Multivariate Analysis of Effects of Asthmatic Patient Respiratory Profiles on the In Vitro Performance of a Reservoir Multidose and a Capsule-Based Dry Powder Inhaler.

PURPOSE: The aim of this work was to evaluate the effect of two different dry powder inhalers, of the NGI induction port and Alberta throat and of the actual inspiratory profiles of asthmatic patients on in-vitro drug inhalation performances. METHODS: The two devices considered were a reservoir multidose and a capsule-based inhaler. The formulation used to test the inhalers was a combination of formoterol fumarate and beclomethasone dipropionate. A breath simulator was used to mimic inhalatory patterns previously determined in vivo. A multivariate approach was adopted to estimate the significance of the effect of the investigated variables in the explored domain. RESULTS: Breath simulator was a useful tool to mimic in vitro the in vivo inspiratory profiles of asthmatic patients. The type of throat coupled with the impactor did not affect the aerodynamic distribution of the investigated formulation. However, the type of inhaler and inspiratory profiles affected the respirable dose of drugs. CONCLUSIONS: The multivariate statistical approach demonstrated that the multidose inhaler, released efficiently a high fine particle mass independently from the inspiratory profiles adopted. Differently, the single dose capsule inhaler, showed a significant decrease of fine particle mass of both drugs when the device was activated using the minimum inspiratory volume (592 mL).

Supercritical fluid technologies: an innovative approach for manipulating the solid-state of pharmaceuticals.

Solid-state, crystallographic purity and careful monitoring of the polymorphism of drugs and excipients are currently an integral part of the development of modern drug delivery systems. The reproducible preparation of organic crystals in a specific form and size is a major issue that must be addressed. A recent approach for obtaining pharmaceutical materials in pure physical form is represented by the technologies based on supercritical fluids. The present work aims to provide a critical review of the recent advances in the use of supercritical fluids for the preparation and control of the specific physical form of pharmaceutical substances with particular attention to those fluids used for drug delivery systems. These innovative technologies are highly promising for future application in particle design and engineering.

Are pharmaceutics really going supercritical?

The present work focuses on some applications of supercritical fluids in the pharmaceutical field, provides a critical review of the most recent advances and aims to give a vision on the future of this technology. In particular, processes such as particle and crystal engineering, formation of cyclodextrin complexes, coating, foaming and tissue engineering, extrusion, production of liposomes, formulation of biotechnological compounds, sterilization and solvent removal are described and discussed.

Swelling, melting point reduction and solubility of PEG 1500 in supercritical CO2.

The knowledge of the solubility of PEG 1500 as well as the swelling and melting point variation in supercritical CO(2) in a relatively high-pressure range is a necessary prerequisite to set-up pharmaceutical processes dealing with the polymer in the molten state. Experiments carried out in a pressurized view cell indicated that the PEG 1500 progressively decreases its melting point and increases its volume as a consequence of the absorption of the CO(2). The melting point depression was pronounced (from 46 to 28 degrees C) up to 8.7 MPa. Thereafter a constant value was attained. Analogously, under CO(2) the polymer increased its volume (about 34%) until 10 MPa; after this pressure, the polymer volume no longer increased. PEG 1500 showed solubility in SC-CO(2) at 35 and 55 degrees C in the 10-40 MPa range in the order of 10(-6)mole fraction. An empirical model based on solubility parameters was used to fit the experimental data and to predict the maximum concentration achievable by the polymer in the dense gas, as well as to quantify the polymer concentration at low pressures where the experimental determination may be extremely difficult.

Primary microparticles and agglomerates of morphine for nasal insufflation.

The aim of this work was to study the characteristics of powders of morphine HCl suitable for nasal administration to be employed for pain treatment as alternative to injection. Primary microparticles of morphine were prepared by spray drying of aqueous drug solutions using sugars or sugar derivatives as drying protectors and particle shapers. The spray drying procedure modified morphine crystallinity making the substance amorphous and affecting its stability in dependence on the excipient employed. A tendency of the spray-dried powders to turn to varying degrees of yellow was observed. Tumbling the powder in a rotating pan allowed the agglomeration of the primary microparticles. Agglomerates were also obtained by tumbling a mixture of morphine crystals and spray-dried microparticles of excipients, with advantages for the stability of the preparation. A nasal device quantitatively insufflated all the morphine agglomerates. The in vitro transport of morphine through rabbit nasal mucosa was faster using nasal powders than with the saturated solution of morphine. Lactose was the most effective excipient for agglomerate manufacturing and delivery of spray-dried morphine. The agglomerates of morphine crystals mixed with mannitol/lecithin microparticles showed superior stability. However, the drug permeation through rabbit mucosa was slower than with spray-dried morphine microparticle agglomerates.

Solid-state chemistry and particle engineering with supercritical fluids in pharmaceutics.

The present commentary aims to review the modern and innovative strategies in particle engineering by the supercritical fluid technologies and it is principally concerned with the aspects of solid-state chemistry. Supercritical fluids based processes for particle production have been proved suitable for controlling solid-state, morphology and particle size of pharmaceuticals, in some cases on an industrial scale. Supercritical fluids should be considered in a prominent position in the development processes of drug products for the 21st century. In this respect, this innovative technology will help in meeting the more and more stringent requirements of regulatory authorities in terms of solid-state characterisation and purity, and environmental acceptability.

Effect of Flow Rate on In Vitro Aerodynamic Performance of NEXThaler(®) in Comparison with Diskus(®) and Turbohaler(®) Dry Powder Inhalers.

BACKGROUND: European and United States Pharmacopoeia compendial procedures for assessing the in vitro emitted dose and aerodynamic size distribution of a dry powder inhaler require that 4.0 L of air at a pressure drop of 4 kPa be drawn through the inhaler. However, the product performance should be investigated using conditions more representative of what is achievable by the patient population. This work compares the delivered dose and the drug deposition profile at different flow rates (30, 40, 60, and 90 L/min) of Foster NEXThaler(®) (beclomethasone dipropionate/formoterol fumarate), Seretide(®) Diskus(®) (fluticasone propionate/salmeterol xinafoate), and Symbicort(®) Turbohaler(®) (budesonide/formoterol fumarate). METHODS: The delivered dose uniformity was tested using a dose unit sampling apparatus (DUSA) at inhalation volumes either 2.0 or 4.0 L and flow rates 30, 40, 60, or 90 L/min. The aerodynamic assessment was carried out using a Next Generation Impactor by discharging each inhaler at 30, 40, 60, or 90 L/min for a time sufficient to obtain an air volume of 4 L. RESULTS: Foster(®) NEXThaler(®) and Seretide(®) Diskus(®) showed a consistent dose delivery for both the drugs included in the formulation, independently of the applied flow rate. Contrary, Symbicort(®) Turbohaler(®) showed a high decrease of the emitted dose for both budesonide and formoterol fumarate when the device was operated at airflow rate lower that 60 L/min. The aerosolizing performance of NEXThaler(®) and Diskus(®) was unaffected by the flow rate applied. Turbohaler(®) proved to be the inhaler most sensitive to changes in flow rate in terms of fine particle fraction (FPF) for both components. Among the combinations tested, Foster NEXThaler(®) was the only one capable to deliver around 50% of extra-fine particles relative to delivered dose. CONCLUSIONS: NEXThaler(®) and Diskus(®) were substantially unaffected by flow rate through the inhaler in terms of both delivered dose and fine particle mass.