Dry powder inhaler (DPI) products have traditionally comprised a simple formulation of micronised drug mixed with a carrier excipient, typically lactose monohydrate. The presence of the carrier is aimed at overcoming issues of poor flowability and dispersibility, associated with the cohesive nature of small, micronised active pharmaceutical ingredient (API) particles. Both the powder blend and the DPI device must be carefully designed so as to ensure detachment of the micronised drug from the carrier excipient on inhalation. Over the last two decades there has been a significant body of research undertaken on the design of carrier-free formulations for DPI products. Many of these formulations are based on sophisticated particle engineering techniques; a common aim in formulation design of carrier-free products being to reduce the intrinsic cohesion of the particles, while maximising dispersion and delivery from the inhaler. In tandem with the development of alternative formulations has been the development of devices designed to ensure the efficient delivery and dispersion of carrier-free powder on inhalation. In this review we examine approaches to both the powder formulation and inhaler design for carrier-free DPI products.

25In the present study, in vitro permeation experiments in a Franz diffusion cell were performed 26 using different synthetic polymeric membranes and pig ear skin to evaluate a rivastigmine

The present study investigated the effect of operating parameters of a laboratory spray dryer on powder characteristics, in order to optimise the production of trehalose and raffinose powders, intended to be used as carriers of biomolecules for inhalation.The sugars were spray dried from 80:20 methanol:n-butyl acetate (v/v) solutions using a 30Büchi Mini Spray dryer B-290. A 2 4 factorial design of experiment (DOE) was undertaken. Process parameters studied were inlet temperature, gas flow rate, feed solution flow rate (pump setting) and feed concentration. Resulting powders where characterised in terms of yield, particle size (PS), residual solvent content (RSC) and outlet temperature. An additional outcome evaluated was the specific surface area 35 (SSA) (by BET gas adsorption), and a relation between SSA and the in vitro deposition of the sugar NPMPs powders was also investigated.The DOE resulted in well fitted models. The most significant factors affecting the characteristics of the NPMPs prepared, at a 95% confidence interval, were gas flow:yield, PS and SSA; pump setting: yield; inlet temperature: RSC. 40Raffinose NPMPs presented better characteristics than trehalose NPMPs in terms of their use for inhalation, since particles with larger surface area resulting in higher fine particle fraction can be produced. 45

For therapeutic peptides, the lung represents an attractive, noninvasive route into the bloodstream. To achieve optimal bioavailability and control their fast rate of absorption, peptides can be protected by coprocessing with polymers such as polyethylene glycol (PEG). Here, we formulated and characterized salmon calcitonin (sCT)-loaded microparticles using linear or branched PEG (L-PEG or B-PEG) and hydroxypropyl-beta-cyclodextrin (HPβCD) for pulmonary administration. Mixtures of sCT, L-PEG or B-PEG and HPβCD were co-spray dried. Based on the particle properties, the best PEG:HPβCD ratio was 1:1 w:w for both PEGs. In the sCT-loaded particles, the L-PEG was more crystalline than B-PEG. Thus, L-PEG-based particles had lower surface free energy and better aerodynamic behavior than B-PEG-based particles. However, B-PEG-based particles provided better protection against chemical degradation of sCT. A decrease in sCT permeability, measured across Calu-3 bronchial epithelial monolayers, occurred when the PEG and HPβCD concentrations were both 1.6 wt %. This was attributed to an increase in buffer viscosity, caused by the two excipients. sCT pharmacokinetic profiles in Wistar rats were evaluated using a 2-compartment model after iv injection or lung insufflation. The maximal sCT plasma concentration was reached within 3 min following nebulization of sCT solution. L-PEG and B-PEG-based microparticles were able to increase T(max) to 20 ± 1 min and 18 ± 8 min, respectively. Furthermore, sCT absolute bioavailability after L-PEG-based microparticle aerosolization at 100 μg/kg was 2.3 times greater than for the nebulized sCT solution.

The co-spray drying of raffinose or trehalose with HPβCD results in powders with improved physicochemical characteristics, physical stability and aerodynamic behaviour compared to spray-dried raffinose/trehalose particles, constituting improved potential drug-carrier systems for pulmonary delivery.