Development and Pharmacokinetics of a Novel Acetylsalicylic Acid Dry Powder for Pulmonary Administration.

Aspirin is an historic blockbuster product, and it has been proposed in a wide range of formulas. Due to exacerbation risks, the pulmonary route has been seldom considered as an alternative to conventional treatments. Only recently, owing to overt advantages, inhalable acetylsalicylic acid dry powders (ASA DPI) began to be considered as an option. In this work, we developed a novel highly performing inhalable ASA DPI using a nano spray-drying technique and leucine as an excipient and evaluated its pharmacokinetics compared with oral administration. The formulation obtained showed remarkable respirability and quality features. Serum and lung ASA DPI profiles showed faster presentation in blood and higher retention compared with oral administration. The dry powder was superior to the DPI suspension. The relative bioavailability in serum and lungs claimed superiority of ASA DPI over oral administration, notwithstanding a fourfold lower pulmonary dose. The obtained ASA DPI formulation shows promising features for the treatment of inflammatory and infectious lung pathologies.

Design of experiments (DoE) in pharmaceutical development.

At the beginning of the twentieth century, Sir Ronald Fisher introduced the concept of applying statistical analysis during the planning stages of research rather than at the end of experimentation. When statistical thinking is applied from the design phase, it enables to build quality into the product, by adopting Deming's profound knowledge approach, comprising system thinking, variation understanding, theory of knowledge, and psychology. The pharmaceutical industry was late in adopting these paradigms, compared to other sectors. It heavily focused on blockbuster drugs, while formulation development was mainly performed by One Factor At a Time (OFAT) studies, rather than implementing Quality by Design (QbD) and modern engineering-based manufacturing methodologies. Among various mathematical modeling approaches, Design of Experiments (DoE) is extensively used for the implementation of QbD in both research and industrial settings. In QbD, product and process understanding is the key enabler of assuring quality in the final product. Knowledge is achieved by establishing models correlating the inputs with the outputs of the process. The mathematical relationships of the Critical Process Parameters (CPPs) and Material Attributes (CMAs) with the Critical Quality Attributes (CQAs) define the design space. Consequently, process understanding is well assured and rationally leads to a final product meeting the Quality Target Product Profile (QTPP). This review illustrates the principles of quality theory through the work of major contributors, the evolution of the QbD approach and the statistical toolset for its implementation. As such, DoE is presented in detail since it represents the first choice for rational pharmaceutical development.

Development of a fast, lean and agile direct pelletization process using experimental design techniques.

A novel hot melt direct pelletization method was developed, characterized and optimized, using statistical thinking and experimental design tools. Mixtures of carnauba wax (CW) and HPMC K100M were spheronized using melted gelucire 50-13 as a binding material (BM). Experimentation was performed sequentially; a fractional factorial design was set up initially to screen the factors affecting the process, namely spray rate, quantity of BM, rotor speed, type of rotor disk, lubricant-glidant presence, additional spheronization time, powder feeding rate and quantity. From the eight factors assessed, three were further studied during process optimization (spray rate, quantity of BM and powder feeding rate), at different ratios of the solid mixture of CW and HPMC K100M. The study demonstrated that the novel hot melt process is fast, efficient, reproducible and predictable. Therefore, it can be adopted in a lean and agile manufacturing setting for the production of flexible pellet dosage forms with various release rates easily customized between immediate and modified delivery.

Spray-dried amikacin sulphate powder for inhalation in cystic fibrosis patients: The role of ethanol in particle formation.

A Central Composite Design (CCD) was applied in order to identify positive combinations of the production parameters of amikacin sulphate spray-dried powders for inhalation, with the intent to expand the experimental space defined in a previous half-fractional factorial design. Three factors, namely drying temperature, feed rate and ethanol proportion, have been selected out of the initial five. In addition, the levels of these factors were increased from two to three and their effect on amikacin respirability was evaluated. In particular, focus was given on the role of ethanol presence on the formation of the microparticles for inhalation. The overall outcome of the CCD was that amikacin respirability was not substantially improved, as the optimum region coincided with areas already explored with the fractional factorial design. However, expanding the design space towards smaller ethanol levels, including its complete absence, revealed the crucial role of this solvent on the morphology of the produced particles. Peclet number and drug solubility in the spraying solution helped to understand the formation mechanism of these amikacin sulphate spray-dried particles.

Spray dried amikacin powder for inhalation in cystic fibrosis patients: a quality by design approach for product construction.

An amikacin product for convenient and compliant inhalation in cystic fibrosis patients was constructed by spray-drying in order to produce powders of pure drug having high respirability and flowability. An experimental design was applied as a statistical tool for the characterization of amikacin spray drying process, through the establishment of mathematical relationships between six Critical Quality Attributes (CQAs) of the finished product and five Critical Process Parameters (CPPs). The surface-active excipient, PEG-32 stearate, studied for particle engineering, in general did not benefit the CQAs of the spray dried powders for inhalation. The spray drying feed solution required the inclusion of 10% (v/v) ethanol in order to reach the desired aerodynamic performance of powders. All desirable function solutions indicated that the favourable concentration of amikacin in the feed solution had to be kept at 1% w/v level. It was found that when the feed rate of the sprayed solution was raised, an increase in the drying temperature to the maximum value (160 °C) was required to maintain good powder respirability. Finally, the increase in drying temperature always led to an evident increase in emitted dose (ED) without affecting the desirable fine particle dose (FPD) values. The application of the experimental design enabled us to obtain amikacin powders with both ED and FPD, well above the regulatory and scientific references. The finished product contained only the active ingredient, which keeps low the mass to inhale for dose requirement.

Recent advances in pulsatile oral drug delivery systems.

It is well established that several diseases exhibit circadian behavior, following the relevant rhythm of the physiological functions of the human body. Their study falls in the fields of chronobiology and chronotherapeutics, the latter being essentially the effort of timely matching the treatment with the disease expression, in order to maximize the therapeutic benefits and minimize side effects. Pulsatile drug delivery is one of the pillars of chronopharmaceutics, achieved through dosage form design that allows programmable release of active pharmaceutical ingredients (APIs) to follow the disease's time profile. Its major characteristic is the presence of lag phases, followed by drug release in a variety of rates, immediate, repeated or controlled. The scope of this review is to summarize the recent literature on pulsatile oral drug delivery systems and provide an overview of the ready to use solutions and early stage technologies, focusing on the awarded and pending patents in this technical field during the last few years.

Pelletization processes for pharmaceutical applications: a patent review.

Pellets exhibit major therapeutic and technical advantages which have established them as an exceptionally useful dosage form. A plethora of processes and materials is available for the production of pellets, which practically allows inexhaustible configurations contributing to the flexibility and versatility of pellets as drug delivery systems. The scope of this review is to summarize the recent literature on pelletization processes for pharmaceutical applications, focusing on the awarded and pending patents in this technical field. The first part of the article provides an overview of innovation in pelletization processes, while the second part evaluates their novel applications.

Effect of physical state and particle size distribution on dissolution enhancement of nimodipine/PEG solid dispersions prepared by melt mixing and solvent evaporation.

The physical structure and polymorphism of nimodipine were studied by means of micro-Raman, WAXD, DSC, and SEM for cases of the pure drug and its solid dispersions in PEG 4000, prepared by both the hot-melt and solvent evaporation methods. The dissolution rates of nimodipine/PEG 4000 solid dispersions were also measured and discussed in terms of their physicochemical characteristics. Micro-Raman and WAXD revealed a significant amorphous portion of the drug in the samples prepared by the hot-melt method, and that saturation resulted in local crystallization of nimodipine forming, almost exclusively, modification I crystals (racemic compound). On the other hand, mainly modification II crystals (conglomerate) were observed in the solid dispersions prepared by the solvent evaporation method. However, in general, both drug forms may appear in the solid dispersions. SEM and HSM microscopy studies indicated that the drug particle size increased with drug content. The dissolution rates were substantially improved for nimodipine from its solid dispersions compared with the pure drug or physical mixtures. Among solid dispersions, those resulting from solvent coevaporation exhibited a little faster drug release at drug concentrations lower than 20 wt%. Drug amorphization is the main reason for this behavior. At higher drug content the dissolution rates became lower compared with the samples from melt, due to the drug crystallization in modification II, which results in higher crystallinity and increased particle size. Overall, the best results were found for low drug content, for which lower drug crystallinity and smaller particle size were observed.