Printing technologies in fabrication of drug-

delivery systems

Niklas SandlerPharmaceutical Sciences Laboratory

Åbo Akademi University, Turku, Finland

ÅBO AKADEMI

UNIVERSITY

CONTENT

1. Perspectives of printing technologies in • personalization of products &individualized dosing, • fabrication of delivery-systems & medical devices

2. Case studies:• Accurate dosing of drug substances • 3D printing of medical devices • Quality control of printed systems

3. Conclusions and perspectives

Why printing in manufacturing?

Customisation - printing processes allow mass customisation

Flexibility and on-demand - products are produced where they are

needed

Allowing complexity - digital design > new levels of complexity

Sustainable / Environmentally Friendly - energy/raw material efficient

technology

1

2

3

4

http://3dprinting.com/wp-

content/uploads/2013/10/3d-

printing.jpeg

3D printing is changing the way we manufacture things

http://3dprinting.com/wp-

content/uploads/2013/10/3d-printing.jpeg

http://3dprint.com/wp-

content/uploads/2014/12/3d2.jpg

http://static4.businessinsider.com/image/52ceb68469beddfe0f1c32cc/resear

chers-are-making-a-3d-printer-that-can-build-a-house-in-24-hours.jpg

http://hansencojewelry.com/create/pres

pective-new.jpg

http://images.boomsbeat.com/data/images/full/1747

30/kinematics-dress-jpg.jpg

Shift in manufacturing strategies of the future to meet the need of more individualized medicines

(Source: Rebecca Vangenechten, SIEMENS: MIT perspective to Pharma manufacturing, 2011)

NEED FOR PERSONALIZED DOSINGBecause no two patients are alike

1. Age appropriate

formulations

• Pediatric and

elderly patients

2. Gender differences

3. Life style differences

4. Metabolic capacity

• Ethnic differences

• Diseases compromising

metabolic activity

Personalised solutions using printing technologies

Individualiseddosing

Multidrug systems

Medical devices

3D2D

Schematic picture of the 3D printing process (Billiet et al. 2012).

Medical 3D printing prospects

Many printing technologies exist

Technologies

Piezoelectric inkjet printing Thermal inkjet printing

Flexographic printing

3D printing/ additive

manufacturing

Comparison of printing technologies

Ref: Roth and Rau

Why inkjet printing?

Drop-on-demand (DoD) technology:

y = 7.8936x -

2.7919

R² = 0.9996

0

100

200

300

0 20

Dru

g …

Number of passes …

Uniformly spaced and sized droplets

Accuarate deposition

Drops of ink are only ejected when required

Precision patterns of the ink

Flexible dosing

INKJET PRINTINGInkjet dispensing technology has started to be a widely applied methodology inmany fields incl. drug discovery (miniaturised assays, drug screening etc.)

Inkjet and other printing technologies have recently emerged as possibility in theproduction of dosage forms and delivery systems

Great potential for low dose treatments with a narrow therapeutic window due tothe accurate deposition capabilities

On-demand individualized dosing and tailored manufacture of medicines

INKJET PRINTING OF DRUG-DELIVERY SYSTEMS

Ink formulation

Drug substance

Solvent

+

Viscosity modifier

Ink formulation

Substrate

The ink is printed on e.g.edible films (sugar, cellulose,starch), a buccal deliverysystem, implant etc.

Drug-

delivery

systems

Printing

Sandler et al. 2011

Janßen et al. 2013Digital design

Pattern, geometry,drop spacing, layeringetc.

Genina et al. 2012

Inkjet-printing (Dimatix DMP-2800)

Dimatix DMP-2800 piezoelectric inkjet

16 nozzles (d~23 µm, V~10 pl)

Piezo inkjet cartridges Pattern editor Cartridge has 16 nozzles linearly spaced Drop sizes of 1 and 10 picoliter (1 picoliter

= 1 x 10-9 milliliter) Ink requirements: viscosity 1-40 mPa,

surface tension 25-50 mN/m

Inkjet-printing (PixDro LP50)

CONFIDENTIAL

Q130614 Quote ADA Software Lease 6/14

1.2 Flexible tool that grows with your ambitions

During the many years we are active in functional printing we encountered many different

applications. Therefore we understand that a research tool must be flexible and expandable. First of

all the LP50 accommodates a range of print heads serving a wide variety of processes. Whether you

are working with nano material inks, aqueous solutions, acidic inks, UV-curing materials, large

droplets, small droplets, we will be able to advise you in the selection of the best print head. Currently

the LP50 accommodates heads from Spectra, Konica Minolta, Trident and Xaar.

Because of the modular setup, the LP50 is easily expandable. When you expand your field of

research to new materials or applications, you can simply upgrade the system with other print heads.

Also when you are scaling up your process to an industrial level, we will be able to grow with you. Our

production platform IP410 uses the same core technology as the LP50, so you can transfer your

processes to the production tool on a one-to-one basis.

1.3 Focus on your experiments, not on your tool

We want you to concentrate on your experiments and your application, not on the tool. Therefore we

have put a lot of effort in making the LP50 easy to use. First of all we made it easy to install with e.g.

single phase power supply, included PC and its small footprint. Secondly we designed an intuitive

user interface taking you through all relevant settings of the print head and print recipe. Because we

place print heads each in a standard mechanical interface, it is extremely fast to swap between print

heads. All it needs is replacing the print head adapter and reconnecting its electrical connections and

ink supply. The procedure takes under 3 minutes as recalibration is not needed.

Furthermore, the LP50 comprises several maintenance tools to keep your print heads in optimal

shape. You can purge and wipe the head or cap it under vacuum conditions. Optionally we can offer a

Spectra Konica Minolta Trident XAAR

• Overall system pattern resolution

5μm

• Print Head Assemblies for

numerous types of industrial print

heads

• Integrated vision system for drop

view, print view and accurate

alignment, including analysis and

calibration software

Inkjet specifications

Viscosity range 1 - 10 Centipoise

Nozzle range 1 - 1,000 nozzles

4 -200 picoliter drop volume range

Inkjet-printing with the LP50 (Roth&Rau)

Inkjet printing process optimisation and quality control

Optimising drop formation

DRUG FORMULATION SUBSTRATE

Water soluble?

Soluble in oils?

Not soluble enough in any of the above?

Water-based / cosolvents

Emulsions

Nanosuspensions with suspension stabilizing agent

Viscosity modifiers + Moisturizer +surfactants

ANALYSIS PRINTING

Porous Non-porous

Flexography PIJ

AFM/SEM

Optical microscopy

Spectroscopy/XRD

LC-MS/TOF-SIMS

Mechanical strength

Formulation should not dissolve/disintegrate substrate

AddedfunctionalityFilm/coating

Uniformity/

dose accuracy

Yes

NoYes

Selected based

on printing method

Critical

for

Edible Non-edible

Physical

Chiral Distinctelement

SONICC SEM-EDX

No

Chemical

NoYes

NoYes Yes

TIJ

Soluble in organicsolvents?

NoYes

Org. solvent based /

Cosolvents

HPLC

SONICC-second order nonlinear optical imaging

Preliminary Roadmap for development of Printable Dosage Forms

PIJ-piezoelectric inkjet,

TIJ-thermal inkjetSEM-scanning electron microscopy, EDX-energy dispersive X-ray spectroscopy AFM-atomic force microscopy

D. Raijada et. al., J Pharm Sci, 2013

Inkjet-printing example – microparticle fabrication

Schematic representation of the

basic concept of the combining

of inkjet and flexographic

printing techniques for

fabrication of drug-delivery

systems

Each flexographic

deposition cycle

applies approx. a 100

nm layer of

ethylcellulose

Tailoring

drug release

properties

Printability –substrate properties

Microscopic and digital

camera images of

riboflavin sodium

phosphate printed on

the different substrate:

a) Substrate A, matt

side; b) Substrate A,

glossy side; c) Substrate

B; d) Substrate C. Top

row: cross-section

images; middle row: top

view images; bottom

row – digital camera

images of printed areas.

The quality of a printed pattern of API onto a porous substrates

depend on the characteristics of the substrates; particularly its

wettability, surface roughness and homogeneity of substrate

surface

Example: Flexible dosing of loperamide and caffeine

Dimatix DMP-2800 piezoelectric inkjet

16 nozzles(d~23 µm, V~10 pl)

Two model APIs – caffeine and loperamide hydrochloride

Ink base – propylene glycol/water (caffeine) and

propylene glycol/ethanol (loperamide)

Substrates – commercial sugar icing sheets, HPC films, PET films

Droplet spacing – from 10 µm (highest dose) to 50 µm (lowest dose)

Surface area of a single dose 4 cm2

Example 3

RESULTS Content analysis

Accurate dosing

Very small standard deviations – important for dosing of potent APIs

Example 3

EDIBLE INKS AND RICE & SUGAR-BASED SUBSTRATES: Accurate dosing of propranolol

Printing of the proranolol formulation

Drug release Drug content

QC by colorimetry

Quality control: Data visualisation using principal component analysis (PCA)

Flexible dosing of a theophylline formulation

Contour plot of the spectral data from the image

Score plotto cluster data with similar spectral features

Loadings plotto indicate which spectral regionsare contributing to the variability in the data

NIR spectra from the region of interest

Vakili et. al., Int J Pharm. 2015 10;483(1-2):244-9

Building a quantitative PLS model to for drug substance content measurement –Flexible dosing of a theophylline formulation

Accurate dose escalation of 7.8 micrograms of

theophylline per printing pass (per square)

y = 7.8936x - 2.7919

R² = 0.9996

0

50

100

150

200

250

300

0 10 20 30

Dru

g d

eposi

tion (

µg c

mˉ²

)

Number of passes under the print head

0

20

40

60

80

100

0 20 40 60 80 100P

redic

ted A

PI

con

ten

t %

Real API content %

Y= 1,0211x -

Vakili et. al., Int J Pharm. 2015 10;483(1-2):244-9

Exploring 3D printing for contraceptive devices

Intra uterine system, IUS Intra vaginal ring, IVR Implant, rod, cylinder

http://unhysterectomy.com/wp-content/uploads/2013/05/Mirenasmall.jpg,http://i.bnet.com/blogs/nuvaring2.jpg,http://www.fisterra.com/salud/1infoConse/images/ah7.jpg

Extrusion/Injection

molding

PDMS

Mirena, Bayer

Extrusion/Injection

molding

EVA

Nuvaring, Merck

Extrusion/Injection

molding

EVA, PDMS

Jadelle, Bayer

Implanon, Merck

Example: 3D Printing of Medical Devices (IUS)

Digital Design 3D printing 3D printed devices

Flexiblity of design and manufacture – future opportunities:

- Tailored devices based on the patient’s need > size and shape

- Tailored functionality > controlled drug release properties > tailor-made

treatments and devices

Study perfomed in

Collaboration between

Published in:Holländer et al. Eur. J .Pharm, Sci 2015

3D printing of drug-loaded EVA 5 filaments:

• Hot-melt extrusion:

• 0%, 5% &15% drug-loading

• Extrusion at 105-110 °C

• 3D printing at 165 °C0%

5%

15%

In vitro release studies (30 days)

Printer

Printer

Printer

Individual

dose

Base film

Patient A

Patient B

Patient C

Print on demand Patient

supply

Preis M, Breitkreutz J, Sandler N. Perspective: Concepts of printing technologies for oral film

formulations. International Journal of Pharmaceutics. 2015.

Perspectives: On-demand manufacture

Printing concepts: Complete surface Central Point by point Lines

symmetric

asymmetric

Fixed dose

combinations

Anti-counterfeiting

and identification

Serialization Barcode Identification

Preis M, Breitkreutz J, Sandler N. Perspective: Concepts of printing technologies for oral film

formulations. International Journal of Pharmaceutics. 2015.

Perspectives: Dose flexibility

Hospital Pharmacy

Patient A Patient B Patient C

Patient A Patient B Patient C

Individual patient supplyDiagnosis, Treatment & Therapy plan

Preparation & Printing of individual dosage forms and doses

Drug-loaded

filaments

3D

Printer

Printer

(e.g, Inkjet)Edible substrate

Hospital

Continuous manufacturing line-would allow fabrication of tailored dosage forms in an industrial setting

Printing line for large scale manfucature

Ovens

Spray Coating

Reverse Gravure

Flexography

Inkjet

Infrared

Infrared

Alignment Camera

Unwinder Rewinder

The FunMat (Functional Materials) printer at Åbo Akademi Univeristy which is used as a lab-scale

modular prototype printer that can be operated in a continuous manner and can use sequentially up to six

different printing units (gravure, flexo, coating, ink-jet, lamination).

Future challenges

• Technological development of printers and production lines

• Development of printable formulations and carrier substrates

• Quality control and characterization

• Regulatory aspects regarding bringing manufacturing closer to the patient/the pharmacies

• Regulatory perspectives regarding flexible dosing/fabrication and manufacture of patient adapted dosage forms

40

Conclusions

Closer to

the patient

Lean production based

on demand

Faster

availability

Personalised

therapies

Modular and

mobile

manufacturing

Safety maximisation through

better quality control

Acknowledgements

Maren PreisMirja PaloJohan NymanHenrika WickströmHeidi ÖblomEmrah YildirHossein VakiliJenny HolländerPaul VuorelaRuzica KolakovicPetri Ihalainen Anni MäättänenJouko Peltonen

Natalja GeninaDhara RaijdaJukka RantanenJorrit WaterJohan Boetker

Harri JukarainenPirjo Kortesuo

+ many others

Prof Joerg BreitkreutzEva Janssen

Mathieu MarmionHarri Karjalainen