1 1 Preparation of MUPS （multiple unit particles system) tablet using Celphere TM and preliminary blend of MCC and pregelatinized starch ExcipientFest, San Juan, Puerto Rico ASAHI KASEI CHEMICALS CORPORATION Ceolus R&D Department Masayuki KAKIZAWA May 5, 2010 2 Contents 1. Background, Objective and Approach to problems of MUPS tablet 2. Introduction of Ceolus TM and Celphere TM 3. Experimental data of Sustained release and Enteric release MUPS tablets 4. Comparison between Celphere TM and sugar sphere 5. Conclusions
Transcript
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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
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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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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
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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.
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
《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.
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.
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
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
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.
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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%
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3-10．Stability of dissolution profile (SR)
Dissolution test:JP 15 Dissolution Test Method 2(Paddle method).
Rotation speed of paddle: 100rpmMeasurement wavelength of UV: 445nm
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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 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.
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20
40
60
80
100
0 1 2 3 4 5
Tim e [h]
Drug released [%]
M UPS tablet
Film coated pellets
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10
20
30
40
50
0 1 2 3
Tim e [h]
Drug released [%]
M UPS tablet
Film coated pellets
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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
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)
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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
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20
40
60
80
100
0 2 4 6 8 10
Tim e[h]
Drug released [%]
C oated pelletsM U P S tablet
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40
60
80
100
0 2 4 6 8 10
Tim e[h]
Drug released [%]
C oated pelletsM U P S tablet
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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
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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.
