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1 Excipient Fest Porto Rico May 2010 MEGGLE Excipients & Technology, Wasserburg Germany Dr. Franz Karl Penz Location Meggle headquarters, Wasserburg Germany 5/5/2010 ExcipientFest Puerto Rico 2 1

2 123 Years of MEGGLE Founded: Company Name: 1887 as a small dairy since 2002 MEGGLE AG Head Office: Employees: about 2000 Wasserburg a. Inn, Germany Josef Anton Meggle Turnover 2008: 750 mn Euro (consolidated) 5/5/2010 ExcipientFest Puerto Rico 3 MEGGLE AG Holding MEGGLE Holding Molkerei MEGGLE Wasserburg GmbH & Co. KG 100 % MEGGLE Eastern Europe GmbH 100 % MEGGLE International GmbH 100 % Food Industry Animal Feed Pharmaceut. Excipients 5/5/2010 ExcipientFest Puerto Rico 4 2

3 MEGGLE International (Pharma) 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 in White Plains, NY. Sales of pharmaceutical Functional Products in North America. Own Production of pharmaceutical Lactose in USA, Minneapolis (La Sueur), MN at the beginning of Representative Office MEGGLE Shanghai Founded in 2002 and situated in Shanghai. High demand for pharmaceutical Lactose in the Chinese market. MEGGLE Singapore Ltd. Founded in 2003 and situated in Singapore. Sales of pharmaceutical Functional Products in South East Asia. 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. 5/5/2010 ExcipientFest Puerto Rico 5 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 our first co-processed excipient 1990 RetaLac In the nineties until now extension of DC-range 2000 InhaLac Introduction of products for Dry-Powder-Inhaler 5/5/2010 ExcipientFest Puerto Rico 6 3

4 Lactose Production Production > 30,000 tons Countries worldwide > 110 Agents worldwide > 50 Products > 20 Latest development RetaLac 5/5/2010 ExcipientFest Puerto Rico 7 Co-processing, a versatile pathway to modify excipients: Lactose excipients from Lactose excipients fast disintegrating to modified release from fast disintegrating to modified release 5/5/2010 ExcipientFest Puerto Rico 8 4

5 Granulation Process Direct Compression Dry Compaction Wet Granulation Mixing and blending of API and adjuvants Compression Mixing and blending of API and adjuvants Compression into slugs Mixing and blending of API and adjuvants Preparation of binder Milling and sieving of slugs Mixing of granules with adjuvants Compression 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 5/5/2010 ExcipientFest Puerto Rico 9 Direct Compression of Tablets Advantages Economy Avoidance of heat, moisture and compression Minimal variability compared to wet granulation Viscosity of binder solution, wetting and drying parameters. Fewer long-term problems Dissolution profile, chemical stability 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. Lower microbial level Direct compressed tablets have lower microbial level compared to those produced by wet granulation. 5/5/2010 ExcipientFest Puerto Rico 10 5

6 Direct Compression of Tablets Limitations Choice of DC-Excipients blending, compactability, flowability, lubricant, stability No flaws in raw materials constant quality No satisfying colouring, dust Poor reworkability 5/5/2010 ExcipientFest Puerto Rico 11 Reasons for developing new co-processed Excipients with improved Functionalities Rising technical standards High speed machines Poor compressiblity of actives Synergic functionality needed Demands of the customer Mask unfavourable properties High costs of development and toxicologic testing Risk with new chemical entities Co-processed Excipients 5/5/2010 ExcipientFest Puerto Rico 12 6

7 Definition & Aim Combining two or more established excipients by an appropriate process Formation of excipients with superior properties compared to the simple physical mixtures of their components To obtain a product with added value related to the ratio of its functionality vs. price. Co-processed Excipients 5/5/2010 ExcipientFest Puerto Rico 13 Methods of Preparation Chemical Modification MC, HPMC, Lactitol Physical Modification Sorbitol, Dextrates, Compressible Sugars Sieving, Blending α-lactose monohydrate, Lactitol Cristallisation Di-Pac, ß-Lactose Spray-drying α-lactose monohydrate, Karion instant Agglomeration Tablettose, RetaLac Dehydration Anhydrous Lactose Modified Excipients 5/5/2010 ExcipientFest Puerto Rico 14 7

8 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 Co-processed Excipients 5/5/2010 ExcipientFest Puerto Rico 15 Lactose in co-processed Excipients for DC Lactose together with: Cellulose derivatives Powder cellulose Cellactose 80 MCC MicroceLac 100 HPMC (new) RetaLac Lactitol Pharmatose DCL 40 PVP, PVP CL Ludipress, Ludipress LCE Starch StarLac Co-processed Excipients 5/5/2010 ExcipientFest Puerto Rico 16 8

9 Lactose in co-processed Excipients (DC) Co-processed Excipients Cellactose 80 5/5/2010 ExcipientFest Puerto Rico 17 Lactose in co-processed Excipients (DC) Cellactose 80 Cellactose 80 75% α-lactose Monohydrate [Ph.Eur./USP-NF/JP] 25% Powdered Cellulose [Ph.Eur./USP-NF/JP] spray-dried d µm, Hausner ratio = /5/2010 ExcipientFest Puerto Rico 18 9

10 Compaction Profile Hardness [N] Tablettose 80+25% Vivacel 102 Tablettose 80 Cellactose 80 Cellactose Compaction force [MPa] 5/5/2010 ExcipientFest Puerto Rico 19 Compaction Profile: Tablets with Extractum Hippocastani Cellactose 80 C Cellactose 80 H Extr. Hippocast. AZ Physical mixture: A Avicel Z Zepharox (spray-dr. Lact.) By courtesy of Prof. Armstrong, University of Wales College of Cardiff 5/5/2010 ExcipientFest Puerto Rico 20 10

11 High Dilution Potential Hardness [N] Punch: 12mm Vitamin C 98% DC 345,0 [69%] Cellactose ,0 [30%] 20 Compritol 888 5,0 [1%] 500, Compression force [kn] (comprex I) Cellactose 80 5/5/2010 ExcipientFest Puerto Rico 21 Adherence Capacity I Micronized Glibenclamide Dry Compaction Premixing Mixing Turbula 30 min Carrier Cellactose 80 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); /5/2010 ExcipientFest Puerto Rico 22 11

12 Adherence Capacity II Cellactose 80 5/5/2010 ExcipientFest Puerto Rico 23 Characteristics High adherence capacity High (up to 75%) dosage formulations Spherical form, good flowability Strong hardness depending disintegration Good mouthfeel Avoiding incompatibilities with MCC (Furosemide) Applications: Difficult to compress formulations as herbal extracts or inorganic salts Suitable alternative to undergo MCC/Lactose in patents Cellactose 80 5/5/2010 ExcipientFest Puerto Rico 24 12

13 Lactose in co-processed Excipients (DC) Co-processed Excipients MicroceLac 100 5/5/2010 ExcipientFest Puerto Rico 25 Lactose in co-processed Excipients (DC) MicroceLac % α-lactose Monohydrate [Ph.Eur./USP-NF/JP] 25% Microcrystalline Cellulose [Ph.Eur./USP-NF/JP] spray-dried MicroceLac 100 d 50 MicroceLac = 150µm, Hausner ratio = /5/2010 ExcipientFest Puerto Rico 26 13

14 Improving Content Uniformity I Micronized Glibenclamide 5% V-type mixer MicroceLac 100 Physical Blend Sample taken at prescribed (2, 5, 10, 15, 20 and 30 min.) time and defined points Assay MicroceLac 100 By courtesy of Prof. Sunada, Meijo University, Nagoya 5/5/2010 ExcipientFest Puerto Rico 27 Improving Content Uniformity II glibenclamide [%] Formulation 1 5% Glibenclamide / Physical Blend glibenclamide[%] Formulation 2 5% Glibenclamide / MicroceLac MicroceLac Demixing! time [min] time [min] 5/5/2010 ExcipientFest Puerto Rico 28 14

15 Tablet Hardness MicroceLac 100 produced the hardest tablets with/without API MicroceLac 100 M 0 - MicroceLac 100 M 2-75% spray-dried lactose + 25% Avicel PH102 M 1-75% anhydrous β lactose + 25% Avicel PH102 M 3-75% a lactose monohydrate + 25% Avicel PH102 Michoel, A., Rombaut, P., Verhoye, A., 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), /5/2010 ExcipientFest Puerto Rico 29 Characteristics Improving content uniformity High and consistant tablet hardness Sperical form, good flowability Very low to high (up to 80%) dosage formulations Hard and smooth tablet surface (saving coating material) Improving rheology MicroceLac 100 Applications: Conventional tabletting Formulations with poor flowable, micronized APIs 5/5/2010 ExcipientFest Puerto Rico 30 15

16 Lactose in co-processed Excipients (DC) Co-processed Excipients RetaLac 5/5/2010 ExcipientFest Puerto Rico 31 Lactose in co-processed Excipients (DC) RetaLac RetaLac 50% α-lactose Monohydrate [Ph.Eur./USP-NF/JP] 50% HPMC [Ph.Eur./USP-NF/JP] spray-agglomerate 5/5/2010 ExcipientFest Puerto Rico 32 16

17 Compaction Profile and Drug Release RetaLac Tabletting behaviour and dissolution of Theophylline (98 mg) in atablet formulation in the presence of 0.5% of Mg-stearate, using 8mm punches (weight 400mg). 5/5/2010 ExcipientFest Puerto Rico 33 Characteristics Enables direct compression of sustained release formulations Superior compressibility to physical mixture, minimizes friability Structured surface, good flowability Low/medium (up to 50%) dosage formulation Improves wettability of HPMC Applications: Direct compression of sustained release formulations Facilitates preparation of dispersions containing HPMC/Lactose RetaLac 5/5/2010 ExcipientFest Puerto Rico 34 17

18 Lactose in co-processed Excipients (DC) Co-processed Excipients Pharmatose DCL 40 Pharmatose DCL40 5/5/2010 ExcipientFest Puerto Rico 35 Lactose in co-processed Excipients (DC) Pharmatose DCL 40 95% Anhydrous ß-Lactose [Ph.Eur./USP-NF/JP] 5% Lactitol [Ph.Eur./USP-NF/JP] Source: technical brochure DFE Pharmatose DCL 40 blend 5/5/2010 ExcipientFest Puerto Rico 36 18

19 Compaction Profile Pharmatose 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 /5/2010 ExcipientFest Puerto Rico 37 Characteristics High dilution potential High tablet strength, low friability Spherical form, good flowability, narrow PSD Not sensitive to level of lubriction Low moisture uptake (<1% at 20 o C / 80% RH) Sweet taste, impacts a cooling sensation Applications: Conventional tablets, chewable tablets, high dosage formulations Pharmatose DCL 40 Source: technical brochure DFE 5/5/2010 ExcipientFest Puerto Rico 38 19

20 Lactose in co-processed Excipients (DC) Co-processed Excipients Ludipress Ludipress LCE Ludipress 5/5/2010 ExcipientFest Puerto Rico 39 Lactose in co-processed Excipients (DC) Ludipress LCE 96,5 % α-lactose Monohydrate [Ph.Eur./USP-NF/JP] 3,5% PVP (Kollidon K30) [Ph.Eur./USP-NF/JP] Ludipress Ludipress Additional 3,5% (Kollidon CL) spray-dried Source: technical brochure BASF 5/5/2010 ExcipientFest Puerto Rico 40 20

21 Characteristics Superior compression characteristics, to a simple physical mixture of its constituents Fast release despite excellent hardness and low friability Excellent flowability Reduced process steps (three-in-one system) Applications: Conventional low dosage formulations Effervescent tablets (L. LCE) Ludipress LCE /Ludipress 5/5/2010 ExcipientFest Puerto Rico 41 Lactose in co-processed Excipients (DC) Co-processed Excipients StarLac 5/5/2010 ExcipientFest Puerto Rico 42 21

22 Lactose in co-processed Excipients (DC) StarLac StarLac 85% α-lactose Monohydrate [Ph.Eur./USP-NF/JP] 15% extra white Corn Starch [Ph.Eur./USP-NF/JP] spray-dried d 50 StarLac = 160µm, Hausner ratio = /5/2010 ExcipientFest Puerto Rico 43 Disintegration StarLac 5/5/2010 ExcipientFest Puerto Rico 44 22

23 Disintegration: Influence of Lubricants I StarLac 5/5/2010 ExcipientFest Puerto Rico 45 Disintegration: Influence of Lubricants II StarLac 5/5/2010 ExcipientFest Puerto Rico 46 23

24 Dissolution and Flowability Flowability Angle of repose [ ] Content of Ascorbic Acid [%] 100 Physical blend StarLac StarLac Dissolution Up to 40 % faster, probablydue to wicking Dissolution [%] Time [min] Tablets with 30% Vitamin C, DC grade 5/5/2010 ExcipientFest Puerto Rico 47 Characteristics Fast, hardness independent disintegration Minimal influence of lubricant Spherical form, excellent flowability Low-dose to mid-dose (up to 20%) dosage formulations Applications: Homeopathic formulations ODT StarLac 5/5/2010 ExcipientFest Puerto Rico 48 24

25 Comperative Product Functionality Product Dilution potential Flowability Compressibility Disintegration LOD [<%] Cellactose (+) 3,5 MicroceLac ,5 RetaLac ++(+) Concentration dependent 1,3 Pharmatose DCL Ludipress Ludipress LCE +(+) ,75 StarLac +(+) +++ +(+) +++ 3,0 5/5/2010 ExcipientFest Puerto Rico 49 Thank you for your attention. Visit us at our booth. 25