CAPSULES Films & Foils MACHINES INSPECTION SYSTEMS. Partnering in Excellence

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1 CAPSULES Films & Foils MACHINES INSPECTION SYSTEMS Partnering in Excellence

2 Our Vision, Mission and Values 2

3 Comprehensive Solution for cdpi: Opportunities, Trends & Possibilities Webinar 9 th November 2017

4 Content Introduction Inhalation Technology Capsules Based Inhalers Types of Capsules Advantages - Case Studies Products in the Market / Pipeline ACG Holistic solution 4

5 Inhalation milestones Ultibro Breezhaler approval 2016 Spiriva Handihaler approval 2004 R. Altounyan. Spinhaler D. Jack. Rotahaler/Salbutamol 1911 A. Newton. First DPI patent 1864 Kaplin. Adrenalin inhaled Bennet. First published Inhaler illustration Chloroform 400BC Greek physicians inhalation of volcanic Sulphur vapours

6 Research Literature: Capsules in DPI Analysis of papers reporting test results from Year Number of Papers

7 Inhalation Technology 7

8 Lung structure 8

9 Alveolar region Surface: 140 m2 Number: 500 millions Volume air: 2-6 l. Volume blood = ml 9

10 Comparison of Dosage Forms Available to Treat Respiratory Diseases Advantages Attribute Oral delivery Inhaled delivery Total dose 400 mg daily 40 mg daily Lung to plasma exposure ratio Bioavailability Low 55 % (in Itraconazole) High 60% directly to site of administration Lung exposure Variable, affected by diet Consistently high Side effects Systemically & orally driven: Gastrointestinal Phototoxicity(Voriconazole) Drug-drug interactions Locally driven Source: Sermet-Gaudelus et al, Antimicrobial agents Chemotherapy (2001), Cold Spring Harb Perspect Med (2015) Simple Easy-to-use Better patient outcome Pulmonary route provides consistent drug delivery with high lung deposition

11 Inhalation: The Golden Rule Particle size does matter. Only particles in the 1-5 micron range are active Aerodynamic diameter Geometric diameter Particle density Particle shape 11

12 Why Particle Size is Important? From Fischler et al. Particle dynamics (2015) 12

13 Indicators EMITTED DOSE (µg): TOTAL MASS OF DRUG DEPOSITING IN THE MOUTH PIECE, INDUCTION PORT, PRESEPARATOR AND NGI (Next Generation Impactor) STAGES FINE PARTICLE DOSE (µg): MASS OF DRUG DEPOSITED IN THE NGI WITH AERODYNAMIC DIAMETERS <4.46µM 13

14 Dry Powder Inhalation (DPI) Nebulizers Transforms liquid medication into aerosol Requires coordination between the actuation of device and inhalation MDI Formulated in solution or suspension using a liquid propellant Requires coordination between the actuation of device and inhalation Drug is inhaled by inspiratory mechanism The powder formulation does not require use of propellant cdpi is an optimal solution for drug delivery because of recent particle engineering

15 Types of DPIs Blister based Dry Powder Inhaler Reservoir based Dry Powder Inhaler Capsule based Dry Powder Inhaler

16 DPI Formulation Design

17 Use of Excipients in Pulmonary Drug Delivery EXCIPIENTS DESCRIPTION COMMENTS Sugars: Lactose, Mannitol, Glucose Hydrophobic additives: Mg stearate Amino acids: Leucine, Trileucine Surfactants: Poloxamer. Bile salts Biodegradable polymers: PLGA Coarse fine carrier Protection for drug moisture Improved aerosol efficiency Production of light and porous particles Used in sustained release formulation Approved and commonly used Approved Endogenous substance but no data on lung toxicity Accepted at low dose Immunogenicity effect observed

18 Capsule Based Inhalers From Seebri Neohaler guide 18

19 Mechanism of Action Puncturing: opening of capsule. Aerosolization: after inspiration, drug is released to the lung. 19

20 POSITIONS OF OPENINGS

21 Capsule Puncturing (1/2) Source Powder Capsule and Device. Aurelie Schouben et al. IJP 2015

22 Capsule Puncturing (2/2)

23 Force (N) Force / Deformation for Hard Capsules (1) (2) (3) Deformation (mm) Torrisi et al. IJP 2013

24 Capsule Spinning At 60 l/m the capsule s angular velocity can reach 2800 rpm The low moment of inertia of the capsule makes possible such high values The forces generated at this rotation deagglomerate the mixture Source Pierce and Inhale. F. Martinelli et al

25 Computational Fluid Dynamics Source Use of computational modelling Zhou et al

26 Agglomerates Dispersed by Drag Force Redrawn from Kou et al. Powder dispersion mechanism. IJP (2016)

27 CAPSULE TYPES Gelatin Gelatin PEG HPMC 27

28 Ezeeflo Capsule Properties GELATIN GELATIN-PEG HPMC ORIGIN ANIMAL ANIMAL VEGETABLE STRUCTURE PROTEIN PROTEIN CELLULOSE MOISTURE CONTENT (%) BRITTLENESS AT LOW RH Yes Medium Very low CROSSLINKING Yes Yes No 28

29 Puncturing From Birchall et al. Drug delivery Pharm

30 % GOOD CAPSULES Puncturing: 40 Total with 1 Cyclohaler 100 % GOOD 75% RH / 20ºC Gelatin A ACG Gelatin ACG HPMC TYPE OF CAPSULE From J. Kalafat et al. Inhalation delivery Using DOE to optimize puncturing AAPS

31 % GOOD CAPSULES Puncturing: 40 Total with 2 Cyclohalers (20+20) 100 % GOOD 75% RH / 25ºC Gelatin A ACG Gelatin ACG HPMC TYPE OF CAPSULE From J. Kalafat et al. Inhalation delivery. Using DOE to optimize puncturing. AAPS 2017

32 Aerosolization Gelatin Lactose +salbutamol HPMC 60L/m 4s From Saleem et al. Comparison of two different types of inhalation capsules AAPS

33 Aerosolization From Saleem et al. Comparison of two different types of inhalation capsules AAPS

34 Capillary Condensation

35 Case Studies: Advantages High drug doses products Moisture sensitive products Amorphous powders Reproducibility Cost Environmental 35

36 High Dose Drugs Pulmonary delivery can achieve a superior therapeutic effect at a fraction of the systemic dose. Oral dose of 2-4 mg Salbutamol is therapeutically equivalent to ug by inhalation Diseases as cystic fibrosis and lung infections require high drug concentrations in lung. High intravenous doses may carry systemic toxicity From Labiris & Dolovich: Pulmonary Drug Delivery. Part I. Physiological factors affecting therapeutic effectiveness of aerosolized medications 36

37 High Dose Drugs MDI DPI cdpi Nebulizer 1 mg 10 mg 100 mg 1000 mg Lung Dosage 37

38 High Dose Drugs Colobreath Turbospin. Lung infections. Forest Laboratories. Gelatin capsule 125mg 38

39 High Dose Drugs 39

40 Moisture Sensitive Drugs Most of the inhaled drugs are moisture sensitive In order to avoid drug degradation it is convenient that the container has low moisture content The HPMC capsules moisture content can be reduced at very low values storing the capsule at the convenient relative humidity 40

41 Capsule moisture content (%) Correlation RH / HPMC Capsule Moisture Content 16 HPMC Capsule Moisture Content vs Relative Humidity y = e x R² = RH (%) 41

42 Moisture Sensitive Drugs EMPTY CAPSULES (3-8%) CAPSULES FILLING STORING CAPSULES AT LOW RELATIVE HUMIDITY PACKAGING AND BLISTERING 42

43 Moisture Sensitive Products TIP (Tobramycin in powder) 0.5 Ug/ml TIS (Tobramycin in solution) Source: Newhouse et al. Chest 2003 Time (h) cdpi delivers effective, evidence based dosage outcome

44 Amorphous Powders Some inhalation drugs are more effective in amorphous state Amorphous solids are unstable and can undergo crystallization HPMC capsules are a good solution to the problem 44

45 Amorphous Powders Braltus. Amorphous Tiotropium in HPMC capsules. 22 ug of Spiriva are therapeutically equivalent to 14 ug of Braltus 45

46 Reproducibility Formoterol delivered in different platforms Foradil cdpi Gelatin Formagal. cdpi HPMC DPI DPI MDI 46

47 Reproducibility: Formoterol in DPI cdpi (gel) cdpi (HPMC) DPI DPI MDI Source: Marketed Formoterol inhalation aerosols Wauthoz et al. RDD 2015

48 Cost Device costs are mainly originated by the number of high precision parts needed and the assembly costs Reservoir based and blister based DPI devices normally require more then 20 plastic and metal parts Capsule based systems are composed between 6-10 parts including needles It is easier filling a capsule than a blister or reservoir 48

49 Capsule based Blister based 49

50 Environmental MDIs use in the formulation propellants. The Montreal protocol ensured a planned phasing out of CFC. They were replaced by HFC. HFCs do not deplete the ozone layer but they are powerful greenhouse gases. They have a global warming effect of up to 3800 times that the carbon dioxide. DPIs does not use propellants and have a carbon footprint 18 times lower than MDI. 50

51 Products in the Market / Pipeline 51

52 cdpi Commerical Products Product Capsule Material Company Onbrez Gelatin Novartis Foradil Gelatin Novartis Seebri HPMC Novartis Ultibro HPMC Novartis Spiriva Gelatin-PEG Boehringer

53 DPI Products in Pipeline Drug product Substance Target Type Company Status Tobi-Podhaler Tobramycine P. Aeruginosa DPI Novartis Approved (USA only) Colobreathe Colistin P. Aeruginosa DPI Forest Approved (EU only) Ciprofloxacin Ciprofloxacin PAeruginosa DPI Bayer Phase 3 Aerovanc Vancomycin MRSA DPI Savara Phase 3 PUR 1900 Itraconazole Aspergillus DPI Pulmatrix Preclinic CIC/FF/TIO Unknown COPD DPI CIPLA Phase 3 Oxitocine Oxitocine Hormone DPI GSK Phase 2 Levodopa Levodopa Parkinson s DPI Civitas Phase 2 Unknown Unknown COPD DPI Novartis Phase 3 Unknown Unknown COPD DPI Zambon Phase 3

54 New Therapies in DPI Parkinson's disease Inhaled Levodopa for the treatment of Parkinson s disease ARCUS inhaler allows delivery of 10 mg of drug in a single inhalation Migraine Inhaled Sumatriptan (nasal delivery) is used in treatment of acute migraine

55 ACG s Holistic DPI Solution Ezeeflo Capsules Formulation expertise ACG s Holistic DPI Solution DPI capsule filling machine Packaging solutions

56 ACG Capsules : Global Footprint Global Head Office: India Manufacturing: Brazil*, Europe, India Subsidiaries: Argentina, Bangladesh, Brazil, Canada, China, Croatia, Indonesia, Thailand, UAE, UK, USA Co. Sales Manager: Colombia, Germany, France, Spain Warehouses: Argentina, Brazil, Europe, Indonesia, Thailand, USA *Manufacturing plant under construction

57 Evolution of ACG From a small beginning in 1961 in India, ACG Worldwide has established as a leading global player and continues to grow ACG-INSPECTION Visual Inspection Systems ACG-PHARMAPAC Packaging/ Barrier Films 2010 ACG-ACPL Empty Hard Capsules ACG-PAM Pharma Machines ACG-VALUE LINKS Hitech Machinery Agency ACG-PHARMATECH Process Equipment ACG-PAMPAC Packaging Machines 57

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59 Explore What Can We Achieve Together We believe that our responsibility does not end by supplying the capsules as per specifications, it begins there. With strive to add tangible value to our strategic key customers and create a win-win partnership with them

60 ACG - Values VALUES WE LIVE.. VALUES THAT MAKES US ACG.. Transparent Aesthetics Nurturing Safety Synergy Customer Centric Empowerment Dignity