Novel drug delivery system

Nanos-in-Micros

Janne Raula

The annual symposium of the Finnish Society of Physical Pharmacy

February 9th, 2012

Medicinal treatment

Indications-Neurosurgery-General surgery-Medicine-Opthalmology (eye)-Orthopaedics-Chambers-Ent (ear, nose and throat)-Plastic surgery-Skin

Administrations-Oral -Intra-venous (i.v.)-Intra-muscular (i.m.)-Pulmonary-Transdermal (through skin)-Mucosal (ocular, nasal, buccal, intestine, vaginal)

Drug delivery platforms-Tablets-Capsules-Implants-Solutions-Suspensions-Gels-Powders-Pastes-Sprays

Drug dosing-Immediate relese-Sustained release-Triggered / delayed release-Responsive release-Targeted (active / passive) release

Drug delivery systems-Micelles-Liposomes-Prodrugs-Nanoparticles-Complexes

Challenges for formulation and delivery

Problems frequently occuring with many drugs

-Poor solubility

-Insufficient in-vitro stability (shelf life)

-Too low bioavailability

-Too short in-vivo stability (half life)

-Regulatory issues / hurdles

-Lack of large scale production

-Strong side effects -> targeted delivery

Classification of drugs

Water-soluble drugs

-Most ’old’ drugs

Pros-Freely soluble-Low doses-Good bioavailability-Good absorption

Cons-Controlled release

Poorly soluble drugs

-Most ’new’ potent drug candidates, 70-90%

Pros-Improved medical treatment

Cons-Poorly soluble in water-Low absorption-Low bioavailablity-High doses-Toxicity

Poorly water-soluble drugsDownsizing drug particles

Dissolution

-Number of surface atoms increases

Improved solubility anddissolution

Ostwald-Freundlich

Sr = e SVm

rRT

Sr/S

Diameter (nm)

1

1E40

10010

Agglomeration

-Nanoparticles tend to minimize energy by agglomeration

Rabinow, Nature Reviews, 2004

Solubility

Crystalline nanosuspensionsMilling in aqueous solution-Downsizes large drug crystals to nano-sized crystals-Surface-active materials are needed for stable colloids

Rabinow, Nature Reviews, 2004

Surfactants-wet particle surface (hydrophilize)-increase energy barrier for agglomeration

Stable formulations are solids

Solid crystalline formulations are the most stable-against chemical degradation-against physical transformations-against bacteria growth

Lyophilization Spray-drying Tabletting

Necking-> agglomerates

Cohesive-> low flowability

Packing and sintering-> strongly agglomerated

Factors influencing powder properties

Particle shapeSurface textureSurface roughnessSize and size distributionSurface energyHygroscopicityRelative humidityElectrical propertiesParticle density

Minimizing contact area

Surface roughness

Minimize contact areaMaximize separation distance

Katainen et al. J. Colloid and Interface Sci. 2006

1.0E+00

1.0E+01

1.0E+02

1.0E+03

1.0E+04

1.0E+05

1.0E+06

1.0E+07

1.0E+08

1.0E+09

0.0001 0.001 0.01 0.1 1 10 100 1000 10000 100000

Adh

esio

n fo

rce

(nN

)

Asperity density (#/mm2)

Edge=1 micronEdge=10 micronEdge=30 micronEdge=100 micron

r

Followcontact points

2 µm 2 µm

L-leucine concentrationL-leucine concentration

Tem

pera

ture

Tunable surface morphologyCoating can applied onany solid material not depending on crystallinity and particle size

0

1

2

3

4

Commercial powder

Coated powder

Em

itte

d d

ose

(m

g) 22 l/min

55 l/min

0

10

20

30

40

50

Commercial powder

Coated powder

Fin

e P

art

icle

Fra

cti

on

(%)

L-leucine coated

salbutamol sulphate

Micronized salbutamol

sulphate

Fine

Par

ticle

Fra

ctio

n %

Emitt

ed d

ose

(mg/

dose

)

Aerolization performanceCarrier-free inhalation experiments

High emitted doseHigh deep lung deposition

The rough L-leucine coating offer Independent on inhalationLow dose variation

Inhalation flow rate22 l/min55 l/min

L-leucine coated

salbutamol sulphate

Micronized salbutamol

sulphate

Concept of Nanos-in-Micros

Collaboration with University of Helsinki (Pharm. Tech.) and University of Eastern Finland (Pharm. Tech.)

Pharm. Res. 2011 Intact Nanoparticulate Indomethacin in Fast Dissolving Carrier Particles by Combined Wet Milling and Aerosol Flow Reactor MethodsLaaksonen T., Liu P., Rahikkala A., Peltonen L., Kauppinen E.I., Hirvonen J., Järvinen K., Raula J.

Powder processing Drug release and dissolution

Nanosuspension of poorly soluble drug

Nanostructured carrier particle

Mannitol binder

L-leucine coatingStabilizer

Drug material with

low water solubility

Wet milling

Mannitol and L-leucine dissolve quickly in water

Fast drud dissolution from the individual NPs

DissolutionAerosol flow reactor

1) 2)

Published work

Originalnanosuspension

Aerosol processednanosuspension at 100 °C

Aerosol processednanosuspension at 160 °C

Particle structure of Nanos-in-Micros

AFR 100-3 AFR 160-3

IND 14 w%; F68 3 w%; MAN 55 w%; LEU 28 w%

Dg 820 nm Dg 580 nm

Crystallinity and re-suspension of Nanos-in-Micros

Drug nanoparticles remained crystalline and as nano-sized

Nanocrystals from AFR 100-3 re-suspended fromNanos-in-Micros

<<

Drug dissolution of Nanos-in-Micros-Dissolution of indomethacin was highly improved by nanocrystal domains-Nanos-in-Micros offered stable delivery platform

Particle assembly in drug combination Nanos-in-Micros

Budesonide nanocrystalsF68: 1.5 w%

Phos: 0.7 w%

SurfactantF68 0.8 w%

Phos 0.4 w%

Salbutamol sulphateF68: 2.8 w%

Phos: 2.7 w%

MannitolF68: 63 w%

Phos: 64 w%

L-leucine encapsulation

L-leucine coating

F68: 32 w%Phos: 32 w%

Morphology of the combinationNanos-in-Micros particles

Surfactant: Pluronic® F68 Surfactant: Phospholipids

1 µm 1 µm

Carrier-free inhalation experiements ofthe combination N-in-M powders

0

1

2

3

4

5

6

7

8

9

10

N-in-M Phospholipids

N-in-M Pluronic F68

Micronized salbutamol

sulphate

Spherolac carrier lactose

Emitt

ed d

ose

(mg/

dose

)

0

10

20

30

40

50

60

N-in-M Phospholipids

N-in-M Pluronic F68

Micronized salbutamol

sulphate

Spherolac carrier lactose

Fine

Par

ticle

Fra

ctio

n (%

)

n.d.

Inhaler Easyhaler®; fast inhalation; flow rate 55 l/min; 10 inhalations

1 µm1 µm 1 µm 200 µm

N-in-M Phospholipids N-in-M Pluronic F68 Micr. salbutamol sulph. Spherolac 100

Dissolution of the drugs from N-in-MBoth the drugs dissolve quickly within 20 min => fast dissolution

Budesonide Salbutamol sulphate

0 20 40 60 80 100 120 140 160 180 2000

20

40

60

80

100

Rele

ase

of b

udes

onid

e (%

)

Time (min)

0 5 10 15 20

0

20

40

60

80

100

0 20 40 60 80 100 120 140 160 180 2000

20

40

60

80

100

Rele

ase

of sa

lbut

amol

sulp

hate

(%)

Time (min)

0 5 10 15 20

0

20

40

60

80

100

Concluding remarks

The coated Nanos-in-Micros particle assemblies offer

- stable solid formulations of nanocrystals of poorly soluble drugs

- readily redispersible powder formulations

- notably improved dissolution of poorly soluble drugs=> enhanced bioavailability ?

- combination drug formulations(two or more)

- potential future particle formulationsfor peroral and pulmonary drug deliverysystems

Acknowledgements

Division of Pharmaceutical Technology, Faculty of Pharmacy, University of HelsinkiFaculty Dean Prof. Jouni HirvonenD.Sc. Timo LaaksonenD.Sc. Leena PeltonenM.Sc. Peng LiuM.Sc. st. Jenni Pessi

School of Pharmacy, Faculty of Health Sciences, University of Eastern FinlandProf. Kristiina Järvinen

Department of Applied Physics, Aalto University School of ScienceProf. Esko I. KauppinenM.Sc. Antti RahikkalaM.Sc. st. Tuomas Halkola