the weight of enteric coated pastilles
31Slide32
Evaluation
AssayDrug content uniformityDrug release study (USP Appt. II, 500 ml of 0.1 N HCl, 50 rpm, 37±0.5°C for 2 h followed by 2 h followed by pH 6.8 phosphate buffer for next 2 h)Scanning electron microscopyStability studies (40°C/75%RH for 3 months)32Slide33
Contact angle
Pastilles with A) desired contact angle (above 85°), B) with contact angle ≤ 45°, C) with contact angle above 70°33Slide34
Explanation for formation offlat pastilles
Friability B-I :0.596%B-II :0.104%Contact angle improvement of PEG pastilles at large scale34Slide35
Assay and drug content uniformity
Assay (%)Drug content uniformityP-I100.12 ± 1.11
100.19 ± 2.13
P-II100.09 ± 1.91
99.98 ± 2.21
P-III
99.61 ± 2.17
98.89 ± 1.81
P-IV
98.12 ± 1.21
99.01 ± 0.91
P-V
98.08 ± 2.19
98.21 ± 1.27
P-VI
99.06 ± 1.98
99.12 ± 2.12
35Slide36
Drug release profile
36Slide37
Scanning electron microscopy
Surface morphology of coated pastilles using SEM A) Batch P-IV, B) Batch P-V, C) Batch P-VI37Slide38
Coated PEG pastilles floating in dissolution medium
38Slide39
Dissolution of initial and three months stored samples
39Slide40
Conclusion
A novel technology ‘pastillation’ was successfully employed for the development of immediate release pastilles. This dosage form after coating with enteric and floating coat were also found to be effective to achieve the required delay in drug release for treatment of nocturnal asthma. The prepared formulations showed desired drug release profile with an initial lag phase in the in vitro drug release study. The in vivo pharmacokinetic study would be helpful in further evaluating the potential of this formulation in the chronotherapeutic treatment of nocturnal asthma.40Slide41
Components of Research
Background Drug delivery systemTherapeutic applicationExperimental workDevelopment of controlled release pastillesDevelopment of pulsatile release pastillesIn vivo animal study41Slide42
In-vivo animal study
Animal study protocol were approved by the Animal Ethical Committee of Banaras Hindu University.(No. 2010-11/153) Male albino rats of 250 ± 20 g12 h fasting prior to dosing5.70 mg drug/kg body weight administered orallyPastilles were administered with 5.0 ml of 1.0% aqueous polyvinyl alcohol solutionBlood (0.5 mL) was collected via retro-orbital vein0, 0.25, 0.50, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h
Blood samples were allowed to clotThey were centrifuged for 10 min at 3000 rpm The serum obtained was transferred to clean tube for storage
at −20 °C until analysis
42Slide43
Study design of pharmacokinetic studies
PEG Pastilles (IR)Stearic acid pastilles (CR)For controlled release pastilles
For pulsatile release pastilles
PEG Pastilles (uncoated)
PEG pastilles (enteric coated with floating layer)
PEG Pastilles (enteric coated)
43Slide44
Serum drug estimation
Drug separation from serum by liquid-liquid extraction method Serum (containing drug) (500 μl) + methanol (400 μl) Supernatant (400 μl)
Residue + mobile phase (200 μl
)
Reconstituted sample (20 μl
) injected for HPLC analysis
Vortexed (8 min) &
centrifuged at 3500 rpm for 10 min
Evaporated in vacuum oven at 40°C
Reconstituted
44Slide45
Serum drug estimation
Serum drug estimation by Reverse phase HPLC methodChromatographic conditions:Column: C18 reverse-phase 250×4.6 mm 5 μm ODS2 column (Waters, Ireland)Mobile phase: 18:82 acetonitrile–12.5 mM potassium dihydrogen orthophosphate buffer (pH adjusted to 3.0 with
orthophosphoric acid) Flow rate: 1 ml/min
Injection volume: 20 μl
λ
max: 275 nm
Retention Time: 9.75 min
45Slide46
Pharmacokinetic estimation
Cmaxpeak serum concentration Tmaxtime to reach peak concentrationAUC0-tarea under the curve from time zero to last measured concentration
HVD t50% Cmax
time span during which the serum concentrations were at least 50% of the C
max
R∆
ratio between the HVD
t50% Cmax
values of the test formulation and the drug suspension
Kinetica
®
software
GraphPad Prism
®
software
46Slide47
HPLC chromatograms and Calibration curve of doxophylline extracted from serum
47Slide48
Pharmacokinetic profile of PEG and lipid based pastilles
48Slide49
Pharmacokinetic data of PEG and lipid based pastilles
Pharmacokinetic parametersPEG based pastillesLipid based pastillesCmax (
ng/ml)
31.83 ± 1.28
16.32 ± 3.69
T
max
(h)
0.75 ± 0.06
6.0 ± 1.58
AUC
last
(
ng
/ml*h)
182.56 ± 19.98
210.39 ± 59.6
HVD (h)
3.18 ± 0.21
11.43 ± 1.52
$
R
∆
-
3.59
$
R∆ =of 1.5, 2 and >3 indicates, low, intermediate and strong sustained release effect, respectively
Data are shown as mean
+
SEM
49Slide50
Pharmacokinetic profile of uncoated and coated PEG pastilles
50Slide51
Pharmacokinetic data of uncoated and coated PEG pastilles
Pharmacokinetic parametersP-II (Uncoated pastilles)P-V (Enteric coated pastilles)
P-VI
(Enteric & floating coated pastilles)C
max (
ng/ml)
31.83 ± 1.28
30.92 ± 2.12
25.12± 2.41
T
max
(h)
0.75 ± 0.06
3.0 ± 0.27
6.0 ± 0.82
AUC
last
(
ng
/ml*h)
182.56 ± 19.98
201.47 ± 29.7
241.68 ± 42.7
HVD
t50% Cmax
(h)
3.18 ± 0.21
4.23 ± 0.15
6.70 ± 0.13
R∆
-
1.33
2.11
Data are shown as mean
+
SEM
51Slide52
Gamma scintigraphic method
Radiolabeling of PastillesTechnetium (99mTc) was chosen for radio-labeling of the pastilles because of its short half-life of 6 hrs and very less amount of electron emission TLC (Silica Gel) After 2 min After 99% reduction
100 ml 99m
TC5 mg stannous chloride
dihydrate (1 mg/ml in 10% acetic acid) of pH 7.5 (adjusted with 0.5M NaHCO3
1g pastilles + 5 ml water
5 mg stannous chloride
dihydrate
(1 mg/ml in 10% acetic acid) of pH 7.5 (adjusted with 0.5M NaHCO
3
radiolabeling
efficiency was evaluated by TLC-SG strips as stationary phase & acetone as mobile phase
52Slide53
Gamma scintigraphic method
Stability of radiolabeled pastilles pH 1.2 0.1N HCl 1g pastilles pH 6.8 buffer pH 7.2 buffer
0.2 ml filtered solution checked for radioactivity by auto gamma counter
Kept under stirring in a water bath maintained at 37° C for 6 hr
53Slide54
Study design of gamma scintigraphy
For pulsatile release pastillesMale albino rats of 250 ± 20 g, 12 h fasting prior to dosing5.70 mg drug per kg body weight administered orallyAfter light anaesthetizationserial scintigraphic examination was done at 0.5, 1, 1.5, 2, 3, 4 and 5, 6 hrs depending on type of formulation using a large field view gamma camera Images were recorded for a preset time of 1 min/view to include the 140 keV photopeak of 99m
Tc
PEG Pastilles (uncoated)
PEG pastilles (enteric coated with floating layer)
PEG Pastilles (enteric coated)
54Slide55
Gamma scintigraphic set up
A
B
C
D
55Slide56
Stability data of radiolabeled pastilles
pHP-II(Uncoated pastilles)P-V(Enteric coated pastilles)
P-VI
(Enteric & floating coated pastilles)1.2
0.13
0.21
0.16
6.8
0.25
0.32
0.27
7.2
0.36
0.34
0.31
56Slide57
Gamma scintigraphy study of uncoated PEG pastilles
Gamma Scintigraphy study of uncoated PEG pastilles on rats at time point (A) 0.5 hr and (B) 1 hr57ABSlide58
Gamma scintigraphy study of uncoated PEG pastilles
OBSERVATION: Attenuation of radioactivity within 0.5 hrs. INFERENCE: In the presence of gastric fluid, PEG matrix dissolved completely and behaved as an immediate release dosage form. 58Slide59
Gamma scintigraphy study of enteric coated PEG pastilles
Gamma Scintigraphy study of enteric coated PEG pastilles on rats at time point (A) 0.5 hr and (B) 1 hr, (C) 1.5 hr, (D) 2 hr and (E) 3 hr 59AB
C
D
ESlide60
Gamma scintigraphy study of enteric coated PEG pastilles
OBSERVATION: The pastille maintained its matrix integrity till 1.5 hrs in the gastric region. At 2 hrs the pastille was located in the jejunum area where it started to dissociate.INFERENCE: No influence of gastric fluid on the enteric coating applied on the pastilles. 60Slide61
Gamma scintigraphy study of pastilles with floating coat
AB
CD
E
F
Time point (A)1 hr, (B) 2 hr and (C) 3 hr, (D) 4 hr, (E) 5 hr and (F) 6 hr
61Slide62
Gamma scintigraphy study of pastilles with floating coat
OBSERVATION: The pastille was retained in the stomach for 2 h. In the next hour, the intact pastille migrated into the jejunum. Further, in the 4th hour the dosage form was found to reach the ileum region where it started to disperse. The image of 6th hour shows complete disintegration of the dosage form. INFERENCE: This indicates that the floating coat is not only valuable to retain the dosage form in the stomach for more than two hours but also to protect the enteric coat from alkali environment for an hour. 62Slide63
Conclusion
The pharmacokinetic and gamma scintigraphic imaging confirms the ability of the formulations to release the drug only after a desired period of time as specifically required for the treatment of noctural asthma. The results are also in agreement with the in vitro drug release study which indicates the efficiency of the coating system. The present study also confirms the ability of PEG based pastilles to act as an immediate release dosage forms. Further coating of the PEG pastilles with appropriate polymers can significantly impart functional properties to modify the release of the drug in a pre-determined fashion.
63Slide64
Major findings
Use of pastillation technology for the first time in pharmaceutical fieldNovel drug delivery system “PASTILLES” were successfully formulated as: immediate release dosage form pulsatile release dosage form sustained release dosage form64Slide65
Important references
Cheboyina, S. and Wyandt, C.M., Wax-based sustained release matrix pellets prepared by a novel freeze pelletization Technique . I. Formulation and process variables affecting pellet characteristics, Int
J Pharm
, 359, 158-166, 2008.Reitz, C. and
Kleinebudde, P., Spheronization of solid lipid
extrudates, Powder
Technol
, 189 238-244, 2009.
Van G.F.,
Rao
Y.M., Modified release composition comprising doxofylline, Patent application No.WO2009/112436A1, 2009.
Huang, H.F., Lu, Y., He, H.B., and Tang, X., Preparation and bioavailability of sustained-release doxofylline pellets in beagle dogs, Drug Dev
Ind
Pharm
, 34, 676-682, 2008.
Gils, P.S., Ray D.,
Sahoo
P.K., Controlled release of doxofylline from biopolymer based
hydrogels
, Am J Biomed
Sci
, 2, 373-383, 2010.
Gannu
, R.,
Bandari
S,.
Sudke
S.G.,
Rao
, M. and Shankar, B.P., Development and validation of a stability-indicating RP-HPLC method for analysis of doxofylline in human serum. Application of the method to a pharmacokinetic study,
Acta
Chromatographica
, 9,149-160, 2007
Sandvik
Materials Technology. Available
at:http
://
www.processsystems.sandvik.com/ Rxlist. Available at: www.rxlist.comCipla Therapeutic Index, Respiratory drugs, Zordox.
CiplaDoc
. Available at: http://www.cipladoc.com/therapeutic/admin.php?mode=prod&action=disp&id=650
Aulton
, M.E., Dyer, A.M. and Khan, K.A., The strength and compaction of
millispheres
, Drug Dev
Ind
Pharm
, 20, 3069-3104, 1994.
Breitenbach
, J., Melt extrusion: from process to drug delivery technology,
Eur
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Biopharm
, 54, 107-117, 2002.
65Slide66
Publications from research work
S. NoPublication Details
Impact Factor
1.
Shukla
D,
Chakraborty
S, Singh S,
Mishra
B
.
Doxofylline
: a promising
methylxanthine
derivative for the treatment of asthma and chronic obstructive pulmonary disease.
Expert
Opin
Pharmacother
.
10(14): 2343-2356,
2009.
3.205
2.
Shukla
D,
Chakraborty S, Singh S,
Mishra B
.
Lipid based oral multiparticulate formulations – Advantages, technological advances and industrial applications.
Expert
Opin
Drug
Deliv
. 8(2):207-224,
2011
.
4.896
3.
Shukla
D,
Chakraborty
S, Singh S,
Mishra
B
.
Pastillation: A novel technology for development of oral lipid based multiparticulate controlled release formulation.
Powder Technol.
209 (1-3): 65-72,
2011.
2.080
4.
Shukla D, Chakraborty S and
Mishra B.
In vitro and in vivo evaluation of multilayered pastilles for
chronotherapeutic
management of nocturnal asthma.
Expert
Opin
Drug
Deliv
9(1):9-18,
2012
4.896
5.
Shukla
D,
Chakraborty
S and
Mishra
B.
Evaluation of in vivo behavior of controlled and pulsatile release pastilles using pharmacokinetic and γ-
scintigraphic
techniques.
Expert
Opin
Drug
Deliv
9(11):
1333-1345,
2012.
4.896
66Slide67
Dr. (Mrs) Dali Shukla
This Presentation is taken from the Ph.D. Thesis of Mrs Dali Shukla who has worked under my direct supervision. Slide68Slide69
Varanasi GhatsSlide70
Lord Vishwanath (Varanasi)Slide71
BHU GateSlide72
Vishwanath Temple (in BHU)Slide73
IIT(BHU), VaranasiSlide74
Department of PharmaceuticsSlide75
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