Recent Advances in Oral Granules and Bi-Layer Tablet Technologies, Solubility Enhancement Solutions, and Oral Disintegrating Tablet Applications

Transcription

1 Recent Advances in Oral Granules and Bi-Layer Tablet Technologies, Solubility Enhancement Solutions, and Oral Disintegrating Tablet Applications Michael J. Valazza, R.Ph. Vice President Global Modified Release Technologies

2 Catalyst + Talent. Our name combines these ideas. From drug and biologic development to delivery technologies and supply solutions, we are the catalyst for your success. 01 FEB

3 As the #1 drug development and delivery partner in the world, we provide leading development solutions, advanced delivery technologies and innovative supply solutions to the global pharmaceutical, biotech and consumer health industries. Whether you are looking for a single, tailored solution or multiple answers throughout your product s lifecycle, we can improve the total value of your treatments from discovery to market and beyond. Catalent. More products. Better treatments. Reliably supplied. 01 FEB

4 WHY CATALENT? Unrivaled experience, deepest expertise and a track record of market success on a global scale. We are the #1 industry partner in the development and formulation of drugs, biologics and consumer health products and a world leader in drug delivery technology We partner with 90 of the top 100 pharmaceutical and 44 of the top 50 biotech companies, as well as hundreds of smaller innovators We operate 20+ global sites serving 1,000+ customers in over 100+ countries We support 40% of recent new U.S. drug approvals and are now working on 500+ new development programs We use a multi-faceted approach to improve bioavailability, therapeutic profiles and patient adherence We are fully dedicated to high standards of quality, cgmp leadership and LEAN operational excellence 01 FEB * source: United Nations World Investment Report, 2011

5 Presentation Overview 1. OSDrC OptiDose TM Concept an advancement in tab-in-tab and bi-layer tablet technology 2. Developing Better Treatments for Poorly Soluble Compounds with OptiMelt TM HME 3. Oral Disintegrating Tablets case studies of Zydis fastdissolve applications. 4. Appendix

6 The OSDrC OPTIDOSE TM Concept An advancement in tab-in-tab and bi-layer tablet technology

7 About OSDrC OPTIDOSE TM One-Step Dry-Coating Single-step manufacturing opens the door to a host of new formulations February 2012 OSDrC OPTIDOSE TM Technology 1

8 About OSDrC OPTIDOSE TM One-Step Dry-Coating Single-step manufacturing opens the door to a host of new formulations An innovative first-of-its-kind manufacturing process Newly developed rotary punch tableting machine Research and technical collaboration between pharmaceutical manufacturer and tableting machine manufacture February 2012 OSDrC OPTIDOSE TM Technology 1

9 OSDrC OPTIDOSE TM Tablet Press February 2012 OSDrC OPTIDOSE TM Technology 2

10 The Key to OSDrC OPTIDOSE TM Manufacturing Technology: OSDrC Variable Double-Punch Configuration Cam Upper outer punch Upper center punch Die Lower center punch Lower outer punch February 2012 OSDrC OPTIDOSE TM Technology Cam 3

11 Process Flow for an OSDrC OPTIDOSE TM Tablet Three individual hoppers containing bulk powders Excess powder is removed between each layer First two layers receive a light compression Thieving mechanisms at each stage to continuously monitor process February 2012 OSDrC OPTIDOSE TM Technology 4

12 OSDrC Basic Technology Structure of an OSDrC OPTIDOSE TM Tablet Outer layer forms sides and top Active pharmaceutical ingredients form core Outer layer forms base February 2012 OSDrC OPTIDOSE TM Technology 5

13 Representative Punches for OSDrC OPTIDOSE TM Various tablet configurations can be produced simply by changing punches February 2012 OSDrC OPTIDOSE TM Technology 6

14 OSDrC OPTIDOSE TM Technology: Flexibility to Improve Your Treatments OSDrC OPTIDOSE TM technology the broadest range: controlled release, combination products (tabletwithin-a-tablet and pellets-within-a-tablet) and dividable tablets optimized dosing, therapeutic, and plasma release profiles to meet patient needs in a high quality, one step manufacturing process. Broad Range of Tablet Options: Bi-Layer Tablets Dividable Tablets IR/ER Combination Tablets Combination Products (multiple API in single tablets) Direct Compression Orally Disintegrating Tablets (ODT) Pulsatile Release Tablets February 2012 OSDrC OPTIDOSE TM Technology 7

15 Three Enabling Technologies comprise OSDrC OPTIDOSE TM One-Step Dry-Coating Technology Supports single-step manufacturing of pharmaceutical products Accurate & Flexible Control Technology allows accurate and flexible positioning of cores Poor-Compressibility Encasing Technology allows incorporation of core ingredients with poor compressibility February 2012 OSDrC OPTIDOSE TM Technology 8

16 One-Step Dry-Coating Technology Supports single-step manufacturing of pharmaceutical products Ultimate one-step compression system Permits commercial scale production of conventional cored tablets Requires no separate core preparation or supply Permits production of a broad spectrum of high-quality formulations at low cost Potential replacement for sugar- or film-coated tablets February 2012 OSDrC OPTIDOSE TM Technology 9

17 Accurate & Flexible Control Technology Allows accurate and flexible positioning of cores Allows positioning of any number of cores Allows positioning in various configurations Permits release control by varying either the positioning of core or thickness of coating Permits commercial-scale production of cored tablets without misaligned cores February 2012 OSDrC OPTIDOSE TM Technology 10

18 Poor-Compressibility Encasing Technology Allows incorporation of core ingredients with poor compressibility Allows incorporation of pharmacological agents with poor compressibility (e.g. pure API with a flow aid) Incorporation of pellets in the core permits use as a replacement for capsules Permits development of oral rapid disintegration tablets (ODT) and various other innovative formulations February 2012 OSDrC OPTIDOSE TM Technology 11

19 Delivery Capabilities of OSDrC OPTIDOSE TM Controlled Release Positioning technology enables control over the release of the API by the altering thickness of the outer coating. Divided Core Since the core remains fully encased in the coating even when the tablet is divided, the intended release profile remains unaffected by dividing the tablet. Pellet Core By using pellets in the core instead of powders, drugs that normally must be formulated as capsules can be produced as tablets. Thin Coated Able to produce cored tablets with extremely thin coats in a one-step process and can replace sugar and film-coated tablets, substantially reducing manufacturing stages and production costs. Variable Core Tablets do not have to be round. The shape of the core, coating thickness, and tablet configuration can be varied simply by changing the punches. February 2012 OSDrC OPTIDOSE TM Technology 12

20 Controlled Release Based on Thickness of Outer OSDrC Coating Tablets Layer OSDrC OPTIDOSE TM makes it possible to control API release by altering the thickness of the outer layer. Advantages over film-coated tablets include: Simplified manufacturing process No solvents required Low manufacturing cost Simplified process control February 2012 OSDrC OPTIDOSE TM Technology 13

21 Developing Better Treatments for Poorly Soluble Compounds with OptiMelt TM HME A solubility enhancement solution

22 Bioavailability enhancement represents the biggest challenge in oral drug delivery What is your biggest challenge in oral drug delivery/formulation development? N=12 Other 2 We are seeing more poorly soluble drugs in early phase development. Most of the compounds I have right now are poorly soluble VP, Pharmaceutical Development It can be quite resource intensive to develop formulations for poorly-soluble drugs. The problem is most severe when the molecule has both low solubility and high-dose Exe. Director, Pharmaceutical R&D 10 Bioavailability enhancement Historically, our infrastructure is based on conventional technologies. We don t have enough capacity and capability in new technologies that address bioavailability issues Director, Formulation Development SOURCE: Mckinsey & Company Customer interviews

23 Drug Delivery Technology Platform - What attributes are needed to capture full value? An An effective solution delivers drug precisely, reproducibly & safely Fully integrated solution equipment, materials, human resource from End-to-End Compliant solution equipment, controls, scientific knowledge are are current & approvable Exclusive solution / Freedom to to Operate IP IP or or technical barriers to to competition, Operational solution acceptable unit unit dose cost cost

24 Technology Platform Attributes Hot Melt Extrusion Critical Attributes An effective solution OptiMelt TM HME dispersions achieve a specific solubility increase in vivo & utilize GRAS excipients Fully integrated solution Compliant solution HME is a continuous process suited for scale-up, and finished dosage forms may be made using conventional equipment Numerous oral products and devices have been filed with regulatory agencies Exclusive solution HME technology requires significant know-how to commercialize. The drug delivery profile may be patentable Operational solution Proven in pharma & other industries as a robust process readily integrated into a manufacturing operation

25 OptiMelt TM HME Technology Platform GMP Bench to Pilot to Commercial scale, with global capabilities Schorndorf, Germany and Somerset, New Jersey Broadest selection of downstream processing technologies, colocated with OptiMelt TM hot melt extrusion Integrated solutions provider, with over 75 years of industry experience Development, formulation, scale-up, manufacturing, packaging Formulation acceleration and optimization with open Catalent- BASF bioavailability alliance Broad range of excipients designed specifically to enhance solubility, particularly with hot melt extrusion Non-exclusive arrangement to increase development efficiency and deliver better treatments for your molecules 2 4

26 The Amorphous State & Solid Dispersions

27 Amorphous State Properties The Amorphous State of a Poorly Soluble API can generate enhanced dissolution and bioavailability due to increased apparent solubility The Amorphous State is a thermodynamically unstable relative to the crystalline state, which must be considered when developing a viable drug product The Amorphous State is formed by quenching from a melt (e.g. extrusion, granulation, capsule filling) or by controlled precipitation (rotary evaporation, spray drying, freeze drying)

28 Amorphous State Stabilization Amorphous State Stabilization is directed at preventing the initiation and/or reducing the rate of crystal nucleation and growth Regulatory Agencies will demand to see good control and understanding of this property Available strategies: Avoid Tg reduction (e.g. moisture protection) Elevate Tg significantly above room temperature Chemical interactions (H-bonding, complexation) Anti-nucleation methods (additives, surface modification)

29 Principles of Solid Dispersions Solid Dispersions are intimate mixtures of two (or more) components that typically have a high degree of miscibility. Poorly Soluble Drug Dispersions can achieve enhanced solubility by creating a physically stable and processable noncrystalline form. Crystalline active + polymer Solid Dispersion Tablets HME Precipitate methods 28 GRAPHIC SOURCE: Modified from BASF Pharma Ingredients & Services

30 OptiMelt TM Hot Melt Extrusion (HME)

31 Catalent s OptiMelt TM hot melt extrusion addresses many needs Approximately 40% of compounds on the market and >80% in development are poorly soluble (BCS class 2/4) OptiMelt TM hot melt extrusion enhances solubility to bring more products and better treatments to market: Achieve desired efficacy, progressing more molecules to approval Differentiate product profiles; enhanced solubility Enhance patient compliance; reduced pill size/pill burden Optimize product performance; controlled release dosage forms

32 Catalent s OptiMelt TM hot melt extrusion offers multiple benefits OptiMelt TM hot melt extrusion provides many benefits beyond solubility enhancement: polymeric formulation matrix eliminates hydrolysis associated with wet agglomeration suitability for sustained/controlled release or enteric coating ability to form capsules, tablets, and multi-particulate dosage forms control dose over a wide range of solubilities or dispersion concentrations film capability for buccal dosage forms very high drug loading up to 90%, decreases tablet size robust, compact, high-throughput manufacturing with little waste solvent-free processing, eliminating need for explosion-proof equipment potential for patient abuse deterance formulations for certain compounds potential for improved safety and side effect profile with lower dosing taste-masking

33 OptiMelt TM HME Process Advantages Twin-screw design delivers excellent co-mixing of components Solvent free Process is well-controlled and scalable Good materials handling/ containment Extrudate downstream processing is flexible Feasibility trials are easy to design and predictive

34 OptiMelt TM Hot Melt Extrusion The Basics Twin-screw extruders with varying screw design / rotation achieve intimate mixing of drug and excipient Shear forces drive co-melting of drug and excipient Cooled mixture is a Solid Dispersion preferably containing amorphous (noncrystalline) drug Process opportunities Liquid drugs Potent drugs Labile drugs (solvent or moisture sensitive)

35 Hot Melt Extrusion Formulation Case Studies

36 Itraconazole Kollidon Solubility Enhancement Solubility ITRACONAZOLE + KOLLIDON VA 64 Solubility [mg/l] 125,00 100,00 75,00 50,00 25,00 0, Time [minutes] extrudate Itraconazole+Kollidon VA extrudate Itraconazole+Kollidon VA powder mix Itraconazole+Kollidon VA 64 suspension - tested at ph ~ 1 solubility enhancement [mg/l] Itraconazole < 1./. physical mixture 8.1 > extrudate 114 > extrudate 124 >124 SOURCE: Catalent Pharma Solutions Schornforf site

37 Drug Release from Soluplus Extrudates USP II, 50 rpm, 700 ml 0.1 N HCl, cut extrudates, 100 mg API (n=3) 100 drug release [%] t [min] 15% itraconazole in Soluplus 30% itraconazole in Soluplus 45% itraconazole in Soluplus 60% itraconazole in Soluplus Very high drug loads (~50%) are possible without affecting the release profiles in a negative way SOURCE: BASF Pharma Ingredients & Services

38 In vivo Performance of Solid Dispersion Itraconazole 10 mg / kg bw, beagle dogs (n=5) fasted state blood concentration [ng/ml] solid solution physical mixture crystalline itraconazole t [h] Massively increased bioavailability of itraconazole from Soluplus extrudates compared to physical mixture and crystalline API SOURCE: BASF Pharma Ingredients & Services

39 Stability of Solid Dispersion (3 month 40 o C/75%RH) 100 USP II, 50 rpm, 700 ml 0.1 N HCl, granulated extrudates with 100 mg itraconazole, (n=3) Drug release [%] after production - after storage Time [min] After accelerated storage conditions dissolution rates are still comparable SOURCE: BASF Pharma Ingredients & Services

40 HME: Capturing Value in the future Relative to crystalline references, Amorphous Solid Dispersions improve bioavailability in 82% HME provides the platform to realize this potential and capture the full value of your API Source: Newman et al. Journal of Pharmaceutical Sciences, Vol. 101, No. 4, April 2012

41 Future of OptiMelt TM Platform Technology Critical Attributes An effective solution OptiMelt TM Expertise in selecting formulations that maximize solubility enhancement potential of Solid Dispersions Fully integrated solution Parallel R&D effort on downstream processing (e.g. milling, compression, calendering) Compliant solution Leverages Catalent s strong audit record. Working with reliable equipment and raw materials suppliers Exclusive solution Operational solution Optimized HME formulations may yield IP for customers. Opportunities to combine with Catalent proprietary platforms Fully integrated with other manufacturing, analytical and packaging services

42 In Summary OptiMelt TM : A Viable Platform Technology An An effective solution delivers drug precisely, reproducibly & safely Fully integrated solution equipment, materials, human resource from End-to-End Compliant solution equipment, controls, scientific knowledge are are current & approvable Exclusive solution / Freedom to to Operate IP IP or or technical barriers to to competition, Operational solution acceptable unit unit dose cost cost

43 Oral Disintegrating Tablets Case studies of Zydis fast-dissolve applications

44 Selegiline Zydis fast dissolve: anti-parkinsons market 43

45 Zydis Fast Dissolve buccal reformulation of Selegiline: Impact on Product Profile Selegiline vs. Zelapar fast-dissolve tablets Tablet/Capsule Selegiline Zelapar formulated with Zydis fast-dissolve (traditional formulation) (innovative formulation) Lower Dose and Less Frequent Dosing Increased Bioavailability/Faster Onset of Action Lower Side Effect Potential 5-mg doses, taken twice a day (BID). Pill or capsule that must be swallowed. Tmax=1 hour. Digested in the gut, absorbed through the small intestine, processed by the liver. Processed through the liver, producing undesired metabolites mg or 2.5-mg doses, taken once a day (QD). Tablet that dissolves in mouth within seconds, without water. Tmax=15 minutes. Innovative transmucosal drug delivery absorbed rapidly through the lining of the mouth directly into the blood. Significantly by-passes the liver, producing lower undesired metabolites. Patients benefited from less frequent dosing, reduced side effects and shorter off-periods 44

46 Zydis re-formulation improved patient compliance Zelapar has highest Patient Compliance for Medicare patients, based on 12 month longitudinal patient records analysis. % % Compliance % 81.0% ZELAPAR ZYDIS ELDEPRYL SELEGILINE HCL Zelapar, Age: Total, Gender: Total, Pay Type: Medicare Data Source: SDI Health Patient Data, 2011 Additional Cohort Compliance Improvements: Zelapar Selegiline All Ages, Female, All Payers 91.6% 83.7% Age 19-65, All genders, All Payers 87.3% 83.8% 45

47 Zelapar was launched as a branded generic and experienced substantial sales growth US Sales Selegiline Class: Anti-Parkinson Market US Sales Selegiline Class: Anti Parkinson Market $25,000,000 $20,000,000 Sales Sales $15,000,000 $10,000,000 $5,000,000 Zydis Zelapar(Zydis) Eldepryl Selegiline Generics Generics $ Year Year Data Source: IMS Health, 2010 Zelapar 2010 $ market share: 39.3% Zelapar 2010 Unit market share: 10.1% 46

48 Allergy Market: Ebastine antihistamine 47

49 Zydis formulation of Ebastine for allergic rhinitis has delivered substantial market impact Launch of a new bioequivalent line extension increased overall sales for the marketer of this product Ebastine Units Sold G5 (1,000's) Total Units Sold G5 (1,000's) 300, , , , ,000 50, Other Sales Zydis Sales Zydis Product has maintained 50% overall unit market share for the entire ebastine class 83% of patients stated they preferred Zydis fast dissolve tablets vs. standard tablets 2011 IMS data 48

50 Allergy Market: Grazax oral immunotherapy 49

51 GRAZAX oral immunotherapy: An innovative application of Zydis fast dissolve technology First once-daily, oral allergy immunotherapy tablet (AIT) approved as a disease altering agent for grass allergy Efficacy and compliance benefits shown in multiple studies. Benefits over sub-cutaneous delivery: Patient preference for oral treatment (needle phobia) Improved patient adherence and compliance, supported by studies Prevents accidental needle sticks for patients and providers Eliminates needle (sharps) disposal Value enhancement for patients, physicians and payers in management of this chronic condition Positive Phase 3 results recently released for US approval 50

52 Catalent drug delivery technologies enhance product value by differentiating product profiles Efficacy Safety / Tolerability Payer Value Dosage / Admin. Indications/ Populations Increased bioavailability Faster onset of action Targeted drug delivery Sustained drug plasma profile (pk) Controlled drug plasma profile (pk) to match specific treatment needs Targeted drug delivery Controlled drug plasma profile (pk) Reduction in first pass metabolism through the liver Increased patient compliance Reduction in patient pill burden Extended and flexible dosing lower cost to treat with increased convenience Less frequent dose regimen (eg. Once daily vs. BID) Orally Disintegrating tablets disperses in mouth without water in usually <3 seconds Tablets, Pills, Capsules Orally Dissolving Powder loose free flowing powder granules Entire labeled patient population Elderly patient segment Pediatric patient segment On the go life style patient segment Poly-therapy with a single dose Catalent delivers Better Treatments: Broadest range of Drug Delivery Technologies and deep Expertise 51

53 Catalent s full range of value added services: 52

54 DEVELOPMENT BIOLOGICS GPEX CELL LINE ENGINEERING BIOMANUFACTURING PRE-FORMULATION & FORMULATION ORAL DOSE FORMS: SOFTGEL, CONTROLLED RELEASE, IMMEDIATE RELEASE, ORALLY- DISINTEGRATING TABLETS INHALATION PARENTERAL OPTIFORM TECHNOLOGY & SOLID STATE SERVICES PHARMACEUTICAL & BIOPHARMACEUTICAL LAB SERVICES COMPENDIAL, RELEASE, POTENCY & MICROBIOLOGY TESTING METHOD DEVELOPMENT & VALIDATION PHYSICAL, MATERIAL & BIOPHYSICAL CHARACTERIZATION STABILITY TESTING & STORAGE IMPURITY & STRUCTURAL CHARACTERIZATION FACILITY & PROCESS VALIDATION VIRAL CLEARANCE & VIRAL SAFETY PK & IMMUNOGENICITY REGULATORY CONSULTING EARLY STAGE DEVELOPMENT SERVICES LATE STAGE DEVELOPMENT SERVICES COMPLETE LIFE-CYCLE MANAGEMENT CUSTOMIZED EDUCATION PROGRAMS

55 DELIVERY SOFTGEL TECHNOLOGIES SOFTGEL CAPSULES VEGICAPS CAPSULES ZYDIS & LYOPAN FAST- DISSOLVE TECHNOLOGIES CONTROLLED RELEASE TECHNOLOGIES OSDrC OPTIDOSE TM COMPLEX TABLETS COATED PELLETS & BEADS ADVANCED CAPSULES INNOVATIVE API SOLUTIONS COMBINATION SOLID PHARMACEUTICALS FIXED DOSE COMBINATIONS INHALATION PRESSURIZED METERED-DOSE INHALERS DRY POWDER INHALERS NASAL SPRAYS NEBULIZED SOLUTIONS/SUSPENSIONS INJECTABLES FORMULATION DEVELOPMENT PREFILLED SYRINGES CLICK-IN SAFETY DEVICE PROTECTOR SAFETY SHIELD SYSTEM ASI AUTOINJECTOR PHASE I/II VIALS CONSUMER HEALTH

56 SUPPLY CLINICAL SUPPLY GLOBAL COMPARATOR SOURCING MANUFACTURING & BLINDING PACKAGING & LABELING ANALYTICAL SERVICES DISTRIBUTION & WAREHOUSING COMMERCIAL PACKAGING BOTTLING BLISTER PACKAGING CUSTOMIZED BLISTERS/WALLETING INJECTABLE PACKAGING & KITTING SPECIALTY PRODUCT HANDLING MANUFACTURING SOFTGEL & VEGICAPS CAPSULES CONTROLLED RELEASE TABLETS ZYDIS & LYOPAN FAST-DISSOLVE TABLETS STERILE: BLOW/FILL/SEAL, IV BAGS, INJECTABLES PACKAGING DELIVERY SOLUTIONS INTEGRATED SUPPLY CHAIN LATE-STAGE CUSTOMIZATION PRODUCT LIFECYCLE MANAGEMENT ANTI-COUNTERFEITING DESIGN SOLUTIONS PATIENT ADHERENCE SOLUTIONS DELPOUCH UNIT DOSE DELIVERY SYSTEM MEDIA ENHANCED PACKAGING TECHNOLOGY

57 THANK YOU To discover more, please continue on to the Appendix slides which follow. discover more. CATALENT PHARMA SOLUTIONS 14 SCHOOLHOUSE ROAD SOMERSET, NJ OSDrC is a registered trademark of Sanwa Kagaku Kenkyusho Co., Ltd

58 APPENDIX

59 OSDrC OPTIDOSE TM Technology July 2011 OSDrC OPTIDOSE TM Technology 8

60 OSDrC Technology OPTIDOSE TM Tableting Process Only the lower center punch slides down July 2011 OSDrC OPTIDOSE TM Technology 11

61 OSDrC Technology OPTIDOSE TM Tableting Process Space is filled with powder for the coating, which becomes the base layer of the tablet; at this time, the lower outer punch acts as a die July 2011 OSDrC OPTIDOSE TM Technology 12

62 OSDrC Technology OPTIDOSE TM Tableting Process Pre-compression by the upper and lower center punches July 2011 OSDrC OPTIDOSE TM Technology 13

63 OSDrC Technology OPTIDOSE TM Tableting Process July 2011 OSDrC OPTIDOSE TM Technology 14

64 OSDrC Technology OPTIDOSE TM Tableting Process Space is filled with powder for the API layer July 2011 OSDrC OPTIDOSE TM Technology 15

65 OSDrC Technology OPTIDOSE TM Tableting Process Pre-compression by the upper and lower center punches July 2011 OSDrC OPTIDOSE TM Technology 16

66 OSDrC Technology OPTIDOSE TM Tableting Process July 2011 OSDrC OPTIDOSE TM Technology 17

67 OSDrC Technology OPTIDOSE TM Tableting Process Die is filled with remaining powder for the coating July 2011 OSDrC OPTIDOSE TM Technology 18

68 OSDrC OPTIDOSE TM Tableting Process Pre-shaped API layer is pushed up inside the die; the API layer is now completely surrounded by the coating July 2011 OSDrC OPTIDOSE TM Technology 19

69 OSDrC Technology OPTIDOSE TM Tableting Process Compression is completed by the upper and lower punches in flush alignment July 2011 OSDrC OPTIDOSE TM Technology 20

70 OSDrC Technology OPTIDOSE TM Tableting Process Finished tablet is released July 2011 OSDrC OPTIDOSE TM Technology 21

71 OSDrC OPTIDOSE TM Tablets July 2011 OSDrC OPTIDOSE TM Technology 22

72 OSDrC Merits Tablets of Cored Tablet Permits controlled interaction of APIs Permits controlled release of API Can mask bitter taste of API Permits more visually appealing formulations OSDrC OPTIDOSE TM permits creation of various value-added tablet formulations July 2011 OSDrC OPTIDOSE TM Technology 23

73 Controlled Release Based on Thickness of Outer OSDrC Coating Tablets OSDrC OPTIDOSE TM makes it possible to control API release by altering the thickness of the outer coating. Advantages over film-coated tablets include: Simplified manufacturing process No solvents required Low manufacturing cost Simplified process control July 2011 OSDrC OPTIDOSE TM Technology 24

74 Controlled Release Based on Thickness of Outer OSDrC Coating Tablets OSDrC OPTIDOSE TM makes it possible to control API release by altering the thickness of the outer coating. Advantages over film-coated tablets include: Simplified manufacturing process No solvents required Low manufacturing cost Simplified process control Percent dissolved mm mm 0.5 mm July Time (h) Yuichi Ozeki, Masaki Ando, Yukinao Watanabe, Kazumi Danjo, Evaluation of novel one-step dry-coated tablets (OSDRC Yuichi Ozeki, Masaki Ando, Yukinao Watanabe, Kazumi Danjo, OPTIDOSE TM ) as a platform for delayed-release tablets, Evaluation of novel one-step dry-coated tablets (OSDRC ) as a platform for delayedrelease Journal tablets, of Controlled Release, vol 95/1 pp (2004) Journal of Controlled Release, vol 95/1 pp (2004) OSDrC OPTIDOSE TM Technology 25

75 OSDrC Dividable TabletsCore Tablets Target drug release profiles can be maintained, whether the tablets are divided or not With conventional technology, enteric tablets could not be divided July 2011 OSDrC OPTIDOSE TM Technology 26

76 OSDrC Dividable TabletsCore Tablets Target drug release profiles can be maintained, whether the tablets are divided or not With conventional technology, enteric tablets could not be divided Percent dissolved core only whole divided two-half divided one-half 25 ph1.2 ph Time (h) Yuichi Ozeki, Yukinao Watanabe, Hirokazu Okamoto, Kazumi Danjo, Development Yuichi Ozeki, of Yukinao Dividable Watanabe, One-Step Hirokazu DRy-Coated Okamoto, Tablets Kazumi Danjo, (OSDRC Development OPTIDOSE of Dividable TM Dividable) One-Step and DRy-Coated Their Evaluation Tablets as (Dividable-OSDRC ) a New Platform for and Controlled Their Evaluation Drug Release, a New Platform for Controlled Drug Release, Pharmaceutical Research, vol 21(7) pp (2004) July 2011 OSDrC OPTIDOSE TM Technology 27

77 OSDrC Replacing Tablets Capsules with Tablets Capsule Issues Do not facilitate dosage control (cannot be divided) Difficult to swallow Difficult to prevent tampering Relatively high manufacturing cost July 2011 OSDrC OPTIDOSE TM Technology 30

78 OSDrC Replacing Tablets Capsules with Tablets Possible to encase pellets as a replacement for capsules Tests have obtained same release characteristics as capsules July 2011 OSDrC OPTIDOSE TM Technology 31

79 OSDrC Replacing Tablets Capsules with Tablets Possible to encase pellets as a replacement for capsules Tests have obtained same release characteristics as capsules Percent dissolved Capsule whole divided one-half divided two-half July Time (h) Yuichi Ozeki SKK company data (2004) OSDrC OPTIDOSE TM Technology 32

80 OSDrC Pulsatile Tablets Release Tablets Accurate placement of multiple cores makes it possible to manufacture pulsatile release formulations July 2011 OSDrC OPTIDOSE TM Technology 33

81 OSDrC Pulsatile Tablets Release Tablets Accurate placement of multiple cores makes it possible to manufacture pulsatile release formulations Percent dissolved ex. 1 st core 2 nd core July Time (h) Yuichi Yuichi Ozeki, Ozeki, "The Yuichi "The Nakai Ozeki, Nakai Award Award winner's winner's article" article" Development Development of one-step of one-step dry-coated dry-coated tablets "The tablets Nakai Award winner's article" Development of one-step dry-coated tablets (OSDRC (OSDRC) (OSDRC) OPTIDOSE TM ) and the study for its physical characteristics. Journal and the study for its physical characteristics. and Journal the of study Japan of Japan for Society its Society physical of Pharmaceutical of Pharmaceutical characteristics. Machinery and Engineering, Japan. Machinery and Engineering, Journal vol Japan. of 14/4 vol Japan pp. 14/4 Society (2005) pp of Pharmaceutical (2005) Machinery and Engineering, OSDrC Japan. OPTIDOSE vol TM 14/4 Technology pp (2005) 34

82 OSDrC Potential Tabletsfor a Host of New Formulations Oral rapid disintegration (OD) tablets Made possible by technology that permits encasement of core pharmaceutical powders in powder form July 2011 OSDrC OPTIDOSE TM Technology 35

83 OSDrC Potential Tabletsfor a Host of New Formulations Various core configurations Various tablet configurations can be produced simply by changing double punches July 2011 OSDrC OPTIDOSE TM Technology 36

84 OSDrC OPTIDOSE TM Data July 2011 OSDrC OPTIDOSE TM Technology 37

85 OSDrC Core Data Misalignment OSDrC OPTISODE rotary tableting TM rotary machines tabletingshowed machines core showed alignment of core less alignment of less than 0.1mm, a level that is not than considered 0.1mm, significant a level to that performance is not considered significant to performance r (mm) 0.4 DC 0.2 OSDrC Core July 2011 Tabletting speed (tab hr. -1 Yuichi Ozeki ) The Nakai Award winner s article Development of one-step dry-coated tablets (OSDRC Yuichi Ozeki OPTIDOSE TM ) and the study for its physical characteristics, Journal of Japan Society of Pharmaceutical Machinery and Engineering, The Nakai Award winner s article Development of one-step dry-coated Japan. tablets vol 14/4 (OSDRC ) pp (2005) and the study for its physical characteristics, OSDrC OPTIDOSE Journal TM Technology of Japan Society of Pharmaceutical Machinery and Engineering, 40 Japan. vol 14/4 pp (2005)

86 Individual Coatings OSDrC rotary OPTIDOSE tableting TM rotary machines tableting showed machines the ability showed to the produce ability to individual produce coatings individual comparable coatings comparable to film coating to film coating mm Percent coefficient of variation mm 0.5 mm Individual July Tabletting time in minute Yuichi Ozeki Advanced dry-coated tablets as a solid coating technology (2) Yuichi Evaluation Ozeki of novel one-step dry-coated tablets (OSDRC OPTIDOSE TM ) as Advanced the delayed- dry-coated release tablets tablets and as a its solid machine coating performance, technology (2) Evaluation of novel one-step dry-coated tablets (OSDRC ) as the delayed-release PHARM TECH JAPAN, tablets vol 21/9 pp (2005 and its machine performance, OSDrC PHARM OPTIDOSE TECH TM Technology JAPAN, vol 21/9 pp (2005) 41

87 Cross-Contamination Cross-contamination was an extremely low 0.03% OSDrC can OPTIDOSE effectively TM can control effectively the interaction control the between interaction the API and between the coating the API excipient and the coating excipient Acetaminophen content (%) side surface bottom surface upper surface Cross July Time (min) Yuichi Ozeki The Nakai Award winner s article Development of one-step dry-coated tablets Yuichi (OSDRC Ozeki OPTIDOSE TM ) and the study for its physical characteristics, Journal The of Nakai Japan Award Society winner s of Pharmaceutical article Development Machinery and of one-step Engineering, dry-coated tablets (OSDRC ) Japan. vol 14/4 pp (2005) and the study for its physical characteristics, Journal of Japan Society of Pharmaceutical Machinery and Engineering, OSDrC OPTIDOSE Japan. vol TM 14/4 Technology pp (2005) 42

88 The Amorphous State & Solid Dispersions

89 Amorphous State Structure Hexagonal Close Packing Random Close Packing fraction of voids = 0.26 fraction of voids > 0.36 DATA SOURCES: Jalali, J. Chem. Phys. 120 (2004) 1138; Bates, et al. Pharm.Res. 23 (2006) 2333

90 Amorphous State Thermodynamics Enthalpy Liquid Supercooled Liquid Amorphous (glass) Crystal Temp. T g T m Higher Energy State of Amorphous phase is shown relative to Crystalline phase

91 Amorphous State Thermal Analysis Power (uw) T g T c T m Endothermic Temperature ( o C) Differential Scanning Calorimetry of Amorphous Indomethacin API

92 Amorphous State Properties The Amorphous State of a Poorly Soluble API can generate enhanced dissolution and bioavailability due to increased apparent solubility The Amorphous State is a thermodynamically unstable relative to the crystalline state, which must be considered when developing a viable drug product The Amorphous State is formed by quenching from a melt (e.g. extrusion, granulation, capsule filling) or by controlled precipitation (rotary evaporation, spray drying, freeze drying)

93 Amorphous State Materials Characterization Critical Properties Absence of crystal lattice (no 3D structure) Molecular conformation / mobility Moisture absorption Increased apparent solubility Analytical Tools X-ray Diffraction (XRD) Differential Scanning Calorimetry (DSC) Polarized Light Microscopy Spectroscopy (Raman, SSNMR) Relaxation times (SSNMR, rheology) Dynamic Vapor Sorption (DVS) Kinetic solubility studies (e.g. dissolution, supersaturation)

94 Amorphous State Stability Model glass-former: Indomethacin (IMC) T g ~ 45 o C Weight Fraction Crystallized C 30 C 20 C Time (days) Critical relationship between Glass Transition Temp (T g ) and storage temperature SOURCE: Andronis and Zografi, J. Non-Cryst. Solids 271 (2000) p236

95 Amorphous State Stability Crystallization kinetics for different particle sizes of amorphous IMC at 30 o C 100 Percent crystallinity μm μm μm μm Time (days) SOURCE: Crowley and Zografi, Pharm. Res. 20 (2003) p1417

96 Amorphous State Stabilization Amorphous State Stabilization is directed at preventing the initiation and/or reducing the rate of crystal nucleation and growth Regulatory Agencies will demand to see good control and understanding of this property Available strategies: Avoid Tg reduction (e.g. moisture protection) Elevate Tg significantly above room temperature Chemical interactions (H-bonding, complexation) Anti-nucleation methods (additives, surface modification)

97 Principles of Solid Dispersions Solid Dispersions are intimate mixtures of two (or more) components that typically have a high degree of miscibility. Poorly Soluble Drug Dispersions can achieve enhanced solubility by creating a physically stable and processable noncrystalline form. Crystalline active + polymer Solid Dispersion Tablets HME Precipitate methods 96 GRAPHIC SOURCE: Modified from BASF Pharma Ingredients & Services

98 Solid Dispersions Control of T g Stabilization of Amorphous IMC using poly(vinylpyrrolidone) by increasing T g in a molecular dispersion Cl 200 O N CH CH 3 O CH 2 COOH Tg ( o C) Indomethacin PVP content (%w/w) N C H CH 2 O n PVP SOURCE: Yoshioka et al. J. Pharm. Sci. 84 (1995) p983

99 Solid Dispersions Drug-Polymer Interactions Amorphous IMC containing 5% PVP has greatly increased physical stability stored at 30 o C storage for 100 days 100 Percent crystallized pure IMC 5%PVP Time (days) IMC-PVP H-bonding reduces crystal nucleation and growth SOURCE: Matsumoto and Zografi, Pharm. Res. 16 (1999) p1722

100 OptiMelt TM Hot Melt Extrusion (HME)

101 Catalent s OptiMelt TM hot melt extrusion addresses many needs Approximately 40% of compounds on the market and >80% in development are poorly soluble (BCS class 2/4) OptiMelt TM hot melt extrusion enhances solubility to bring more products and better treatments to market: Achieve desired efficacy, progressing more molecules to approval Differentiate product profiles; enhanced solubility Enhance patient compliance; reduced pill size/pill burden Optimize product performance; controlled release dosage forms

102 Catalent s OptiMelt TM hot melt extrusion offers multiple benefits OptiMelt TM hot melt extrusion provides many benefits beyond solubility enhancement: polymeric formulation matrix eliminates hydrolysis associated with wet agglomeration suitability for sustained/controlled release or enteric coating ability to form capsules, tablets, and multi-particulate dosage forms control dose over a wide range of solubilities or dispersion concentrations film capability for buccal dosage forms very high drug loading up to 90%, decreases tablet size robust, compact, high-throughput manufacturing with little waste solvent-free processing, eliminating need for explosion-proof equipment potential for patient abuse deterrence formulations for certain compounds potential for improved safety and side effect profile with lower dosing taste-masking

103 OptiMelt TM HME Process Advantages Twin-screw design delivers excellent co-mixing of components Solvent free Process is well-controlled and scalable Good materials handling/ containment Extrudate downstream processing is flexible Feasibility trials are easy to design and predictive

104 OptiMelt TM Hot Melt Extrusion The Basics Twin-screw extruders with varying screw design / rotation achieve intimate mixing of drug and excipient Shear forces drive co-melting of drug and excipient Cooled mixture is a Solid Dispersion preferably containing amorphous (noncrystalline) drug Process opportunities Liquid drugs Potent drugs Labile drugs (solvent or moisture sensitive)

105 OptiMelt TM Hot-Melt HME Extrusion Twin Screw Extruder Equipment Variables Feeder configuration Processing zone configuration Die size / number polymer Main feed API Vent Liquid injection Liquid injection Feed motor Die Side stuffer Drive motor and gearbox Forward Elements Distributive Mixing Dispersive Mixing Conveying Zoning Feeding/ Compressing 30 degree 90 degree

106 OptiMelt TM HME - Process Variables and Outputs Feed rate input polymer API Screw speed input Barrel temperature inputs Main feed Feed motor Die Drive motor and gearbox Material temp, Pressure, PAT Barrel temperature outputs Screw speed Torque

107 OptiMelt TM HME Downstream Extrudate Processing A wide range of finished dosage forms can be generated 1. Upstream Feeder I Feeder II Granulator 2. Compounding Extrusion Extruder 3. Downstream Pellets, Granules, Calendering, Inj molding SOURCE: BASF Pharma Ingredients & Services

108 OptiMelt TM HME Development Feasibility Plan Request for Proposal Technical analysis / IP Miscibility study Formulation concept HME process simulation Accelerated stability study HME small scale trials Stability prediction Downstream dosage form trials GLP / GMP batches Scale-up 107

109 OptiMelt TM HME Feasibility Assessments Miscibility may be assessed by predictive or small-scale experimental techniques DSC of binary mixtures to identify single T g Hot stage microscopy to observe phase melting/dissolution at different temperatures Film casting of binary mixtures from common solvent visual examination for crystal formation A significant benefit of HME is that proof-of-concept evaluations may be performed at small-scale, quickly and with minimal API

110 OptiMelt TM HME Feasibility Assessments The following API information directs formulation strategy: API T g if available or otherwise estimate (T g / T m [Kelvin] Ratio ~0.7 based on fragility theory ) API chemical stability at increased temperature API availability for H-bonding Poorly Soluble Model Drugs: Fenofibrate Indomethacin Itraconazole Tg / Tm ( o C) -20 / / / 166 Solubility at ph7 (µg/ml) ~1 5 ~1

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