Novel drug delivery system Nanos-in-Micros novel particle concept for... · Novel drug delivery...
Transcript of Novel drug delivery system Nanos-in-Micros novel particle concept for... · Novel drug delivery...
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