Gabrielle Pilcer

Formulation strategy and use of excipients in pulmonary drug delivery.

Pulmonary administration of drugs presents several advantages in the treatment of many diseases. Considering local and systemic delivery, drug inhalation enables a rapid and predictable onset of action and induces fewer side effects than other routes of administration. Three main inhalation systems have been developed for the aerosolization of drugs; namely, nebulizers, pressurized metered-dose inhalers (MDIs) and dry powder inhalers (DPIs). The latter are currently the most convenient alternative as they are breath-actuated and do not require the use of any propellants. The deposition site in the respiratory tract and the efficiency of inhaled aerosols are critically influenced by the aerodynamic diameter, size distribution, shape and density of particles. In the case of DPIs, since micronized particles are generally very cohesive and exhibit poor flow properties, drug particles are usually blended with coarse and fine carrier particles. This increases particle aerodynamic behavior and flow properties of the drugs and ensures accurate dosage of active ingredients. At present, particles with controlled properties are obtained by milling, spray drying or supercritical fluid techniques. Several excipients such as sugars, lipids, amino acids, surfactants, polymers and absorption enhancers have been tested for their efficacy in improving drug pulmonary administration. The purpose of this article is to describe various observations that have been made in the field of inhalation product development, especially for the dry powder inhalation formulation, and to review the use of various additives, their effectiveness and their potential toxicity for pulmonary administration.

Lactose characteristics and the generation of the aerosol

The delivery efficiency of dry-powder products for inhalation is dependent upon the drug formulation, the inhaler device, and the inhalation technique. Dry powder formulations are generally produced by mixing the micronised drug particles with larger carrier particles. These carrier particles are commonly lactose. The aerosol performance of a powder is highly dependent on the lactose characteristics, such as particle size distribution and shape and surface properties. Because lactose is the main component in these formulations, its selection is a crucial determinant of drug deposition into the lung, as interparticle forces may be affected by the carrier-particle properties. Therefore, the purpose of this article is to review the various grades of lactose, their production, and the methods of their characterisation. The origin of their adhesive and cohesive forces and their influence on aerosol generation are described, and the impact of the physicochemical properties of lactose on carrier-drug dispersion is discussed in detail.

Inhaled proteins: Challenges and perspectives

Due to recent developments in biochemical engineering and in the understanding of the physiopathology of many diseases, therapeutic biologics are expected to become of increasing importance. Pulmonary delivery of these proteins could constitute an attractive, non-invasive alternative to parenteral delivery. It can be considered for either topical use for treating lung diseases or for systemic use for treating a variety of other diseases. However, administration of proteins to the lungs presents several challenges such as the need for appropriate formulation strategies to overcome high inter-particle interactions and physico-chemical degradation that can lead to loss of biological activity and/or safety issues. In addition, various lung clearance mechanisms have to be avoided to provide a sufficient level of intact protein in the lungs. If systemic action is desired, it is also necessary for the molecule to cross the alveolar epithelium, which is particularly challenging for large proteins with many hydrophilic domains. The purpose of this article is to review the main challenges in the formulation of proteins for inhalation and the possible strategies that can be applied. Because of the particular success of dry formulations in stabilising proteins, there is a special focus on their development, along with the drying techniques and stabilising excipients used. Finally, an overview is given of the existing commercial preparations and of the main clinical developments in inhaled proteins for either topical or systemic applications.

Preparation and characterization of spray-dried tobramycin powders containing nanoparticles for pulmonary delivery

Using high-pressure homogenization and spray-drying techniques, novel formulations were developed for manufacturing dry powder for inhalation, composed of a mixture of micro- and nanoparticles in order to enhance lung deposition. Particle size analysis was performed by laser diffraction. Spray-drying was applied in order to retrieve nanoparticles in dried-powder state from tobramycin nanosuspensions. The aerolization properties of the different formulations were evaluated by a multi-stage liquid impinger. Suspensions of nanoparticles of tobramycin containing Na glycocholate at 2% (w/w) relative to tobramycin content and presenting a mean particle size about 200 nm were produced. The results from the spray-dried powders showed that the presence of nanoparticles in the formulations improved particle dispersion properties during inhalation. The fine particle fraction (percentage of particles below 5 microm) increased from 36% for the raw micronized tobramycin material to about 61% for the most effective formulation. These new nanoparticle-containing tobramycin DPI formulations, based on the use of very low level of excipient and presenting high lung deposition properties, offer very important perspectives for improving the delivery of drugs to the pulmonary tract.

Correlations between cascade impactor analysis and laser diffraction techniques for the determination of the particle size of aerosolised powder formulations

The purpose of the study was to examine the suitability of the Spraytec laser diffraction technique for measuring the size distribution of aerosol particles generated from dry powder inhalators. A range of formulations with different dispersion properties were produced by spray-drying. The percentage of particles below 5.0 microm of these formulations was measured by laser diffraction (Mastersizer 2000 and Spraytec and inertial impaction (MsLI and NGI) using various inhaler devices and at different flow rates between 30 and 100 l/min. Linear relationships and correlations (R(2)>0.9) existed between the results obtained from, on one hand, the Mastersizer 2000 and the Spraytec, and, on the other hand, the MsLI and the Spraytec regardless of flow rates and inhaler devices. The Spraytec could be a reliable technique for the development, evaluation and quality control of dry powder aerosol formulations.

New co‐spray‐dried tobramycin nanoparticles–clarithromycin inhaled powder systems for lung infection therapy in cystic fibrosis patients

The aim of the study was to produce easily dispersible and porous agglomerates of tobramycin nanoparticles surrounded by a matrix composed of amorphous clarithromycin. Nanoparticles of tobramycin with a median particle size of about 400 nm were produced by high-pressure homogenisation. The results from the spray-dried powders showed that the presence of these nanoparticles enhanced powder dispersion during inhalation. Moreover, local drug deposition profiles were similar for the two antibiotics, allowing them to reach the target simultaneously. The dissolution-release profiles showed that tobramycin and clarithromycin might dissolve without any difficulties in the lung. The fine particle fraction increased from 35% and 31% for the physical blend for tobramycin and clarithromycin, respectively, to 63% and 62% for the spray-dried formulation containing nanoparticles. These new formulations, showing high lung deposition properties, even at sub-optimal inspiratory flow rates, represent a great possibility for advancing pulmonary drug administration and local therapy of lung infections.

Spray-Dried Carrier-Free Dry Powder Tobramycin Formulations With Improved Dispersion Properties

Tobramycin was spray dried at different temperatures from different water to isopropanol feed ratios (0:100-20:80) in order to obtain dry powder formulations for inhalation. The spray-dried powders were characterized for their physicochemical properties including crystallinity, morphology, density, water content, and particle size distribution using X-ray powder diffraction, scanning electron microscopy, tapped density measurements and laser diffraction. Aerosol performance was studied by dispersing the powders into a Multi-Stage Liquid Impinger with an Aerolizer device. The results indicate that formulations spray dried at temperatures below 200 degrees C exhibited poor powder flow properties and were therefore unlikely to display optimal aerosolization characteristics. Nevertheless, it is interesting to note that the presence of water in the suspensions used for spray-drying markedly enhanced the fine particle fraction, which was about 37% for the raw tobramycin and about 57% for a powder obtained from a suspension containing 2% (v/v) water. Overall, this latter formulation was shown to keep its initial particle size distribution and aerodynamic behaviour for 12 months of storage at 40 degrees C and 75% RH. These new carrier-free formulations provide an attractive alternative for delivering high doses of antibiotics directly to the site of infection while minimising systemic distribution.

Carrier-free combination for dry powder inhalation of antibiotics in the treatment of lung infections in cystic fibrosis.

The aim of the study was to develop an efficient combination antibiotic formulation containing tobramycin and clarithromycin as a dry powder for inhalation. A carrier-free formulation of the two drugs was produced by spray-drying and characterised for its aerodynamic behaviour by impaction tests with an NGI and release profiles. The particle size distribution, morphological evaluation and crystallinity state were determined by laser diffraction, scanning electron microscopy and powder X-ray diffraction, respectively. Drug deposition profiles were similar for the two antibiotics, which has a synergistic effect, allowing them to reach the target simultaneously at the expected dose. The release profiles show that tobramycin and clarithromycin should probably dissolve without any difficulties in vivo in the lung as 95% of tobramycin and 57% of clarithromycin mass dissolved in 10min for the spray-dried formulation. The FPF increased from 35% and 31% for the physical blend for tobramycin and clarithromycin, respectively, to 65% and 63% for the spray-dried formulation. The spray-dried formulation shows particularly high deposition results, even at sub-optimal inspiratory flow rates, and therefore, represents an attractive alternative in the local treatment of lung infection such as in cystic fibrosis.

Comparative pharmacoscintigraphic and pharmacokinetic evaluation of two new formulations of inhaled insulin in type 1 diabetic patients

In this open, single-dose study, we compared the lung deposition and bioavailability of two newly developed insulin formulations for pulmonary delivery. Twelve type 1 diabetic patients were administered the two insulin products (2 U/kg b.w.), which had been radiolabelled with (99m)Tc. The formulations were either microparticles of insulin without excipients (F1) or lipid-coated insulin microparticles (F2). Lung deposition was assessed by γ-scintigraphy imaging performed immediately after administration. Bioavailability was evaluated by quantifying serum insulin levels over a period of 6 h. Lung deposition was found to be 50 ± 9% and 24 ± 8% for the F1 and F2 formulations, respectively. The insulin AUC₀₋₃₆₀ ratio of F1/F2 was 188%, which was consistent with scintigraphic imaging. The concordance between imaging and biological results suggests that the lower bioavailability of F2 is due to its lower lung deposition and not to a reduced absorption into the blood stream. Additional in vitro experiments indicated that the lower performance of F2 was most probably related to a lower disaggregation efficiency of the powder when administered at a sub-optimal flow rate. The two formulations showed interesting pharmacokinetic profiles (T(max) of 26 and 16 min for F1 and F2, respectively) that mimic the physiological insulin secretion pattern. The bioavailability of the developed formulations was within the range of other DPI insulin formulations that have reached the final stages of clinical development.