Novel drug delivery system. Nanos-in-Micros

Transcription

1 Novel drug delivery system Nanos-in-Micros Janne Raula The annual symposium of the Finnish Society of Physical Pharmacy February 9 th, 2012

2 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 dosing -Immediate relese -Sustained release -Triggered / delayed release -Responsive release -Targeted (active / passive) release Drug delivery platforms -Tablets -Capsules -Implants -Solutions -Suspensions -Gels -Powders -Pastes -Sprays Drug delivery systems -Micelles -Liposomes -Prodrugs -Nanoparticles -Complexes

3 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

4 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

5 Poorly water-soluble drugs Downsizing drug particles Dissolution -Number of surface atoms increases Agglomeration -Nanoparticles tend to minimize energy by agglomeration Improved solubility and dissolution Ostwald-Freundlich 1E40 Solubility S r /S 1 V m rrt S r = e S Diameter (nm) Rabinow, Nature Reviews, 2004

6 Crystalline nanosuspensions Milling in aqueous solution -Downsizes large drug crystals to nano-sized crystals -Surface-active materials are needed for stable colloids Surfactants -wet particle surface (hydrophilize) -increase energy barrier for agglomeration Rabinow, Nature Reviews, 2004

7 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

8 Factors influencing powder properties Particle shape Surface texture Surface roughness Size and size distribution Surface energy Hygroscopicity Relative humidity Electrical properties Particle density Minimizing contact area

9 Surface roughness Follow contact points Minimize contact area Maximize separation distance 1.0E E E+07 r Edge=1 micron Edge=10 micron Edge=30 micron Edge=100 micron Adhesion force (nn) 1.0E E E E E E E Asperity density (#/mm2) Katainen et al. J. Colloid and Interface Sci. 2006

10 Tunable surface morphology Coating can applied on any solid material not depending on crystallinity and particle size L-leucine concentration L-leucine concentration Temperature 2 µm 2 µm

11 Aerolization performance Carrier-free inhalation experiments The rough L-leucine coating offer High emitted dose High deep lung deposition Independent on inhalation Low dose variation 4 50 Emitted Emitted dose (mg/dose) (mg) Inhalation flow rate 22 l/min 22 l/min 55 l/min 55 l/min Commercial Micronized salbutamol powder sulphate Coated L-leucine powder coated salbutamol sulphate Fine Particle Fraction % Fine Particle Fraction (%) Commercial Micronized salbutamol powder sulphate Coated L-leucine powder coated salbutamol sulphate

12 Concept of Nanos-in-Micros Collaboration with University of Helsinki (Pharm. Tech.) and University of Eastern Finland (Pharm. Tech.) Powder processing Drug release and dissolution Drug material with low water solubility Nanosuspension of poorly soluble drug 1) Wet 2) milling Aerosol flow reactor Nanostructured carrier particle Dissolution Mannitol and L-leucine dissolve quickly in water Stabilizer L-leucine coating Mannitol binder Fast drud dissolution from the individual NPs Published work Pharm. Res Intact Nanoparticulate Indomethacin in Fast Dissolving Carrier Particles by Combined Wet Milling and Aerosol Flow Reactor Methods Laaksonen T., Liu P., Rahikkala A., Peltonen L., Kauppinen E.I., Hirvonen J., Järvinen K., Raula J.

13 Particle structure of Nanos-in-Micros IND 14 w%; F68 3 w%; MAN 55 w%; LEU 28 w% Original nanosuspension Aerosol processed nanosuspension at 100 C Aerosol processed nanosuspension at 160 C Dg 820 nm AFR Dg 580 nm AFR 160-3

14 Crystallinity and re-suspension of Nanos-in-Micros Drug nanoparticles remained crystalline and as nano-sized Nanocrystals from AFR re-suspended from Nanos-in-Micros <

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

16 Particle assembly in drug combination Nanos-in-Micros Budesonide nanocrystals F68: 1.5 w% Phos: 0.7 w% Surfactant F w% Phos 0.4 w% Mannitol F68: 63 w% Phos: 64 w% L-leucine encapsulation F68: 32 w% Phos: 32 w% Salbutamol sulphate F68: 2.8 w% Phos: 2.7 w% L-leucine coating

17 Morphology of the combination Nanos-in-Micros particles Surfactant: Pluronic F68 Surfactant: Phospholipids 1 µm 1 µm

18 Carrier-free inhalation experiements of the combination N-in-M powders Inhaler Easyhaler ; fast inhalation; flow rate 55 l/min; 10 inhalations Emitted dose (mg/dose) N-in-M N-in-M Phospholipids Pluronic F68 Micronized salbutamol sulphate Spherolac carrier lactose Fine Particle Fraction (%) N-in-M N-in-M Phospholipids Pluronic F68 Micronized salbutamol sulphate n.d. Spherolac carrier lactose N-in-M Phospholipids N-in-M Pluronic F68 Micr. salbutamol sulph. Spherolac µm 1 µm 1 µm 200 µm

19 Dissolution of the drugs from N-in-M Both the drugs dissolve quickly within 20 min => fast dissolution Budesonide Salbutamol sulphate Release of budesonide (%) Release of salbutamol sulphate (%) Time (min) Time (min)

20 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 formulations for peroral and pulmonary drug delivery systems

21 Acknowledgements Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki Faculty Dean Prof. Jouni Hirvonen D.Sc. Timo Laaksonen D.Sc. Leena Peltonen M.Sc. Peng Liu M.Sc. st. Jenni Pessi School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland Prof. Kristiina Järvinen Department of Applied Physics, Aalto University School of Science Prof. Esko I. Kauppinen M.Sc. Antti Rahikkala M.Sc. st. Tuomas Halkola