Innovation in formulations to improve aerosol delivery

Transcription

1 Innovation in formulations to improve aerosol delivery Peter York Chief Scientist, CrystecPharma DDL Conference Edinburgh, 7-9 th December 2016

2 Triumvirate in design of inhalation medicines Nebulisers, MDI, DPI Device (simple, complex, single dose, reservoir) Patient Regulatory specification Formulation (human factors, age, compliance) (solution, suspension, powder)

3 Route to innovation Innovation = Product Testing/evaluation Idea Thought (Innovate = to create, to introduce especially a product - Oxford English Dictionary)

4 Outline of presentation Current formulation designs and constraints what improvements are needed? Some rule based approaches to improving formulations Examples of recent innovations in drug particle design to improve drug aerosol delivery What next?

5 Key features of the different types of formulations Solutions (nebulisers, MDIs) Aqueous or propellant* solutions, drug/excipient solution stability, liquid aerosol droplet generation and size/size distribution Suspensions (MDIs, nebulisers) Drug particles size/size distribution, sedimentation characteristics, suspension aerosol droplet generation and size/size distribution Powders (DPIs) Generally a drug/carrier powder blend, drug particle size/size distribution, carrier excipient, drug/excipient particle interaction (*Replacement of CFC with HFA propellants)

6 Marketed branded products UK and USA (2015) Nebulisers (21 solutions; 1 suspension) Drug, buffers, tonicity agents, preservative, ST modifier, complexing agent, ph adjusters 16 small molecules, 5 biologic drugs MDIs (11 suspensions; 8 solutions) Drug, HFA, oleic acid, PVP, PEG, HCl, glycerol, citric acid DPIs 26 drug:lactose, 8 drug:lactose:mg stearate: 3 drug alone (2 insulin products)

7 Small droplets/particles big challenges Diagram of aerosol particle size effect on location of preferential deposition in airways Drug deposition from different inhaler devices Gardentire et al., A guide to aerosol delivery devices, Amer Association Resp Care, 2013

8 Current challenges and areas for improving formulations? 20 30% of labelled dose delivered to lungs room for improvement for high dose products and systemic drug delivery? Reduction intra- and inter-patient product performance; patient and inhalation performance flow rate independent Limited number of regulatory approved excipients for drug products for delivery to the lungs Challenges of end of shelf life physicochemical stability and product aerosol performance Carrier free formulations drug particle design Composite particles (two drug combination products)

9 Outline of presentation Current formulation designs and constraints what improvements are needed? Some rule based approaches to improving formulations Examples of recent innovations in drug particle design to improve drug aerosol delivery What next?

10 Powder (DPI) formulations Micronisation (air jet high energy milling) widely used to prepare 1 5 micron sized drug particles Non-ideal process - particles generated often cohesive with high surface charge, and processing creates hygroscopic amorphous domains Periods of equilibration, stabilisation of micronized powders may be required prior to formulation operations (blending with excipient(s) and filling into packaging / device Blending with larger sized carrier (lactose widely used) required for drug particles to adhere to carrier surfaces and form free-flowing powder Content uniformity and non-segregation of blends critically important

11 Drug-carrier blends the mix-demix dilemma Stable uniform blend required for DPI fill and over storage Demix required on operation by patient to detach drug particles Telko & Hickey, Resp Care 50 (2005) 2019

12 Cohesive-adhesive balance (CAB) - guidance on blend properties AFM measurements of adhesive and cohesive forces between API-carrier and API-API respectively CAB graph for theoretical binary system Bisecting line represents equilibrium between adhesive and cohesive forces Defines 2 regions with dominancy of cohesive or adhesive forces Provides predictive tool with regard to blend homogeneity, tendency to segregate and aerosolisation characteristics Begat et al, Pharm Res 2004, 21, 1591

13 Couple in-silico analyses with in vitro (and in vivo ) studies Molecular modelling IV/IV correlation, BCS system for inhalation medicines Computational fluid dynamics Finite and discrete element analysis Artificial intelligence knowledge engineering

14 Outline of presentation Current formulation designs and constraints what improvements are needed? Some rule based approaches to improving formulations Examples of recent innovations in drug particle design to improve drug aerosol delivery What next?

15 Particle design for formulations and products? Concepts of particle design The process of devising a system, component, process (or particle) to meet desired needs, is a decision-making process (often iterative), in which the basic science, mathematics and engineering sciences are applied to convert resources optimally to meet a stated objective Objective: Target product profile (TPP) Target formulation profile (TFP)

16 Strategy of drug particle design for respiratory medicines Prepare tailored drug particles with selected physicochemical, solid state and surface properties for improved aerosolisation Incorporate tailored drug particles into drug-carrier blends (DPIs) Formulations of drug alone or drug composite drug particles (MDIs and DPIs) (Integration with inhaler device)

17 Drug particle design - processing Alternative bottom up processes for producing respirable sized drug particles (rather than top-down milling operations) Controlled process to tune particle properties Single step operation drug(s) solution to dried respirable particle GMP operating at scale, QbD potential (Screw feeder/spheronisation) Spray drying and spray drying/sonication Supercritical fluid based technologies

18 Pulmicort budesonide for Turbohaler Micronised budesonide passed through screw feeder Product then spheronised to form spherical free flowing aggregates Aggregates exhibit sufficient strength for packing and stability Break up into primary particles when expelled from reservoir device

19 Spray drying process Spray drying is single step, bottom up particle formation process from solution (or suspension) to dried product Aqueous or organic solvents Aerosol droplet size is primary determinant of final particle size Amorphous products frequently obtained Widely used technology at scale and GMP Inhalable insulin Exubera spray-dried product to generate amorphous particles (Pulmosol) Composite respirable particles with functional excipients Withdrawn from the market Pulmosol particles

20 Spray drying porous particles Phospholipid and polymer based porous microparticles Low density (<0.4g/ml) particles with geometric diameter >5um exhibit aerodynamic diameter <5µm Spherical particles, free flowing, low tendency to aggregate Claimed larger particles avoid phagocytic clearance in lungs more effectively than smaller non-porous particles Initially manufactured by a double emulsion solvent evaporation technique Range of other formers studied Modified processing via spray drying Examples of spray dried porous inhalable particles (from Healy et al, Adv Drug Del Rev, 75 (2014) 32)

21 Tobramycin DPI Emulsion based spray drying of porous particles DSPC* as emulsifier and hydrophobic shell former Perflubron - pore forming agent removed from final product Scintigraphy study shows 34% whole lung deposition from 80mg single dose In vitro deposition found to be largely independent of inhalation manoeuvre Novartis product approved by FDA (March 2013) SEM images of: (a) micronized and (b,c) Pulmosphere particles (From Geller et al, J Aer Med Pulm Drug Del, 24 (2011) 175) ( * distearoylphosphatidylcholine)

22 Individual particles containing multiple drugs - glyccopyrrolate/formoterol (Aerospheres) Micronised drugs co-suspended then spray dried in organic solvent including phospholipid (DSPC) (Pearl/AZ) Inhalable particles with micronised drug particles separately presented in each carrier particle Avoids sedimentation and interaction between two drug substances Bevespi Aersophere MDI approved by FDA, April 2016; claimed FPF >60%

23 Spray drying + sonication DISCUS, SAX/UMAX processes (Prosonix/Circassia) Fine aerosol of drug solution generated and aerosol droplets concentrated in a non solvent Apply sonication to the viscous dispersed droplets to effect crystallisation Resulting slurry dried (spray or SCF drying) Spherical, smooth surfaced particle suitable for DPI and MDI products UMAX process Fluticasone MDI generic product approved by MHRA, Nov 2015 application based on in vitro demonstration of therapeutic equivalence Potential for combination products (from Ruecroft et al., DDL20, 2009)

24 Supercritical fluid (SCF) processing High solubility of low molecular weight solvents in scco 2 (organic solvents) low residual solvent Triple point C, 5 bar. Critical point 30.9 C, 74 bar, Sublimation point -79 C, 1 bar At STP 0 C, 1 atm) CO 2 never a liquid, sublimes directly to gas Very low solubility of solutes in scco 2 can process most API s x 2 S-Methylbenzylamine S-Mandelate 40x x x x K K K K p / MPa

25 Crystec modified SAS process Single step process API solution introduced into particle formation vessel with supercritical CO 2 Rapid solvent extraction by SCF and precipitation of solid particles low residual solvent Controlled formation of particle solid-state, size and morphology for a wide small and large drug molecules Free flowing, non cohesive, crystalline respirable drug particles; low bulk density Composite particles, co-crystals, amorphous dispersions Scaled, GMP plant API (or API plus additives) Solution Particle Formation Vessel (at supercritical temperature and pressure) PRODUCT CO 2 + Solvent CO 2

26 Standard and supercritical fluid (SCF) processed powders SCF processed powders Conventionally crystallised powder Micronised

27 SCF based MDI product - Semprana MDI formulation suspension of dihydroergotamine mesylate in propellant Lung delivery for rapid absorption into systemic system High bioavailability Rapid relief of migraine To be launched 2017 (Allergan/Actavis)

28 SCF designer drug particles Inhaled tolterodine, CR002 A novel inhaled treatment for urge urinary incontinence Repurposing of an existing drug Oral, high dose product has side-effects Many patients default from therapy (up to 59% in 6 months) Aim for fast onset DPI product for systemic drug delivery Potential to treat urge incontinence events episodically Address unmet clinical need

29 Inhaled tolterodine SCF processed tolterodine X50 µm X90 µm VMD µm Batch Batch Batch SCF processed particles achieve almost three times the level of deep lung deposition (compared with micronised material) - Fast onset of action - - Fewer side effects - Micronised tolterodine Target area for deep lung deposition

30 Exposure modelling - extended release tolterodine in man (EMs) vs. inhaled Tolterodine in rat (4 urges/interventions per day) Reduced side effects and a 40% reduction in anticholinergic burden 4mg ER Clinical 0.3mg/kg rat inhaled [Target] Waking Lunch meeting Key in the door Evening Waking Prelunch Getting home Sex Modelled from own data (single exposure) and Malhorta et al. (2011), Br J Clin Pharm. 72: 226

31 Outline of presentation Current formulation designs and constraints what improvements are needed? Some rule based approaches to improving formulations Examples of recent innovations in drug particle design to improve drug aerosol delivery What next?

32 What next? Multitude of respiratory drug delivery formulations/devices in development and clinical studies Polymeric nanoparticles, liposomes, biologics, vaccines, etc. Carrier free formulations and multidrug therapy for treating diseases of the lung Recent events Aradigm liposomal ciprofloxacin formulation ( ) GSK triple combination for COPD filed ( )

33 What next? Exploit opportunities from drug particle design strategies high performance formulations What happens when a drug particle has landed? Targeting inhaled therapy beyond the lungs Personalised treatments (eg monoclonal antibodies) Programmes to create device/formulation/patient flow rate independence

34 New drug formulations via the lungs are worth holding your breath for H Nazar, Pharmaceutical Journal, July 2012

35 Thank you for your attention