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Our Vision, Mission and Values

Comprehensive Solution for cDPI:

Opportunities, Trends & Possibilities

Webinar 9th November 2017

Content

• Introduction

• Inhalation Technology

• Capsules Based Inhalers

• Types of Capsules

• Advantages - Case Studies

• Products in the Market / Pipeline

• ACG Holistic solution

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Greek physicians inhalation of volcanic Sulphur vapours

Bennet. First published

Inhaler illustration Chloroform

A. Newton. First DPI patentKaplin. Adrenalin inhaled

R. Altounyan. Spinhaler

D. Jack. Rotahaler/Salbutamol

Spiriva Handihaler approval

Ultibro Breezhaler approvalInhalation milestones

400BC

1654

1846

1864

1911

1963

1969

2004

2016

Research Literature:

Capsules in DPI

• Analysis of papers reporting test results from 1971-2013

Year Number of Papers

1971-1980 6

1981-1990 12

1991-2000 45

2001-2005 47

2006-2010 87

2011-2013 95

Inhalation Technology

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Lung structure

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Alveolar region

• Surface: 140 m2

• Number: 500 millions

• Volume air: 2-6 l.

• Volume blood = 100-200ml

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Comparison of Dosage Forms

Available to Treat Respiratory Diseases

Attribute Oral delivery Inhaled delivery

Total dose ≥ 400 mg daily ≤ 40 mg daily

Lung to plasma

exposure ratioLow High

Bioavailability 55 % (in Itraconazole)≥ 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

Advantages

Simple

Easy-to-use

Better patient

outcome

Pulmonary route provides consistent drug delivery with high lung deposition

Source: Sermet-Gaudelus et al, Antimicrobial agents Chemotherapy (2001),

Cold Spring Harb Perspect Med (2015)

Inhalation: The Golden Rule

• Particle size does matter. Only particles in

the 1-5 micron range are active

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Particle density

Particle shape

Geometric diameter

Aerodynamic diameter

Why Particle Size is Important?

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From Fischler et al . Particle dynamics (2015)

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

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Dry Powder Inhalation (DPI)

▪ Transforms liquid medication into aerosol

▪ Requires coordination between the actuation of device and inhalation

Nebulizers

MDI

▪ Formulated in solution or suspension using a liquid propellant

▪ Requires coordination between the actuation of device and inhalation

cDPI is an optimal solution for drug delivery because of recent particle engineering

▪ Drug is inhaled by inspiratory mechanism

▪ The powder formulation does not require use of propellant

Blister based

Dry Powder Inhaler

Reservoir based

Dry Powder Inhaler

Capsule based

Dry Powder Inhaler

Types of DPIs

DPI Formulation Design

Use of Excipients in Pulmonary Drug Delivery

EXCIPIENTS DESCRIPTION COMMENTS

Sugars: Lactose,

Mannitol, Glucose

Coarse fine carrier Approved and

commonly used

Hydrophobic additives:

Mg stearate

Protection for drug

moisture

Approved

Amino acids: Leucine,

Trileucine

Improved aerosol

efficiency

Endogenous substance

but no data on lung

toxicity

Surfactants: Poloxamer.

Bile salts

Production of light and

porous particles

Accepted at low dose

Biodegradable

polymers:

PLGA

Used in sustained

release formulation

Immunogenicity effect

observed

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From Seebri Neohaler guide

Capsule Based Inhalers

Mechanism of Action

• Puncturing: opening of capsule.

• Aerosolization: after inspiration, drug is

released to the lung.

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POSITIONS OF OPENINGS

Source “Powder Capsule and Device”. Aurelie Schouben et al. IJP 2015

Capsule Puncturing (1/2)

Capsule Puncturing (2/2)

0

0.5

1

1.5

2

2.5

3

3.5

0 0.5 1 1.5 2 2.5 3 3.5

Fo

rce

(N)

Deformation (mm)

Force / Deformation for Hard Capsules

(1) (2)

(3)

Torrisi et al. IJP 2013

Source “Pierce and Inhale”. F. Martinelli et al

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

Computational Fluid Dynamics

Source “Use of computational modelling” Zhou et al

Agglomerates Dispersed by Drag Force

Redrawn from Kou et al. Powder dispersion mechanism. IJP (2016)

CAPSULE TYPES

Gelatin

GelatinPEG

HPMC

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GELATIN GELATIN-PEG HPMC

ORIGIN ANIMAL ANIMAL VEGETABLE

STRUCTURE PROTEIN PROTEIN CELLULOSE

MOISTURE

CONTENT (%)

13 - 16 10 - 12 3 - 8

BRITTLENESS AT

LOW RH

Yes Medium Very low

CROSSLINKING Yes Yes No

Ezeeflo™ Capsule Properties

Puncturing

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From Birchall et al. Drug delivery Pharm 2009

Puncturing: 40 Total with 1 Cyclohaler

30

0

20

40

60

80

100

Gelatin A ACG Gelatin ACG HPMC

% G

OO

D C

AP

SU

LE

S

TYPE OF CAPSULE

% GOOD CAPSULES @ 75% RH / 20ºC

From J. Kalafat et al. Inhalation delivery Using DOE to optimize puncturing AAPS 2017

Puncturing: 40 Total with 2 Cyclohalers (20+20)

0

20

40

60

80

100

Gelatin A ACG Gelatin ACG HPMC

% G

OO

D C

AP

SU

LE

S

TYPE OF CAPSULE

% GOOD CAPSULES @ 75% RH / 25ºC

From J. Kalafat et al. Inhalation delivery. Using DOE to optimize puncturing. AAPS 2017

Aerosolization

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Lactose +salbutamol

Gelatin

HPMC

60L/m 4s

From Saleem et al. “Comparison of two different types of inhalation capsules AAPS 2012

Aerosolization

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From Saleem et al. “Comparison of two different types of inhalation capsules AAPS 2012

Capillary Condensation

Case Studies: Advantages

• High drug doses products

• Moisture sensitive products

• Amorphous powders

• Reproducibility

• Cost

• Environmental

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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 100-200 ug by inhalation

• Diseases as cystic fibrosis and lung infections require high

drug concentrations in lung.

• High intravenous doses may carry systemic toxicity

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From Labiris & Dolovich: Pulmonary Drug Delivery. Part I. Physiological factors affecting therapeutic effectiveness of aerosolized medications

High Dose Drugs

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1 mg 10 mg 100 mg 1000 mg

MDI DPI cDPI Nebulizer

Lung Dosage

High Dose Drugs

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Colobreath Turbospin. Lung infections. Forest Laboratories. Gelatin capsule 125mg

High Dose Drugs

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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

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Correlation RH / HPMC Capsule Moisture Content

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y = 0.7832e0.0367x

R² = 0.974

0

2

4

6

8

10

12

14

16

0 10 20 30 40 50 60 70 80 90

Ca

psu

le m

ois

ture

co

nte

nt(%

)

RH (%)

HPMC Capsule Moisture Content vs Relative Humidity

Moisture Sensitive Drugs

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EMPTY CAPSULES

(3 - 8%)

CAPSULES FILLING

STORING CAPSULES AT

LOW RELATIVE HUMIDITY

PACKAGING AND

BLISTERING

Moisture Sensitive Products

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 2 4 6 8 16

TIP (Tobramycin in powder)

TIS (Tobramycin in solution)

10 12 14Source: Newhouse et al. Chest 2003

cDPI delivers effective, evidence based dosage outcome

Time (h)

Ug/ml

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

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Amorphous Powders

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Braltus. Amorphous Tiotropium in HPMC

capsules. 22 ug of Spiriva are

therapeutically equivalent to 14 ug of

Braltus

Reproducibility

• Formoterol delivered in different platforms

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Foradil cDPI Gelatin Formagal. cDPI HPMC DPI DPI MDI

Reproducibility: Formoterol in DPI

Source: “Marketed Formoterol inhalation aerosols” Wauthoz et al. RDD 2015

cDPI (gel) cDPI (HPMC) DPI DPI MDI

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

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Capsule based Blister based

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.

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Products in the Market / Pipeline

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cDPI – Commerical Products

Product Capsule Material Company

Onbrez Gelatin Novartis

Foradil Gelatin Novartis

Seebri HPMC Novartis

Ultibro HPMC Novartis

Spiriva Gelatin-PEG Boehringer

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

DPI Products in Pipeline

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

Ezeeflo™

Capsules

ACG’s Holistic DPI

Solution

DPI capsule

filling machine

Formulation

expertise

Packaging

solutions

ACG’s Holistic DPI Solution

ACG Capsules : Global Footprint

Subsidiaries: Argentina, Bangladesh,

Brazil, Canada, China, Croatia,

Indonesia, Thailand, UAE, UK, USA

Manufacturing: Brazil*, Europe, India

Global Head Office: India

Warehouses: Argentina, Brazil, Europe,

Indonesia, Thailand, USA

*Manufacturing plant under construction

Co. Sales Manager: Colombia,

Germany, France, Spain

Evolution of ACG

From a small beginning in 1961 in India, ACG Worldwide has established as a leading global player and continues to grow

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19611972

1987

1993

1996

2009

2010

ACG-ACPLEmpty Hard Capsules

ACG-PAMPharma Machines

ACG-PAMPACPackaging Machines

ACG-PHARMAPACPackaging/ Barrier Films

ACG-PHARMATECHProcess Equipment

ACG-INSPECTIONVisual Inspection Systems

ACG-VALUE LINKSHitech Machinery

Agency

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

ACG - Values

VALUES WE LIVE.. VALUES THAT MAKES US ACG..

Transparent Aesthetics Nurturing Safety

Synergy Customer Centric Empowerment Dignity