Excipient Fest Porto Rico May 2010 - IPEC-Americasipecamericas.org/sites/default/files/conference10/Franz...Tablets with Extractum Hippocastani 5/5/2010 | ExcipientFest Puerto Rico

5/13/2010

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Excipient FestPorto RicoMay 2010

MEGGLE Excipients & Technology, Wasserburg Germany

Dr. Franz Karl Penz

Location

5/5/2010 | ExcipientFest Puerto Rico 2

Meggle headquarters, WasserburgGermany

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Founded: 1887 as a small dairy

Company Name: since 2002 MEGGLE AG

Head Office: Wasserburg a. Inn, Germany

Employees: about 2000

Turnover 2008: 750 mn Euro (consolidated)

123 Years of MEGGLE

Josef Anton Meggle

35/5/2010 | ExcipientFest Puerto Rico

MEGGLE AG – Holding


MEGGLE Holding

Molkerei MEGGLEWasserburgGmbH & Co. KG100 %

MEGGLEEastern EuropeGmbH100 %

MEGGLEInternationalGmbH100 %

Food Industry

Animal Feed

Pharmaceut. Excipients




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MEGGLE Japan Ltd.

Founded in 1977 and situated in Tokyo.Sales of Functional Products, mostly Lactose.

MEGGLE USA Inc.

Founded in January 2009 and situated inWhite Plains, NY.Sales of pharmaceutical FunctionalProducts in North America.Own Production of pharmaceutical Lactosein USA, Minneapolis (La Sueur), MN at the beginning of 2011.

FormulaB LLC

Centre of Excellence for the pharmaceutical Industry in the Ukrainian town of Odessa.Founded in 2005, it offers research, development and design of solid dosage formulations.

Representative Office MEGGLE Shanghai

Founded in 2002 and situated in Shanghai. High demand for pharmaceutical Lactose inthe Chinese market.

MEGGLE Singapore Ltd.

Founded in 2003 and situated in Singapore.Sales of pharmaceutical Functional Products inSouth East Asia.

MEGGLE International (Pharma)

55/5/2010 | ExcipientFest Puerto Rico

History

Lactose for pharmaceutical use

1950 In the middle of the fifties MEGGLE decided to adopt the standards of the pharmacopeias for Lactose

1970 Tablettose® In the middle of the seventies the first agglomerated Lactose grade for Direct Compression (DC) was developed

1980 FlowLac ® In the beginning of the eighties spray-dried Lactose was introduced

Cellactose® At the end of the eighties we created ourfirst co-processed excipient

1990 RetaLac® In the nineties until now extension of DC-range

2000 InhaLac® Introduction of products for Dry-Powder-Inhaler





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Lactose Production

Production > 30,000 tons

Countries worldwide > 110

Agents worldwide > 50

Products > 20

Latest development RetaLac®


Co-processing, a versatile pathway to modify excipients:

Lactose excipients from fast disintegrating to modified release


Lactose excipients from fast disintegrating to modified release




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Granulation Process


Dry Compaction Wet GranulationDirect Compression

Mixing and blending of API and adjuvants

Compression



Compression into slugs

Milling and sieving of slugs

Mixing of granules with adjuvants

Preparation of binder

Massing of binding solution with powder mixture

Wet screening of damp mass

Drying of wet granules

Risifting of dry granules and blending with adjuvants

Compression

Compression

Direct Compression of TabletsAdvantages

n Economy

n Avoidance of heat, moisture and compression

n Minimal variability compared to wet granulation– Viscosity of binder solution, wetting and drying parameters.

n Fewer long-term problems– Dissolution profile, chemical stability

n Optimisation of tablet disintegration– Individual drug particle released from tablet mass

instead of adherence (glued) onto larger agglomerates in wet granulation, which would reduce surface area for dissolution.

n Lower microbial level– Direct compressed tablets have lower microbial level compared

to those produced by wet granulation.





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Direct Compression of TabletsLimitations

n Choice of DC-Excipients

– blending, compactability, flowability, lubricant, stability

n No flaws in raw materials

– constant quality

n No satisfying colouring, dust

n Poor reworkability


Reasons for developing new co-processed Excipients with improved Functionalities

n Rising technical standards

– High speed machines

n Poor compressiblity of actives

– Synergic functionality needed

n Demands of the customer

– Mask unfavourable properties

n High costs of development and toxicologic testing

– Risk with new chemical entities


Co-p

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Definition & Aim

“Combining two or more established excipients

by an appropriate process”

n Formation of excipients with superior properties compared to the simple physical mixtures of their components

n To obtain a product with added value related to the ratio of its functionality vs. price.


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Methods of Preparation

n Chemical Modification MC, HPMC, Lactitol

n Physical Modification Sorbitol, Dextrates,

Compressible Sugars

n Sieving, Blending α-Lactose monohydrate, Lactitol

n Cristallisation Di-Pac®, ß-Lactose

n Spray-drying α-Lactose monohydrate, Karion instant®

n Agglomeration Tablettose®, RetaLac®

n Dehydration Anhydrous Lactose


Modifie

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Co-processed Excipients for DC

Advantose ® FS-95 Fructose+ Starch SPI Polyols

Avicel ® CE-15 MCC +Guar Gum FMC

Di-Pac ® Sucrose+ Maltodextrin American Sugar

Emdex ® Dextrose+ Maltose JRS

Ludipress® α-Lactose monohydrate + BASF

PVP + PVP CL

Lycatab C ® Pregelatinized Starch Roquette

Pearlitol ® Mannitol Roquette

Plasdone ® Vinyl acetate + Vinyl pyrrolidone ISP

Pharmatose ® DCL 40 ß-Lactose anhydrous + Lactitol DMV

StarLac® α-Lactose monohydrate + Starch Roquette/Meggle

Xylitab® 200 Xylitol+ Na CMC Danisco

Prosolv SMCC® MCC+ Silicon Dioxide JRS


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Lactose in co-processed Excipients for DC

Lactose together with:

n Cellulose derivatives

– Powder cellulose Cellactose 80®

– MCC MicroceLac 100®

– HPMC (new) RetaLac®

n Lactitol Pharmatose® DCL 40

n PVP, PVP CL Ludipress®, Ludipress® LCE

n Starch StarLac®


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Lactose in co-processed Excipients (DC)


Co-processed Excipients

Cellactose® 80


n 75% α-Lactose Monohydrate [Ph.Eur./USP-NF/JP]

n 25% Powdered Cellulose [Ph.Eur./USP-NF/JP]

spray-dried


d50 ≈ 180 µm, Hausner ratio = 1.24

Cella

ctose

®80

Cellactose® 80




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Compaction Profile


Compaction force [MPa]

0

50

100

150

200

250

0 50 100 150 200 250 300

Har

dnes

s [N

]

Tablettose 80+25% Vivacel 102

Tablettose 80

Cellactose 80

Cella

ctose

®80

Compaction Profile:Tablets with Extractum Hippocastani


C Cellactose 80®

H Extr. Hippocast.AZ Physical mixture:

A Avicel®Z Zepharox®

(spray-dr. Lact.)

Cella

ctose

®80

By courtesy of Prof. Armstrong, University of Wales College of Cardiff




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High Dilution Potential


0

20

40

60

80

100

120

140

0 5 10 15 20 25 30 35

Compression force [kN] (comprex I)

Hard

ness [

N]

Vitamin C 98% DC 345,0 [69%]

Cellactose® 80 150,0 [30%]

Compritol 888 5,0 [1%]

500,0

Punch: 12mm

Cella

ctose

®80

Adherence Capacity I


Dry Compaction CarrierMicronized Glibenclamide

Premixing Mixing Turbula 30 min

Sampling

Separation of nonadhered particles by air jet sieving

Assay

Schmidt and Rubensdörfer, 1994, Evaluation of Ludipress as a “Multipurpose Excipient” for DC Part I:Powder Characteristics and Tabletting Properties; Drug dev. ind. Pharm. 20(18); 2899-2925

Cella

ctose

®80




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Adherence Capacity II


Cella

ctose

®80

Characteristics

n High adherence capacity

n High (up to 75%) dosage formulations

n Spherical form, good flowability

n Strong hardness depending disintegration

n Good mouthfeel

n Avoiding incompatibilities with MCC (Furosemide)

n Applications:

– Difficult to compress formulations as herbal extracts or inorganic salts

– Suitable alternative to undergo MCC/Lactose in patents


Cella

ctose

®80




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MicroceLac® 100


MicroceLac® 100


n 25% Microcrystalline Cellulose

[Ph.Eur./USP-NF/JP]

spray-dried


d50 MicroceLac® = 150µm, Hausner ratio = 1.22

Mic

roce

Lac®

100




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Improving Content Uniformity I


By courtesy of Prof. Sunada, Meijo University, Nagoya

V-type mixer MicroceLac® 100 Physical Blend

Micronized Glibenclamide 5%

Sample taken at prescribed (2, 5, 10, 15, 20 and 30 min.) time and defined points

Assay

Mic

roce

Lac®

100

Improving Content Uniformity II


0

2

4

6

8

10

12

0 10 20 30 40time [min]

glib

encl

amid

e [%

]

0

2

4

6

8

10

12

0 10 20 30 40

time [min]

glib

encl

amid

e[%

]

Formulation 15% Glibenclamide / Physical Blend

Formulation 25% Glibenclamide / MicroceLac® 100

Demixing!

Mic

roce

Lac®

100




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Tablet Hardness


Michoel, A., Rombaut, P., Verhoye, A., 2002. Comparative evaluative of co-processed lactose and microcrystalline cellulose with their physical mixtures in the formulation of folic acid tablets. Pharm. Dev. Technol., 7(1), 79-87.

MicroceLac® 100 produced the hardest tablets with/without API

M3 - 75% α lactose monohydrate + 25% Avicel PH102M2 - 75% spray-dried lactose + 25% Avicel PH102

M1 - 75% anhydrous β lactose + 25% Avicel PH102M0 - MicroceLac® 100

Mic

roce

Lac®

100

Characteristics

n Improving content uniformity

n High and consistant tablet hardness

n Sperical form, good flowability

n Very low to high (up to 80%) dosage formulations

n Hard and smooth tablet surface (saving coating material)

n Improving rheology

n Applications:

– Conventional tabletting

– Formulations with poor flowable, micronized APIs


Mic

roce

Lac®

100




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RetaLac®


RetaLac®

n 50% α-Lactose Monohydrate[Ph.Eur./USP-NF/JP]

n 50% HPMC [Ph.Eur./USP-NF/JP]

spray-agglomerate


Reta

Lac®




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Compaction Profile and Drug Release

Tabletting behaviour and dissolution ofTheophylline (98 mg) in a tablet formulationin the presence of 0.5% of Mg-stearate,using 8 mm punches (weight 400mg).


Reta

Lac®

Characteristics

n Enables direct compression of sustained release formulations

n Superior compressibility to physical mixture, minimizes friability

n Structured surface, good flowability

n Low/medium (up to 50%) dosage formulation

n Improves wettability of HPMC

n Applications:

– Direct compression of sustained release formulations

– Facilitates preparation of dispersions containing HPMC/Lactose


Reta

Lac®




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Pharmatose® DCL 40 Pharm

ato

se®

DC

L40


Pharmatose® DCL 40

n 95% Anhydrous ß-Lactose

[Ph.Eur./USP-NF/JP]

n 5% Lactitol

[Ph.Eur./USP-NF/JP]

blend


Pharm

ato

se®

DCL

40

Source: technical brochure DFE




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Compaction Profile


Pharm

ato

se®

DCL

40

Compaction profile of various co-processed materials, open symbols lubricated with Mg-stearate 1% and unlubricated (closed symbols): , Cellactose; , Ludipress; , Pharmatose DCL 40.

Pharm. Powder Compaction Technology, ed. G. Alderborn and C. Nyström Vol. 71; pp. 485

Characteristics

n High dilution potential

n High tablet strength, low friability

n Spherical form, good flowability, narrow PSD

n Not sensitive to level of lubriction

n Low moisture uptake (<1% at 20oC / 80% RH)

n Sweet taste, impacts a cooling sensation

n Applications:

– Conventional tablets, chewable tablets, high dosage formulations

Source: technical brochure DFE


Pharm

ato

se®

DCL

40




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Ludipress® LCE

Ludipress®

Ludip

ress

®


Ludipress ® LCE

n 96,5 % α-Lactose Monohydrate

[Ph.Eur./USP-NF/JP]

n 3,5% PVP (Kollidon K30) [Ph.Eur./USP-NF/JP]

Ludipress ®

n Additional 3,5% (Kollidon CL)

spray-dried


Ludip

ress

®

Source: technical brochure BASF




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Characteristics

n Superior compression characteristics, to a simple physical mixture of its constituents

n Fast release despite excellent hardness and low friability

n Excellent flowability

n Reduced process steps (three-in-one system)

n Applications:

– Conventional low dosage formulations

– Effervescent tablets (L. LCE)


Ludip

ress

®LC

E /

Ludip

ress

®




StarLac®




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StarLac®


n 15% extra white Corn Starch [Ph.Eur./USP-NF/JP]

spray-dried


d50 StarLac = 160µm, Hausner ratio = 1.19

Sta

rLac®

Disintegration


Sta

rLac®




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Disintegration: Influence of Lubricants I


Sta

rLac®

Disintegration: Influence of Lubricants II


Sta

rLac®




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Dissolution and Flowability


Sta

rLac®

Physical blendStarLac®

Tablets with 30% Vitamin C, DC grade

29

31

33

35

37

39

0 10 20 30 40 50 60 70 80

Content of Ascor bic Acid [ %]

0

20

40

60

80

100

0 5 10 15 20 25

Time [min]

Dis

solu

tion

[%]

An

gle

of

rep

ose

[°]

Flowability

Dissolution

Up to 40 % faster, probably due to

„wicking“

Characteristics

n Fast, hardness independent disintegration

n Minimal influence of lubricant

n Spherical form, excellent flowability

n Low-dose to mid-dose (up to 20%) dosage formulations

n Applications:

– Homeopathic formulations

– ODT


Sta

rLac®




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Comperative Product Functionality


3,0++++(+)++++(+)StarLac®

5,75+++++

++++++(+)Ludipress ®

Ludipress ® LCE

1++++++++++Pharmatose®

DCL 40

1,3Concentration dependent

++++++(+)RetaLac®

1,5++++++++++MicroceLac® 100

3,5+(+)++++++++Cellactose® 80

LOD [<%]DisintegrationCompressibilityFlowabilityDilution potential

Product

Thank you for your attention.

Visit us at our booth.




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Excipient Fest Porto Rico May 2010 - IPEC-Americasipecamericas.org/sites/default/files/conference10/Franz...Tablets with Extractum Hippocastani 5/5/2010 | ExcipientFest Puerto Rico