TAILORING DRY POWDER INHALER PERFORMANCE BY - RCPE

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764 Maas et al. suspensions or solutions by the use of liquefied propellants, or dispersion of dry powders in the inspired air, respectively. A prerequisite of the API particles intended to travel along the narrow airways and to finally reach the deep parts of the lungs, is an aerodynamic diameter in the range of 1–5 µm (Daniher and Zhu, 2008; Labiris and Dolovich, 2003a). Because of their small size, these particles are quite cohesive and show poor flowing properties. Precise dosing, which is done volumetrically, however, relies on adequate flowability. For this reason, the micronized API particles are attached to coarser carrier particles by a mixing procedure. Usually the carrier particles have particle sizes of 50–200 µm, ensuring adequate flowability and dosing. On inhalation, the drug has to detach from the carrier in order not to impact together with the carrier on the upper airways. Therefore, interparticle forces between APIs and carrier particles are of utmost importance for the performance of the inhalate. On the one hand, these forces have to be high enough to ensure powder handling and dosing; and on the other hand, they have to be low enough to allow API detachment from the carrier surface on inhalation. Much work has been done on the modification of interparticle forces between API and carrier. According to the literature, carrier surface modification is an appropriate method to control these forces, although other parameters such as particle size and size distribution (Danjo et al., 1989; Mullins et al., 1992), shape and morphology, and chemical identity (Podczeck et al., 1996) affect interparticle interactions. The modification of surface topography targets the area of contact between the active and the carrier. Surface asperities may increase the distance and reduce the contact area between the active and the carrier, resulting in a decrease of the interparticle interactions on the one hand (Fuller and Tabor, 1975; Rabinovich et al., 2000; Rumpf, 1974; Tabor, 1977). On the other hand, surface asperities may also lead to an increase of the contact area between the active and the drug, especially when the scale of the asperities is of a similar order of magnitude as the particle size of the drug. Whether a decrease or increase of the contact area is induced depends on the size, shape, number, position, and distribution of the asperities. The prediction of the impact of surface asperities is therefore difficult (Iida et al., 1993). Most of the commercially available DPI formulations use α-lactose monohydrate carrier particles (Hersey, 1975; Steckel, 2003). Hence, a lot of work has been published about the surface modification of α-lactose monohydrate. For example, surface modification was achieved Begell House Digital Library, http://dl.begellhouse.com Downloaded 2011-3-4 from IP 129.27.117.213 by Technische Universitaet Graz by dispersant removement (Dickhoff et al., 2006; El- Sabawi et al., 2006a,b; Iida et al., 2001, 2003a; Islam et al., 2004a,b, 2005; Zeng et al., 2001a). Iida et al. (2005) and Chan et al. (2003) worked on carrier surface covering. Another way to control carrier surface properties is the addition of micronized carrier particles or other micronized chemical compounds (Adi et al., 2006, 2007; Guchardi et al., 2008; Iida et al., 2003b, 2004a,b; Louey et al., 2003; Louey and Stewart, 2002; Podczeck, 1999; Tee et al., 2000; Zeng et al., 1998, 1999). The surface modification by milling was studied by Steckel et al. (2006), Ferrari et al. (2004), Iida et al. (2004b), and Young et al. (2002). Surface modification by varying crystallization conditions was achieved by Larhrib et al. (2003a,b) and Zeng et al. (2000a,b,c, 2001b). Although α-lactose monohydrate is commonly used as carrier in dry powder inhalates, it has several disadvantages such as incompatibility of the sugars reducing aldehyde group with APIs such as formoterol, budesonide or peptides and proteins (Steckel and Bolzen, 2004). In addition, commercially available crystals of α-lactose monohydrate may show great variability in surface properties depending on the production process (crystallisation, milling, sieving), resulting in varying adhesion forces between the drug and the carrier, and consequently varying drug detachment (Steckel et al., 2004; Young et al., 2008). Another drawback of α-lactose monohydrate is related to its different crystal faces exhibiting different physicochemical properties and affinity to attached drug particles, thereby leading to unequal interparticle interactions between the drug and the carrier and unequal drug particle detachment from the different crystal faces. Consequently, carrier particles with equal affinity to the drug particles over the entire carrier surface are needed as, e.g., obtained in spray drying. Spray-dried particles are usually of spherical shape. They have a homogeneous surface structure, ensuring equal affinity to the active over the entire carrier surface. Additionly, they exhibit excellent flowing properties. Unfortunately, αlactose monohydrate is susceptible to mechanical treatment and spray drying, resulting in amorphicity and giving rise to stability problems (Buckton et al., 1998; Price and Young, 2004), which is a further disadvantage of αlactose monohydrate. An alternative carrier avoiding the disadvantages mentioned above is mannitol. Maas (2009) showed that fairly spherical particles exhibiting a homogeneous surface are obtained by spray drying aqueous mannitol solutions. By varying the spraydrying outlet temperature between 60 ◦ C and 120 ◦ C, he found that the surface roughness of the particles may be Atomization and Sprays
Tailoring Dry Powder Inhaler Performance 765 tailored, leading to smooth particles exhibiting an indentation of their shell at low drying temperatures, and rough particles showing a hole in their shell at high outlet temperatures. Independent of the outlet temperature, particles were hollow and had almost the same particle size. Despite differences in particle surface morphologies, mannitol was crystalline and consisted of modification I. Mannitol has been discussed as an alternative to α-lactose monohydrate already (Adi et al., 2007; Harjunen et al., 2003; Saint-Lorant et al., 2007; Steckel und Bolzen, 2004; Tee et al., 2000). However, no data were reported on the influence of the surface structure of spray-dried mannitol on interparticle forces. This study is dedicated to the investigation of the impact of the surface roughness of the mannitol carrier on the performance of dry powder inhalates, such as dosing and in vitro respirable fraction. 2. MATERIALS AND METHODS 2.1 Materials Mannitol (Pearlitol SD 200) was kindly provided by Roquette, F-Lestrem. Salbutamol suphate was donated by Lindopharm GmbH (DE-Hilden). 2.2 Micronization of Salbutamol Sulphate Salbutamol sulphate representing the active substance was micronized using the air jet mill 50 AS (Hosokawa Alpine, DE-Augsburg). The injection pressure was set to 6 bar, milling pressure to 2 bar, and the feeding rate was adjusted to 1 g/min. The obtained material exhibits a mean particle diameter of 1.82 µm (x10 = 0.65 ± 0.02 µm, x50 = 1.82 ± 0.02 µm, x90 = 5.07 ± 0.22 µm). Particle size distributions were determined using laser diffraction. 2.3 Spray Drying of Mannitol Aqueous mannitol solutions (15% w/w) were fed into a spray dryer (Niro Atomizer, Niro, DK-Copenhagen), with a height of 615 mm of the cylindrical part and 700 mm of the conical part. The diameter of the cylindrical part was 800 mm. The feeding rate was adjusted to 14 mL/min by a flexible-tube pump, and the solution was atomized to small droplets by a rotary atomizer with a rotational speed of 27,500 rpm (4.9 bar air pressure at the turbine). The diameter of the atomizing wheel was 50 mm. It contained 24 bores, which were 6 mm in height and 3 mm in width. The spray-drying outlet air temperature was varied. The obtained products were stored in desiccators containing Volume 20, Number 9, 2010 silica gel until further required. Three batches (A, B, C) per outlet temperature of 60 ◦ C (mannitol 60 ◦ C), 90 ◦ C (mannitol 90 ◦ C) and 120 ◦ C (mannitol 120 ◦ C) were prepared. 2.4 Preparation and Content Uniformity of Ordered Mixtures Batches of ordered mixtures of 8 g were prepared with the spray-dried particles using a carrier-to-drug ratio of 99:1. Half of the carrier material was weighed into a stainless steel vessel, then salbutamol sulphate, and finally the second half of the carrier material was added. The powder was mixed in a Turbula mixer (T2C, Bachofen AG, CH- Muttenz) at 65 rpm for 90 min and allowed to settle for 2 h before further treatment. First, the content uniformity of the mixture was determined retaining 12 samples. The content of the active ingredient was analyzed by HPLC. For the subsequent aerodynamic assessment of fine particles, only ordered mixtures with content uniformities of
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