Upload
others
View
1
Download
0
Embed Size (px)
Citation preview
ExcipientFest Americas 2013 April 30th
1
SuperTab® 24ANA New Generation of Directly Compressible
Lactose
Jian-Xin Li, Ph.D.
|
What is so special about excipients?
DFE Pharma ExcipientFest 20132
All medicines depend on excipients to stabilize and deliver their active ingredients
The quality and effectiveness of the medicine depends greatly on how the excipient performs
Performance of active ingredients and excipients togetherdetermines healthcare benefits for the patient
ExcipientFest Americas 2013 April 30th
2
|
A century long heritage
DFE Pharma ExcipientFest 20133
With roots in dairy producing companies
Our heritage
1900 – HMS (Dutch Milk Sugar Factory) founded
1926 – Six Dutch dairy producers form DMV
1946 – First lactose plant built in Kapuni NZ
1960 – DOMO starts producing pharmaceutical grade lactose
1985 – Start inhalation grade lactose by DOMO in Borculo
2003 – Superdisintegrants acquired from Avebe
2006 – DMV-Fonterra Excipients created from DMV & LNZ
2010 – DOMO-pharma integrated
2011 – Acquisition Brahmar Cellulose India
2011 – Launch new corporate brand name DFE Pharma
2013 – Global launch of MCC by DFE Pharma
|
DFE Pharma – a joint venture between 2 leading global dairy cooperatives
Sales Marketing QA R&D F&A Operations
50% 50%
DFE Pharma ExcipientFest 20134
HR
ExcipientFest Americas 2013 April 30th
3
|
International dairy cooperative
Registered head office in
Amersfoort (the Netherlands)
Turnover € 9.6 billion
19,000 employees
14,400 member dairy farms
International dairy cooperative
Registered head office in
Auckland (New Zealand)
Turnover NZ$ 19,8 billion
Up to 17,300 employees
Up to 10,600 share holders
Our parent companies
DFE Pharma ExcipientFest 20135
|
Responsiveness with global presence
6
Offices, production facilities & global distributor network
DFE Pharma ExcipientFest 20136
Sales Office Japan
Sales Office
Singapore
Production New Zealand
3 Production The Netherlands
Sales Office
US
Production Germany
Global distributor network
Main Office
Germany
Sales Office
India
Production India
ExcipientFest Americas 2013 April 30th
4
|
We want to grow from a lactose supplier to an excipient expert.
DFE Pharma Strategy
Our ambition
7
Lactose supplier
Wide range supplier Excipient expert
DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
5
|
DFE Pharma production facilities
9
FoxholThe Netherlands
BorculoThe Netherlands
Nörten HardenbergGermany
KapuniNew Zealand
VeghelThe Netherlands
CuddaloreIndia
DFE Pharma ExcipientFest 2013
|10
Quality is guaranteed
Production:cGMP production standardsICH Q7A Guidelines (API)Pharmacopoeial standards: USP/ NF ,Ph. Eur., JPEDrug Master FilesISO 9001:2008 certified production facilities, FDA inspected
Shelf life guaranteed:MCC: 4 yearsMilled & sieved lactose: 3 yearsDirect compression lactose: 2-3 years (vary by grade)Starches: 2-4 yearsSuperdisintegrants: 5 years
DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
6
Directly Compressible Excipients
|
Good flowability
High compactability
Good recompactability for dry granulation
Good blending properties
No (drug) segregation
Physical and chemical stability
Chemical compatibility
DC Excipients for Tablet ProductionMost important requirements for DC filler/binders
12 DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
7
|
DCP
Lactose
MCC
Starch
…
Choices for Excipients??
13 DFE Pharma ExcipientFest 2013
|
Direct compression lactose
14
The best DC lactose for your application
Spray-dried lactose (SD)Excellent flowImprovement of compactionLow dose formulationsLow tablet weight variation Anhydrous lactose (AN)
Roller compactionMoisture sensitive drugsHigh dose formulations
Granulated lactose (GR)Low dose applicationsQuick disintegrationCapsule and sachet filing
DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
8
|
Direct compression lactoseSummary of production routes
Crystals of pharmaceutical grade -lactose monohydrate
Spray-drying Roller drying Granulated
Lactopress® Spray Dried 250SuperTab® 11SD or 14 SD
Lactopress® Anhdyrous 250SuperTab® 21AN or 22 AN
Lactopress® GranulatedSuperTab® 30GR
15 DFE Pharma ExcipientFest 2013
AN=anhydrous, GR=granulated, SD=Spray Dried
SuperTab® 24AN“A New Generation of Directly
Compressible Lactose”
ExcipientFest Americas 2013 April 30th
9
|
Introduction SuperTab® 24AN
– Description
– Production process & product properties
Application studies
– Study 1: Mixing potential & Content Uniformity
– Study 2: Quick disintegration with high compaction
– Study 3: High speed tableting properties
Summary
SuperTab® 24ANOverview
17 DFE Pharma ExcipientFest 2013
|
Combines the key properties of granulated and anhydrous lactose
– High powder flowability (granulation)
– Quick disintegration time (granulation)
– Excellent mixing properties (granulation)
– High compactability (granulation of anhydrous material)
– Low moisture content below 1.0 % H2O (anhydrous material)
Product is an anhydrous lactose according to Pharmacopeia
SuperTab® 24ANDescription
DFE Pharma ExcipientFest 201318
ExcipientFest Americas 2013 April 30th
10
|
SuperTab® 24ANProcess flow
19
Patented: EP1851344 (B1), US2009/0081308
DFE Pharma ExcipientFest 2013
|
SuperTab® 24ANProduct properties
20
Property: SuperTab® 24AN SuperTab ® 21AN
H2O content – KF (%) 0.5 0.1
ratio 75/25 80/20
Bulk density (g/cm³) 0.490 0.700
Tapped density (g/cm³) 0.600 0.870
Flodex (mm) 6 20
PSD* % <75m ~ 20 (nmt 30) ~ 19
PSD* % <150 m ~ 65 (55-80) ~ 50
PSD* % <250 m ~ 92 (nlt 80) ~ 83
* By Rotap sieve analysis
DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
11
|
SuperTab® 24ANProduct Properties - visualization
21
Light Microscope
SEM
DFE Pharma ExcipientFest 2013
|
SuperTab® 24ANProduct Properties – PSD (laser diffraction)
22
0
10
20
30
40
50
60
70
80
90
100
Ve
rte
ilun
gss
um
me
Q3
/ %
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
1.4
Ve
rte
ilun
gsd
ich
te q
3*
1 5 10 50 100 500Partikelgröße / µm
Messung
2011-05-23 15:25:44.5980 1304 H
2011-05-23 15:20:40.4700 1304 H
x10= 34 µm
x50= 128 µm
x90= 273 µm
DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
12
|
SuperTab® 24ANProduct properties - flow
23
AN=anhydrous, GR=granulated, SD=Spray DriedExcellent flow: comparable to granulated/spray-dried lactose
DFE Pharma ExcipientFest 2013
|24
SuperTab® 24ANProduct properties – low moisture uptake
< 0.7% of water uptake up to 90% RH when measured by Dynamic Vapour Sorption (DVS)
DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
13
|
Application study 1:Mixing potential & Content Uniformity
25 DFE Pharma ExcipientFest 2013
|
Goal: comparison of mixing properties/potential vs. regular anhydrous lactose
Formulation – 2% Propranolol HCl, 97.5% Lactose , 0.5% Magnesium Stearate – 500 g formulations
Experimental conditions:– Mix API & Lactose for 2, 5, 8 minutes (Turbula 62 rpm)– Add lubricant & mix for 2 min– Compress on rotary Tablet Press (250 mg tablets, 9 mm, fbe
tooling)– Test tablets on content uniformity
SuperTab® 24ANStudy outline
DFE Pharma ExcipientFest 201326
ExcipientFest Americas 2013 April 30th
14
|
SuperTab® 24AN gave excellent content uniformity (RSD 3%) after only 2 minutes; a similar result for regular anhydrous grade is obtained after only 8 minutes mixing time.
SuperTab® 24ANMixing properties
80%
84%
88%
92%
96%
100%
104%
108%
112%
116%
120%
0 1 2 3 4 5 6 7 8 9
Dru
g la
be
l co
nte
nt (
%)
Mixing time (min)
SuperTab® 24AN
Regular anhydrous lactose
DFE Pharma ExcipientFest 201327
|
Goal: comparison of content uniformity over long tableting duration: SuperTab® 24AN vs. regular anhydrous lactose
Formulation – 2% Paracetamol, 97.5% Lactose, 0.5% Magnesium Stearate
Experimental conditions:– Premix API & 10 % Lactose for 5 min, screen through 500m sieve– Add remaining lactose and & mix for 10 min (Turbula 62 rpm)– Add lubricant and mix for 2 min– Compress on rotary Tablet Press (250 mg tablets, 9 mm, flat
beveled tooling)– Test tablets on content uniformity
SuperTab® 24ANStudy outline
DFE Pharma ExcipientFest 201328
ExcipientFest Americas 2013 April 30th
15
|
SuperTab® 24ANContent Uniformity
SuperTab® 24AN gave excellent content uniformity over the entire tabletting duration
SuperTab 22AN
4,25
4,50
4,75
5,00
5,25
5,50
5,75
0 5 10 15 20 25 30 35 40
Tabletting Duration /min
Sin
gle
Tab
let a
ssay
/mg
92% - 105% LS
SuperTab 24AN
4,25
4,5
4,75
5
5,25
5,5
5,75
0 5 10 15 20 25 30 35
Tabletting Duration / min
Sin
gle
Ta
ble
t ass
ay
/mg
98% - 105% LS
DFE Pharma ExcipientFest 201329
|
Application study 2:Quick disintegration combined with high compaction
30 DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
16
|31
Goal: Comparison of placebo tablets on the tablet properties (disintegration & tablet crushing strength)
Formulation:– 95.5% lactose, 4% Primellose® (Croscarmellose Sodium), 0.5% Magnesium
Stearate
– 500 g formulations
Experimental conditions– Mix Lactose & disintegrant for 8 minutes (Turbula, 62 rpm), add Lubricant and mix
for further 2 minutes
– Compress on a R&D rotary tablet press (Rotab T, Luxner)
– 250 mg tablets, 9 mm, flat beveled tooling
– Test tablets on Tablet Crushing Strength (TCS), Disintegration Time (DT)
SuperTab® 24ANStudy outline
DFE Pharma ExcipientFest 2013
|
SuperTab® 24AN25% more compactable vs. regular anhydrous lactose
AN=anhydrous, GR=granulated, SD=Spray Dried250mg tablets, 9mm flat bevel edged tooling, RoTab rotary tablet machine
DFE Pharma ExcipientFest 201332
ExcipientFest Americas 2013 April 30th
17
|
Quicker disintegration at higher tablet hardness
33
SuperTab® 24AN
AN=anhydrous, GR=granulated, SD=Spray Dried 2% and 4% Primojel for 30GR and 11SD respectively
250mg tablets, 9mm flat bevel edged tooling, RoTab rotary tablet machineDFE Pharma ExcipientFest 2013
|
Application study 3:High speed tableting properties
34 DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
18
|
Goal: investigation tableting properties on a high speed tableting machine with a low dose formulation
Formulation:– 0.1% APAP (d50 = 19 m), 99.4% lactose, 0.5% Magnesium Stearate
– 20 kg blends
Experimental conditions: – Premix API & 10 % Lactose (2 min), Premix + Lactose (8 min), Lubrication (2
min) – drum mixer
– Bosch Manesty Xpress 325*, 1300 tpm
– 800 mg tablets, 12,6 mm concaved tooling (precomp. 1.8 kN, maincomp. 5.9
kN)
* Turret speed equal to XPress700 = 1.1 million tablets/h
SuperTab® 24ANStudy outline
DFE Pharma ExcipientFest 201335
|
High consistency of tablet crushing strength & thickness during tablet run
SuperTab® 24ANHigh speed tableting properties
0,0
20,0
40,0
60,0
80,0
100,0
120,0
140,0
160,0
180,0
200,0
1 2 4 6 10
Tabletting Time /min
Ta
ble
t Cru
shin
g S
tre
ng
th /N
6,5
6,55
6,6
6,65
6,7
6,75
6,8
6,85
6,9
6,95
7
Ta
ble
t Th
ickn
ess
/mm
DFE Pharma ExcipientFest 201336
ExcipientFest Americas 2013 April 30th
19
|
SuperTab® 24ANHigh speed tableting properties
Consistent uniformity (range 108-116% label, RSD ~ 2.3%) >> no segregation during tablet run
90
95
100
105
110
115
120
125
130
0 2 4 6 8 10
Tabletting Time / min
% D
rug
La
be
l
DFE Pharma ExcipientFest 201337
|
Agglomerated anhydrous lactose (complies with Pharmacopeia for anhydrous lactose)
Combines the key properties of granulated and anhydrous lactose – High powder flow / excellent mixing properties
– Superior compaction on high speed machine
– Short disintegration time @ high tablet hardness
– Low moisture content, below 1.0 % H2O (anhydrous material)
May provide a solution for:– content uniformity issues in DC (incl. low dose drugs) & transfer WG formulations to DC
(cost & time)
– improving drug dissolution, due to quicker disintegration times
– formulating hygroscopic drugs
– roller compaction
– Medium/high dose drugs
– Bilayer tablets
SuperTab® 24ANSummary
38 DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
20
|
Major drivers: life cycle management– Improve patient compliance– Improve therapeutic outcomes– Decrease adverse reactions– Motivation by regulatory agencies
Distinct layers of active formulations– Chemical incompatibility– Different release profile/rates– Core for osmotic pump
More complicated than single layer tablets
Bilayer or Multi-layer FDC Tablets
39 DFE Pharma ExcipientFest 2013
|
Better flowing formulation is selected as first layer– First layer determines fill and weight control of second layer
Select more re-compactable material as first layer– First layer undergoes 2 compressions
Increase success in compression and layer adhesion– Layers with similar compaction/relaxation properties– Layers with similar expansion (thermal or moisture driven)
Optimization of compaction pressure and tableting speed– Strength of interface adhesion
Considerations guiding excipient selection for bilayer tablets
40 DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
21
|
Effect of materials on the strength of bilayer tablets
Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012DOI: 10.1208/s12249-012-9845-9
Total tablet weight 500 mg with each individual layer being 250 mg.
DFE Pharma ExcipientFest 201341
|
Bilayer tablets made with brittle materials (lactose) in both layers are strongest.
For lactose–lactose tablets, an increase in adhesion between layers was observed, due to the formation of solid bridges upon storage.
More significant fracture is induced when MCC is the bottom layer (MCC 1st) than when it is compressed as the top layer (lactose 1st).
Interface was weakest for the compacts made with plastic materials (MCC) in both layers.
Lactose is good for bilayer tablets
42 Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012DFE Pharma ExcipientFest 2013
ExcipientFest Americas 2013 April 30th
22