Application and Mechanism of Inhalation Profile Improvement of DPI Formulations by Mechanofusion with Magnesium Stearate

Abstract

Dry powder inhaler (DPI) formulations have been utilized in the treatment of respiratory disease [1][2][3] and for systemic administration.4 -7) They have become common in the inhalation therapy field because of various advantages, such as being free from anti-environmental propellants 8) and ease of use with portable small devices.DPI formulations with fine drug particles and coarse carrier particles have been widely used for a long time. Usually their components are simple and they can be manufactured with conventional equipment. Therefore, they appear to be a valuable option as the formulation for clinical trials, especially in the early stages of development. The carrier particles play the critical role in preventing the agglomeration of fine drug particles which possesses high surface energy due to their large specific surface area. On the other hand, it is necessary to achieve the high deposition in the deep lungs to satisfy the required bioavailability. Because only small particles (aerodynamic diameter below 5 mm) can reach the lungs, fine drug particles should be detached from the coarse carrier particles through the inhalation process. The percentage of small particles to the entire dose is defined as fine particle fraction (FPF). Therefore, FPF is an index of the extent of deposition in the lungs.Studies have been conducted to clarify the factors that control the inhalation properties of the carrier-based DPI formulations. [9][10][11][12][13][14] Many studies focused on the carrier surface properties especially rugosity and/or coverage of high energy binding sites. 10,[15][16][17][18][19][20][21] Surface energy of particles would be one of the major factors influencing the inhalation profile of DPI including FPF. 22,23) However the mechanism of FPF increase has not been fully clarified so far. This seems to be because the inhalation profile of DPI is affected by various factors including particle size, morphology electrostatic charge and inhalation condition. 10,12,[24][25][26] Therefore, there is a need for preparation and characterization of series of powder samples that are different in surface properties but similar in other properties and compare them under the same inhalation condition.Mechanofusion can modify the surface energy of lactose carrier particles without drastic change of the particle size and can make the particle shape round to lessen the differences.Inverse gas chromatography (IGC) has been utilized to examine the effect of surface energy on the inhalation behavior of DPI. We reported that mechanofusion on a lactose carrier changed the carrier's surface condition and the inhalation properties of DPI formulations containing the lactose carrier and Compound A.27) The Andersen cascade impactor (ACI) profile suggested that the increase of FPF was accompanied by the decrease of the interaction between Compound A and carrier particles. Begat et al. also reported that mechanofusion of lactose with Mg-St reduced the interaction between drug and lactose particles.28) Mg-St is known as lubri...

Nanosized rods agglomerates as a new approach for formulation of a dry powder inhaler

“…For example, Mg stearate has Mg +2 as a cationic root, so it can interfere with the agglomeration process. 55,56 Stearic acid exists in a solid state at room temperature, which is thought to help in the formation of a thin layer surrounding the drug nanodispersion. 57 The amphiphilic nature of stearic acid makes it perform as a boundary between theophylline nanoparticles and the hydrophilic medium in the lungs.…”

Lactose characteristics and the generation of the aerosol

“…Moreover, because the carrier surface is known to be of particular importance, a mechanofusion process has been developed, which consists of homogenising the particle surface or dispersing a minimally melting or a very fine solid material around the carrier particles using intensive mechanical processing [87,88]. This technique can modify the surface energy of lactose carrier particles without drastically changing the particle size and can make the particle shape round to lessen the differences and variations across the particle surface.…”

“…This technique can modify the surface energy of lactose carrier particles without drastically changing the particle size and can make the particle shape round to lessen the differences and variations across the particle surface. Through the mechanofusion process, compression and shearing energy is added to the lactose particles when they pass through the narrow gap between the rotor and press head of the mechanofusion apparatus [87,88]. These new lactose grades with modified surface properties could find their way into the market in the near future as a novel excipient because there is no need for expensive and time-consuming toxicological studies to be approved by the authorities.…”

“…IGC has been used to evaluate the influence of RH on the surface energy of different processed lactoses [38,43,98,156], examine the influence of lactose pseudopolymorphism on surface energy and its correlation with in vitro aerosol performance [157] and understand the impact of mechanofusion with an additive on the lactose carrier surface and in vitro aerosol performance. The latter seems to be primarily influenced by variation in the acidic parameter [87,88]. Moreover, IGC has been compared with the traditional liquid contact angle technique, the Wilhelmy plate method [158].…”

“…Mechanofusion (rotor-type mixer) + Mg st or sucrose stearate higher and homognenous surface energy , smoother and hydrophobic surface and rounder shape higher dispersibility (higher FPF, lower ED) with fewer drug agglomerates not approved agents, modified drug-carrier interaction, stability of blend [87,88] Wet-smoothing (high shear mixer) using solvent with Mg st smoother and hydrophobic surface, smaller surface area and surface energy, lower fine content, rounder shape higher powder packing, flow properties and higher FPD, lower separation energy modified drug-carrier interaction, stability of blend [94,95] Surface erosion (high-speed elliptical-rotor-type mixer) smoother surface, smaller specific surface area, more spherical shape and high shear force applied on surface higher dispersibility (higher FPF, lower ED) amorphous surface, stability of blend [225] Surface dissolution (temperature) smoother surface, lower fines lactose content and similar flow properties and surface area higher FPF, similar ED by reducing the number and the rank of 'active' sites amorphous surface [90,226] Surface dissolution (aqueousethanol solution at 70%) lower macroscopic asperities decrease and higher microscopic asperities higher dispersibility (higher FPF) by lower macroscopic and higher microscopic roughness amorphous surface, stability of blend [91] Mg st coating ( high-speed ellipticalrotor-type mixer) smoother and hydrophobic surface and smaller surface area…”