blend of mcc and pregelatinized starch - ipec-americas€¦ · blend of mcc and pregelatinized...
TRANSCRIPT
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1
Preparation of MUPS (multiple unit particles system) tablet using CelphereTM and preliminary
blend of MCC and pregelatinized starch
ExcipientFest, San Juan, Puerto Rico
ASAHI KASEI CHEMICALS CORPORATIONCeolus R&D Department
Masayuki KAKIZAWA
May 5, 2010
2
Contents
1. Background, Objective and Approach to problems of MUPS tablet
2. Introduction of CeolusTM and CelphereTM
3. Experimental data of Sustained releaseand Enteric release MUPS tablets
4. Comparison between CelphereTM and sugar sphere
5. Conclusions
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3
1-1. Background
1) Merit of multiple dosage formMultiple dosage forms (Pellets, Capsule, MUPS tablet etc.) show better reproducibility of the drug absorption in the body than single dosage form (Matrix tablet).
2) Merit of MUPS tablet vs. capsule○Easy handling
(Tablet is convenient for carrying and storage.)○Easy administration
(Capsule may stick to throat.)○Lower manufacturing cost
4
nMany types of film-coated pellets products have been developed. And some MUPS tablet products have been developed.nHowever MUPS tablet products tableting which are mixtures of pellets and other excipients may be very challenging in terms of tensile strength of tablet, segregation between pellets and excipients and film damage by compression force.nThis time, we propose MUPS tablet formulations using film polymers resistant to compression force and an type which decreases / prevents segregation.
Today’s experimental data1) Sustained release MUPS tablet2) Enteric release MUPS tablet
1-2.Objective
Celphere
Drug & excipients
Film
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5
1-3. Approach to problem(1)Problem-1 -Poor API uniformity due to segregation of film-coated pellets and other excipients.-Low compactibility of film-coated pellets
《Approach》1) Choose MCC of particle size close to film-coated pellets(→Using CeolusTM PH-200)
2) Add high compactible MCC (→Using CeolusTM KG-802)3) Optimize mixing ratio of PH-200/KG-802 (→7/3)
■Achieve API uniformity■ Practical tablet hardness with low compression force
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2) KG-802・Long, rod-like shape ・High compactibility, ・high inter-particulate friction= Decrease segregation・Insufficient flowability
・The largest particle size・Good flowability
= Decrease segregation・Insufficient compactibility・Low inter-particulate friction
1) PH-200
1-4. Mechanism of preventing segregation
Friction force*SEM Photograph
*Shear Stress at 15 kPa compression stress(Shear Scan TS-12, Sci-Tec)
8.2 kPa
4.6 kPa
Optimize mixing ratio of PH-200 and KG-802
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7
1-5. Optimizing MCC mixing ratio
0
1
2
3
4
5
6
10/0 7/3 5/5 3/7PH-200/KG-802 Ratio
Tabl
et w
eigh
t and
API
con
tent
RSD
[%]
Tablet weight RSD
API content RSD
Optimum mixing ratioPH-200/KG-802 =7/3
1 2 3 4 Required level
0 24 40 56
80 56 40 24
10/0 7/3 5/5 3/7
Average tablet w eight [m g] 250.0 253.2 258.4 245.0
T ablet w eight RSD [%] 0.54 0 .8 4 1.15 1.22 ≦1.0
C om pession Force [kN ] 8.7 8.2 9.9 7.3
Average tablet hardness [N ] 55 54 55 50 ≧50
D isintegration tim e [s] 99 116 178 106
Average API content [%] 89.3 9 9 .7 96.6 101.7 98.5-101.5
API content R SD [%] 3.67 1 .8 8 2.11 5.73 ≦2.0
P H -200/KG -802 Ratio
Exp. N o.
KG -802 [%]
PH -200 [%]
SR-Coated pellets
ExcipientsKG-802/PH-200/PC-10=0-24/80-56/20(Fixed)
1.5kg 1.5kg
Tableting
Evaluation
CleanPress12HUK(3 min)
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1-6. Approach to problem(2)
Problem-2
《Approach》1) Coating film having both flexisible and low adhesive properties
nCompression force may damage coating film, which destroys its function.nHighly flexible and strong film can be durable against compression force, however it easily causes agglomeration during coating process due to high stickiness.nIn order to restrain agglomeration, larger size pellets or slower coating speed is required.⇒Undesirable dissolution property or low productivity
Blend Ethylcellulose aqueous dispersion or Titanium dioxide into formulation of coating film using Eudragit.
2) Use CelphereTM as seed core to decrease the agglomeration Higher coating speed is possible.
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9
2. Introduction of CeolusTM and CelphereTM
CeolusTM : USP-NF/JP/EP compatible MCC (powder)CelphereTM : USP-NF/JPE/EP compatible MCC (seed core)
10
Repose Angle [deg]
Bulk Density[g/cm³]
Av. ParticleSize [µm]
KG-1000 0.12 50 57KGKG--802802 0.210.21 50 49UF-711 0.22 50 42PH-F20JP 0.23 20 >60PH-101 0.29 50 45PH-102 0.30 100 42PH-301 0.41 50 41PH-302 0.42 100 38PHPH--200200 0.35 170170 36
2-1. Powder properties of Ceolus™ grades
Our original products
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2-2. Particle morphology of Ceolus™ grades
PH-101 PH-200
L/D:3.5 L/D:2.8
L/D:1.8 L/D:1.3
KG-1000 KG-802
12
2-3. Relationship between L/D ratio and compactibility
40
60
80
100
120
140
1.5 2.0 2.5 3.0 3.5L/D [-] : measured by classifying in 38-20µm
Har
dnes
s of
MC
C p
lain
tabl
et [
N]
KG-1000
KG-802
PH-102
4.0
160
Hardness of MCC tablet increases as L/D ratio of MCC particle increases.
7
13
★
★
KG-1000
KG
101
102
301302
42°49°57°
PH-101
PH-102
Flowability (Repose angle)
PH-301PH-302
34°
100
150
200
KG-802 UF-711
PH-200
Rat
io o
f ta
blet
ha
rdn
ess
of
APA
P/M
CC
=7
0/3
0 (P
H-1
01
= 1
00)
50Com
pact
ibilit
y In
dex
★
★
KG-1000
KG
101
102
301302
42°49°57°
PH-101
PH-102
Flowability (Repose angle)
PH-301PH-302
34°
100
150
200
KG-802 UF-711
PH-200
Rat
io o
f ta
blet
ha
rdn
ess
of
APA
P/M
CC
=7
0/3
0 (P
H-1
01
= 1
00)
50Com
pact
ibilit
y In
dex
2-4. Relationship between compactibility and flowability of CeolusTM grade
Compactibility Index:Formulation
APAP 70% and MCC 30%Tableting
Static press(ø11.3mm, 7kN)Flat surface, 500mg
Compactibility index(HMCC / H101) × 100cf. H101, HMCC:
Hardness of tablet comprisedof APAP and PH-101 or other MCC
Flowability:Repose angle of MCC alone was measured.
lowlow
high
high
Optimum mixing ratio is important!
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2-5. Introduction of Celphere™
n Celphere™ is a 100% MCC spherical seed core used for film coated pellets with sustained release, enteric release and taste mask coating.
Drug layer
Film coating
Celphere™
Layering
DrugIngredientsBinder
Filmcoating agent
Film
Seed core Layered pellet Film coated pellet
n Celphere™ is an NF/EP/JPE compatible MCC.n Pat.No. USP5,384,130/5,505,983, EP0452862B1, JP02542122B2
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2-6. General properties of Celphere™
CP-203 CP-305 CP-507CP-102
500µm
CP-708
G rade C P -102 C P -203 C P -305 C P -507 C P -708
P article size range [μm ] 106-212 150-300 300-500 500-710 710-850
S phericity 1.2 1.1 1.1 1.2 1.2
B ulk density [g/cm 3] 0.83 0.87 0.97 0.93 0.93
Friability [%] 0 0 0 0 0
W ater absorption [%] 100 100 100 70 65
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2-7. Remarkable features of Celphere™
ð Accurate dissolution
ð Low particle agglomeration during the coating process
ð Tolerant of high stress of coating and tableting machine
ð Suitable for high dose layering / MUPS tablet
ð No pre-coating required
n High sphericity and narrow particle size distribution
n Insoluble, Optimum water absorption
n High mechanical strength
n Small particles
n Low chemial reactivity
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2-8 Application data of CelphereTM (1)(Mechanical strength and friability during layering)
Celphere™ was not abraded by mechanical stress of layering machine because it is very hard, while sugar spheres were broken. The results suggest Celphere has higher resistance to abrasion during drug layering and coating.
0.1
1
10
100
-212 +212 +250 +300 +350 +420 +500Particle size [µm]
Freq
uenc
y [%
]
CP-305Originalafter tumbling
0.1
1
10
100
-212 +212 +250 +300 +350 +420 +500Particle size [µm]
Freq
uenc
y [%
] Originalafter tumbling
NP
Fragments
Rotating fluidized-bed coating machine
(Multipex MP-01, Powrex)
Inlet air70m3/hr
Outletair
Rotor380rpm5min
Seed cores1.5kg
M
Tumbling
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2-9. Application data of CelphereTM (2)(Wurster fluidized bed coating)
Celphere™ showed significantly lower particle agglomeration than sugar sphere at high spray rate due to optimum water absorption.⇒CelphereTM can improve productivity.
0
10
20
30
40
50
4 6 8 10 12 14Spray rate [g/min]
Agg
rega
ted
gran
ules
[%]
CP-305NP-101
0
10
20
30
40
50
4 6 8 10 12 14Spray rate [g/min]
Agg
rega
ted
gran
ules
[%]
CP-305NP-101CP-305NP-101
Coating conditions
Base granule:
Core loaded [kg]:Air volume [m3/kg]:Inlet air temp. [ºC]:Outlet air temp. [ºC]:Spray air volu. [NL/min]:Spray rate [g/min]:
NP-101(32-42)(100)/VB2(2)CP-305(100)/VB2(2)
0.540
70~7534~40
1006~12
Coating conditions
Base granule:
Core loaded [kg]:Air volume [m3/kg]:Inlet air temp. [ºC]:Outlet air temp. [ºC]:Spray air volu. [NL/min]:Spray rate [g/min]:
NP-101(32-42)(100)/VB2(2)CP-305(100)/VB2(2)
0.540
70~7534~40
1006~12
Base granule:
Core loaded [kg]:Air volume [m3/kg]:Inlet air temp. [ºC]:Outlet air temp. [ºC]:Spray air volu. [NL/min]:Spray rate [g/min]:
NP-101(32-42)(100)/VB2(2)CP-305(100)/VB2(2)
0.540
70~7534~40
1006~12
Composition of coating dispersion
85.0
Water
1.42.710.9
HydroxypropylMethylcellulose
TrietylCitrate
EthylcelluloseAqueous Dispersion
Coating level: up to 10% against base granules[wt%]
Composition of coating dispersion
85.0
Water
1.42.710.9
HydroxypropylMethylcellulose
TrietylCitrate
EthylcelluloseAqueous Dispersion
Coating level: up to 10% against base granules[wt%]
1) Experimental condition 2) ResultsAgglomeration vs Spray rate
(particles % larger than 500µm)
*VB2= Riboflavin
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Preparation of Sustained Release (SR) and Enteric Release (ER)MUPS tablet
3.Experiment (1)
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3-1.Experimental Apparatus and materials
◆Seed coreCelphereTM CP-203 (D50; 235μm)
[Asahi Kasei Chemicals Corporation]
◆Drug substanceRiboflavin (VB2)
◆ExicipientsPVP-K30 [ISP]HPMC [Hypromellose, Shin-etsu Chemical Co., Ltd. ]CELIOSCOATTM EC-30A [Asahi Kasei Chemicals
Corporation](Ethylcellulose aqueous. dispersion. [ECD])
Titanium dioxide [Toho Titanium Co., Ltd ](TiO2)Eudragit NE30D [Evonik Degussa Japan Co., Ltd.]Eudragit L30D-55 [Evonik Degussa Japan Co., Ltd.]CeolusTM PH-200 [Asahi Kasei Chemicals Corporation]CeolusTM KG-802 [Asahi Kasei Chemicals Corporation]Pregelatinized Starch PC-10 [Asahi Kasei Chemicals Corp.]Magnesium Stearate [Taihei Chemical Industrial Co., Ltd. ](MgSt)
Wurster fluidized bed coaterGPCG-10
(Powrex Corporation)
Rotating fluidized bed coaterMultiplex MP-25
(Powrex Corporation)
Nozzle 2.2mmφ
Nozzle 2.2mmφ
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3-2. Drug layeringCelphereTM
CP-203
Layering
Protection Coating
Drying
Layered pellets (VB2)
3% PVP-K30 aq. soln.
Water
Mixing
Mixing
VB2
Layering liquid(13wt%)
PVP-K30
Water/PVP-K30/VB2 =87/3/10(Solid content:13wt%)
Propeller 30min
-250µmStraining
Apparatus: GPCG-10 (Wurster Type)Inlet air: 60~70℃ 6m3/minOutlet air: 35~45℃Spray rate: 100~120 g/min, 27 minAtomizing air rate: 400 NL/min
15kg
ca.0.3%(Solid)
242µm
235µm
CP-203/VB2/PVP-K30=97.18/1.94/0.88
CP-203
Propeller 30min
CP-203
VBVB22
CP-203Inlet air: 60~70℃, 6m3/minOutlet air: 48℃
Recovery Rate; 90%Agglomeration (+355μm); 0.3%
ca.2.0% (VB2:Solid)
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3-3.Sustained-release coating
Coating liquid
Mixing
Coating
Curing
Coated Pellets
Layered Pellets(VB2)
ECDHPMC
Layered pellets/Film=83.3/16.7
Mixing
Apparatus: MP-25 (Rotating fluidized bet coater, Rotor speed;300rpm)Inlet air: 40~50 ℃, 7.5 m3/min Outlet air: 25~35 ℃Spray rate: 90~120 g/min, 0.6MPaAtomizing air: 700NL/min
80℃ 1h(Oven)
10kg
280µm
242µm CP-203
VB2
Film
Water TiO2 NE30D
Mixing
MixingPropeller
Homogenizer 4000rpm 10min
Propeller
Propeller
-250µm
Water/HPMC/ECD/TiO2/NE30D=83/0.9/1.6/2.5/12 (Solid:17wt%)
ca.20% (Solid)
CP-203
VB2
CP-203Film thickness=19μm
Recovery Rate; 99%Agglomeration (+355μm); 6.0%
12
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Coating liquid
Mixing
Coating
Curing
Coated pellets
Layered Pellets(VB2)
TEC
Mixing
60℃ 2h(Oven)
10kg
Water TiO2 NE30D
Mixing
MixingPropeller
Homogenizer 4000rpm 10min
Propeller
-250µm
Water/TEC/TiO2/L30D-55/NE30D=83/1.7/1.7/6.8/6.8 (Solid:17wt%)
ca.20% (Solid)
3-4.Enteric-release coating
L30D-55
Homogenizer 4000rpm 10min
Apparatus: MP-25 (Rotating fluidized bet coater, Rotor speed;300rpm)Inlet air: 60 ℃, 7 m3/min Outlet air: 30~42 ℃Spray rate: 90~120 g/min, 0.6MPa Atomizing air: 700NL/min
Layered pellets/Film=83.3/16.7
282µm
242µm CP-203
VB2
Film
CP-203
VB2
CP-203Film thickness=20μm
Recovery Rate; 95%Agglomeration (+355μm); 8.0%
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235µm
3-5.Observation of SR pellets
Layered pellets Coated pellets
CelphereTM CP-203 CP-203/VB2/PVP-K30=97.18/1.94/0.88
(CP-203/VB2/PVP-K30)/Film=83.3/16.7
Seed Core
We obtained smooth SR pellets with little agglomeration due to optimum water absorption of CelphereTM and low film tackiness.
242µm
235µm CP-203CP-203
VBVB22
CP-203 280µm
242µm CP-203
VB2
Film
VB2
CP-203
13
25
CelphereTM CP-203=100 CP-203/VB2/PVP-K30=97.18/1.94/0.88
(CP-203/VB2/PVP-K30)/Film=83.3/16.7
3-6.Observation of ER pellets
We obtained smooth ER pellets with little agglomeration due to optimum water absorption of CelphereTM and low film tackiness.
235µm
Layered pellets Coated pelletsSeed Core
242µm
235µm CP-203CP-203
VBVB22
CP-203 282µm
242µm CP-203
VB2
Film
VB2
CP-203CP-203
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3-7.MUPS Tablet Compaction
10kg(50%)
Tumbler mixer30min
MUPS tablet
Coated pellets (SR or ER)
Tableting
Mixing
Rotary tableting machine (LIBRA2, KIKUSUI)40rpm, with agitating feeder250mg, 8.0mmØ, 12R Tableting time: 50min (sampling; 1, 25, 48min)
[Coated pellets]/[Preliminary blend]/MgSt=49.95/49.95/0.1(VB2:0.81 wt%, 250mg-tab.)
MgStMixingTumbler mixer 3min⇒(Bulk density:0.521g/ml, Repose Angle 42゜)
20g
1st. 2nd. 3rd.
KG-802 PC-10PH-200
5.6kg 2.4kg 2.0kg
Preliminary blend
PH-200/KG-802/PC-10=56/24/20
10kg(50%)
(7) : (3)
SEM Photo of preliminary blend
Photo of MUPS tablet
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3-8.Results -SR tablet properties-
The tablet reached the practical required level in hardness, friability, and disintegration with moderate compression force (5-6kN).
Tablet weight RSD kept the required level (under 1%).Average API content and API content RSD also kept the required level for the whole tableting period (50min). ⇒This formulation shows high content uniformity.Preliminary blend of PH-200/KG-802/PC-10 has the effect of preventing segregation of pellets.
Sam pling tim e 1st (1m in) 2nd (25m in) 3rd (48m in) Required levelAverage tablet w eight [m g] 252.6 251.6 251.6Tablet weight RSD [%] 0.66 0.78 0.86 ≦1.0Average tablet hardness [N] 70 73 76 ≧50Disintegration tim e [s] 93 104 108Friability [%] 0.03 0.04 0 ≦0.5Average API content [%] 101.1 101.0 99.7 98.5-101.5API content RSD [%] 0.87 1.39 1.15 ≦2.0
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3-9.Dissolution profile (SR MUPS tablet)
Dissolution test:JP 15 Dissolution Test Method 2 (Paddle
method).Dissolution media: pH1.20.07mol/L HCl aq.soln., 900mL
Rotation speed of paddle: 100rpmMeasurement wavelength of UV: 445nm
Dissolution rate of MUPS tablet is a little faster than that of film coated pellets, but within the practical acceptable level (within ±10%).⇒There is little film damage by tableting because the flexibility of NE30D absorbs compression force.
0
20
40
60
80
100
0 2 4 6 8 10Tim e [h]
Drug Release
d [%]
Film coated pelletsM U PS tablet系列1
±10%
15
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3-10.Stability of dissolution profile (SR)
Dissolution test:JP 15 Dissolution Test Method 2(Paddle method).
Dissolution media: pH1.20.07mol/L HCl aq.soln., 900mL
Rotation speed of paddle: 100rpmMeasurement wavelength of UV: 445nm
0
20
40
60
80
100
0 2 4 6 8 10
Tim e [h]
Drug Released [%]
Initial 2 w eeks
1 m onth 6 m onths
Dissolution profile hardly changed after 6 months.
■ Stability test condition; 40℃75%R.H. (Sealed glass container)
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3-11.Results -ER tablet properties-
This tablet reached the practical required level in hardness, friability, and disintegration with moderate compression force (5-6kN).
Average tablet weight RSD kept the required level (under 1%).Average API content and API contents RSD also kept the required level for the whole tableting period (50min). ⇒This formulation shows high content uniformity.→Preliminary blend of PH-200/KG-802/PC-10 is effective in preventing segregation of granules.
Sam pling tim e 1st (1m in) 2nd (25m in) 3rd (48m in) Required levelAverage tablet w eight [m g] 251.1 250.8 251.5Tablet w eight RSD [%] 0.78 0.63 0.80 ≦1.0Average tablet hardness [N] 68 69 73 ≧50Disintegration tim e [s] 85 91 94Friability [%] 0.04 0.03 0.03 ≦0.5Average API C ontent [%] 100.7 101.4 100.2 98.5-101.5API content RSD [%] 0.77 0.98 0.88 ≦2.0
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3-12. Dissolution profile (ER MUPS tablet)
Dissolution test: JP 15 Dissolution Test Method 2 (Paddle method).Rotation speed of paddle: 100rpm Measurement wavelength of UV: 445nm
Dissolution media: pH 1.2(Artificial gastric buffer)
Dissolution media: pH6.8(Artificial intestinal buffer)
Dissolution rate of MUPS tablet is slightly faster than that of film coated pellets, but within the practical acceptable level.MUPS tablet shows high tolerance to pH 1.2 and very fast dissolution in pH 6.8.⇒ There is little film damage by tableting because the flexibility of NE30D absorbs compression force.
0
20
40
60
80
100
0 1 2 3 4 5
Tim e [h]
Drug released [%]
M UPS tablet
Film coated pellets
0
10
20
30
40
50
0 1 2 3
Tim e [h]
Drug released [%]
M UPS tablet
Film coated pellets
32
3-13.Stability of dissolution profile (ER)
Dissolution test: JP 15 Dissolution Test Method 2 (Paddle method).Rotation speed of paddle: 100rpm Measurement wavelength of UV: 445nm
Dissolution media: pH 1.2 Dissolution media: pH6.8
■ Stability test condition; 40℃75%R.H. (Sealed glass container)
0
10
20
30
40
50
0 1 2 3T im e [h]
Drug released
[%]
Initial 2 w eeks1 m onth 3 m onths6 m onths
0
20
40
60
80
100
0 1 2 3 4 5
Tim e [h]
Drug released [%]
Initial 2 w eeks1 m onth 3 m onths6 m onths
Dissolution profile hardly changed after 6 months.
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Layered Pellets (VB2=2%)242μm 394μm
435μm
CelphereCelphereTMTM
CPCP--203203CelphereTM
CP-305Sugar Spheres
(32-42mesh)
Coated pellets (SR=20%)275μm 437μm
468μm
MUPS tablet (50% pellets)
MP-01(Rotating Fluidized bed coater, Lab. scale)
Tableting machine (320mg, 8mmφ12R、9kN), 5min
78min (12g/min) 105min (9g/min)
800g
SR film liquid
Preliminary Blend
4.Comparison to CP-305 and Sugar Spheres
Evaluation ・Tablet weight RSD・API content RSD・Drug dissolution profile
Sugar spheres needed 1.33 times coating time in comparison with the Celphere CP-203 and 305 because of their high agglomeration tendency.
[Procedure]or or
MP-01(Rotating Fluidized bed coater, Lab. scale)
34
Seed core C P-203 C P-305Sugar Sphere(32-42m esh)
Tablet w eight RSD [%] 0.65 0.75 1.36API C ontent RSD [%] 0.95 1.02 1.88
0
20
40
60
80
100
0 2 4 6 8 10
Tim e[h]
Drug released [%]
C oated pelletsM U P S tablet
0
20
40
60
80
100
0 2 4 6 8 10
Tim e[h]
Drug released [%]
C oated pelletsM U P S tablet
0
20
40
60
80
100
0 2 4 6 8 10
Tim e[h]
Drug releas
ed [%]
C oated pelletsM U P S tablet
CP-203 showed the lowest tablet weight RSD and API content RSD because of its smallest particle size.
Sugar spheres showed large difference by dissolution rate of coated pellets and MUPS tablet (over 10%).This is because sugar spheres were destroyed due to compression force and film was distorted or torn.
CP-203 CP-305 Sugar Sphere
Celpheres are suitable for MUPS tablet.
[Results]
4.Comparison to CP-305 and Sugar Spheres
18
35
5.ConclusionsWe proposed MUPS tablet formulations using film polymers resistant to compression force and an MCC type which decreases / prevents segregation.
AsahiKASEI provides technical support for its customers.Please contact us. (Please visit our booth No.23.)
Patent Application No.●WO2009/028487 (Preliminary blend of excipients)●WO2009/011367 (Sustained-released film formulation)●WO2009/063916 (Enteric-released film formulation)
◆We proposed coating film formulation having both flexible and low adhesive properties (Eudragit and anti-tacking agent blend).◆CelphereTM is suitable for MUPS tablet because of small particle size, optimum water absorption properties which lead to low agglomeration and its high mechanical strength.◆CeolusTM KG-802 is suitable for MUPS tablet because of its high compactibility and high inter-particulate friction which lead to high tablet hardness and decreased segregation.
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Thank you for your attention.