Philippe Rogueda

The nanoscale in pulmonary delivery. Part 1: deposition, fate, toxicology and effects

This two-part review explores the nanoscale in inhalation delivery. The first part covers the deposition, fate, toxicity and effects of nanoparticles delivered via inhalation. The second part analyses the potential of major inhalation delivery routes. Efficient particle deposition in the lung can be achieved with nanoparticles (50 – 100 nm). However, this particle range has hardly been exploited in a medical setting. Thus, formulation scientists have a rare opportunity to develop new concepts in inhalation delivery. The delivery of nanoparticles raises concern over increased toxicity, but also opens up the possibility for enhanced therapeutic effects and reduced dosage. Toxicity data available so far concerns mainly non-therapeutic molecules, and it remains a moot point as to whether these apply to drug molecules.

Novel hydrofluoroalkane suspension formulations for respiratory drug delivery

Due to the poor solvent properties of hydrofluoroalkanes, suspension is often the only formulation option for respiratory drug delivery. Research in this area has focussed mainly on two main themes over the past 5 years: new design of stabilisers and particle engineering. Among the most important advances, the introduction of secondary particulate systems and the establishment of porous particles as a viable delivery system must be mentioned. Other noteworthy developments include new classes of stabilisers and surface tailoring approaches. Work has been underpinned by new theoretical insights, via the introduction of atomic force microscopy to measure particle interactions, and the development of the surface tension component approach to predict them. Future areas of development include the formulation of nanoparticles and of non-inhalation therapies in non-pressurised hydrofluoroalkanes. All these aspects are reviewed in this article.

HPFP, a Model Propellant for pMDIs

Abstract A novel model propellant for the study of the properties of pMDIs (pressurized metered-dose inhalers) at atmospheric pressure is proposed and extensively characterized. The reasons for the choice of this liquid, with its advantages and drawbacks, are explained and justified. Comparison with existing fluorinated propellants is also documented.

The nanoscale in pulmonary delivery. Part 2: formulation platforms

This article is the second part of a review on the nanoscale in pulmonary drug delivery. Specifically it summarises and analyses the potential of the different inhalation delivery routes: nebulisers, dry powder inhalers, pressurised metered-dose inhalers, for the delivery of nanoparticles or nanodroplets. Few products and experimental studies have managed to fully exploit the nanoscale in inhalation delivery, although some may unknowingly benefit from it. Nebulisers are the most advanced in using the nanoscale, pressurised metered-dose inhalers require further developments to realise its full potential, and dry powder inhalers are specifically in need of a dry solid nanoparticle generation technique to make it a reality.

Particle synergy and aerosol performance in non-aqueous liquid of two combinations metered dose inhalation formulations: an AFM and Raman investigation.

The drug-drug interaction of two pMDI (pressure metered dose inhaler) combination products budesonide-formoterol fumarate dihydrate and salmeterol xinafoate-fluticasone propionate were investigated using in situ atomic force microscopy (AFM), equipped with a liquid cell filled with model a propellant, and Raman spectroscopy. Electron microscopy images of the budesonide-formoterol formulation suggested discrete particulates while the salmeterol-fluticasone formulation appeared agglomerated. Based on the analysis of the AFM curves, it is proposed that interactions in the budesonide-formoterol system (cohesion and adhesion) are dominated by van der Waals forces while interactions between salmeterol and fluticasone are of a chemical nature. Such observations are further substantiated by analysis of the Raman maps produced from pMDI actuations deposited on Andersen cascade impactor plates. The relevance of such synergy between particulates of different chemical nature is discussed. In particular, it is anticipated that strong interactions between particles could lead to heteroflocculation, increase aerosol particle size and consequently reduction of the respirable fine particle fraction.

Micelles of asymmetric chain catanionic surfactants

Abstract The properties of solutions of asymmetric chain catanionic surfactants are reported. The materials are n -propyl-, n -butyl-, n -hexyl- and n -heptylammonium dodecylsulphates (abbreviated as C3C12, C4C12, C6C12 and C7C12 respectively). At 25°C the critical micelle concentrations (CMCs) were determined by air-water surface tension, γ, and electrical conductivity, κ, measurements. It was found that log (CMC) was proportional to the chain length n c . The mean area per molecule, a s , and per hydrocarbon chain, a c , were estimated by applying the Gibbs isotherm to pre-CMC γ versus ln( c ) data. For C3C12, a c ≈ 29 A 2 , increasing to 34 A 2 for the C7C12 material. These values reflect efficient packing in the monolayer as compared with single chain ionic surfactants like sodium dodecyl sulphate, where a s ≈ 45 A 2 . The mesophase sequences were determined at 25°C using polarising microscopy. As n c increases from four to six the hexagonal phase, H 1 (fans), is eliminated, and only L α phases (oily streaks and myelin) form. Small-angle neutron scattering (SANS) experiments and data modelling suggest that the micelles of C4C12, C6C12 and C7C12 are essentially uncharged, and that a cylinder-to-disc transition occurs between n c = 4 and 6. Mean values for the micellar dimensions, number density, n p , aggregation number, n agg , and area per molecule, a s , were obtained from the SANS data. n agg increases from around 300 for the cylindrical to about 6000 for the disc micelles. The value of a s decreases from around 64 A 2 (cylinders) to about 56 A 2 (discs), and this is used to calculate the surfactant packing parameter, P , as a function of n c . The micellar shapes are consistent with the calculated values of P .

The Use of AFM and Surface Energy Measurements to Investigate Drug-Canister Material Interactions in a Model Pressurized Metered Dose Inhaler Formulation

The aim of the project was to investigate the interactions between micronized salbutamol sulphate, budesonide, and formoterol fumarate dihydrate and different canister surfaces materials (Aluminium, anodized aluminium, perfluoroalkoxy, fluorinated ethylene propylene—polyether sulphone, and polytetrafluoroethylene) used in pressurized metered dose inhalers (pMDIs). The surface component approach for polar and apolar interfacial interactions was used to predict the adhesion behavior of micronized drugs with the inner surfaces of pMDI canisters. This was achieved using a combination of in situ colloid probe atomic force microscopy (AFM) measurements and theoretical treatment of the surface free energy measurements, via a contact angle–based technique of the interacting surfaces. All three drugs exhibited similar dispersive surface energy free values. A greater variation was, however, found in the polar component of the surface free energy measurements. These results were also reflected in the dispersive and polar components of the canister materials. Moreover, the linear relationship between the work of adhesion and AFM measured adhesion was shown to be correlated on the polar contributions of the surface free energies of the interacting materials. AFM measurements indicated that salbutamol sulphate was found to have the strongest adhesive forces with respect to the canister surface materials while budesonide and formoterol fumarate dihydrate appeared to have similar adhesive characteristics. The present study suggests that investigations into the design and characterization of pMDI formulations would benefit from considerations of the polar contribution of the surface free energy and relative work of adhesion of the drug and various components of a pMDI system.

Advances in drug delivery: is triple therapy the future for the treatment of chronic obstructive pulmonary disease?

Introduction: Current therapies for chronic obstructive pulmonary disease (COPD) focus on the improvement of clinical symptoms via the use of bronchodilators: β2-adrenoreceptor agonists and muscarinic (M3) acetycholine receptor antagonists. The combination of inhaled corticosteroids (ICSs) and long-acting β2 agonists (LABAs), or LABAs and anticholinergics has become an efficient alternative to single therapies. These combinations consist of a LABA and an ICS together with an anticholinergic, such as ipratropium or tiotropium. Areas covered: This review summarizes the latest thinking and findings on the usefulness of triple therapy in the treatment and management of COPD. Drawing on commercial, clinical, scientific and intellectual property data and publications, it aims to provide an overview to understand the efficacy and need for COPD triple therapy. The reader will gain an in-depth view of the triple therapy approach in managing COPD, existing molecules in the market or in development as well as new chemical entities. Clinical evidence in support of triple therapy, formulations and products are also discussed. Expert opinion: There is limited documented clinical evidence for the use of triple therapy in COPD, reflected in the lack of commercial activity in the field. The future for the management of COPD may lie with triple therapy, but may equally rest on a better understanding of the disease and subsequent development of new chemical entities, such as dimer molecules, longer-acting β-agonists and antimuscarinics.

Explaining the phase behaviour of the pharmaceutically relevant polymers poly(ethylene glycol) and poly(vinyl pyrrolidone) in semi-fluorinated liquids.

Phase behaviour studies of low molecular weight poly(ethylene glycol) (denoted PEG 600 and PEG 1000, corresponding to molecular weights of 600 and 1000 g mol−1, respectively) have been carried out in 2H, 3H‐perfluoropentane (HPFP) with and without added poly(vinyl pyrrolidone). The concentration and temperature dependencies of their phase behaviour and the effect of moisture on these systems have been established. Furthermore, the solubility of PEG 600 in binary mixtures of HPFP and per‐fluoropentane (PFP), as well as HPFP and perfluorodecalin (PFD) have been considered at high HPFP contents. A phase separation phenomenon in fluorinated non‐aqueous media is reported for the first time: PEG 600 and PEG 1000 both show a lower critical solution temperature type phase separation boundary. The size of the PEGs was obtained from small‐angle neutron scattering (radius of gyration) and pulsed‐gradient spin‐echo NMR (hydrodynamic radius) measurements. It is shown that polymer conformation follows a regular trend with solution concentration; the size increases from <10 Å at 3wt% in HPFP to 45 ± 2 Å at 20wt% PEG. On changing the solvent composition by substitution of HPFP by PFP or PFD, the size decreases, consistent with a decrease in the hydrogen‐bonding capacity of the solvent mixture. Computer modelling indicates an interaction between the PEG oxygen and the hydrogen of HPFP, an interaction that is absent for the fully fluorinated solvents. This indicates that hydrogen bonding is the driving force for polymer solubility in these solvents.

Dry powder nasal drug delivery: challenges, opportunities and a study of the commercial Teijin Puvlizer Rhinocort device and formulation

Abstract Purpose: To discuss the challenges and opportunities for dry powder nasal medications and to put this in to perspective by evaluating and characterizing the performance of the Teijin beclomethasone dipropionate (BDP) dry powder nasal inhaler; providing a baseline for future nasal products development. Methods: The aerosol properties of the formulation and product performance of Teijin powder intranasal spray were assessed, with a particular focus on particle size distribution (laser diffraction), powder formulation composition (confocal Raman microscope) and aerosol performance data (British Pharmacopeia Apparatus E cascade impactor, aerosol laser diffraction). Results: Teijin Rhinocort® (BDP) dry powder spray formulation is a simple blend of one active ingredient, BDP with hydroxypropylcellulose (HPC) carrier particles and a smaller quantity of lubricants (stearic acid and magnesium stearate). The properties of the blend are mainly those of the carrier (Dv50 = 98 ± 1.3 µm). Almost the totality of the capsule fill weight (96.5%) was emitted with eight actuations of the device. Using the pharmacopeia suggested nasal chamber deposition apparatus attached to an Apparatus E impactor. The BDP main site of deposition was found to be in the nasal expansion chamber (90.2 ± 4.78%), while 4.64 ± 1.38% of the BDP emitted dose was deposited on Stage 1 of the Apparatus E. Conclusions: The Teijin powder nasal device is a simple and robust device to deliver pharmaceutical powder to the nasal cavity, thus highlighting the robustness of intranasal powder delivery systems. The large number of actuations needed to deliver the total dose (eight) should be taken in consideration when compared to aqueous sprays (usually two actuations), since this will impact on patient compliance and consequently therapeutic efficacy of the formulation.