TAILORING DRY POWDER INHALER PERFORMANCE BY - RCPE

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770 Maas et al. Three batches (A, B, C) of each formulation (mannitol 60 ◦ C, 90 ◦ C, 120 ◦ C) were examined, and the coefficient of variation of the dose of each batch was calculated in order to get a measure of the uniformity of the delivered dose. The mean and the standard deviation of the three coefficients of variation of each formulation were calculated (mannitol 60 ◦ C, 90 ◦ C, 120 ◦ C). They are given in Fig. 6. There is no significant difference between the formulations, the mean of the coefficients of variation having values of 33.6% for formulations containing mannitol 60 ◦ C, 37.8% for formulations containing mannitol 90 ◦ C, and 18.0% for formulations containing mannitol 120 ◦ C. Because the coefficients of variation of the delivered dose are not substantially higher than the coefficients of variation of the metered mass of the formulations metered by the built-in metering device of the inhaler, the poor uniformity of the delivered dose may be attributed to the inadequate flowability and dosing of the formulations, which, in turn, results from the small particle size of the carrier obtained by the laboratory spray dryer. In order to prepare particle sizes of the carrier between 50 and 200 µm, which are normally used in commercially available products, larger spray dryers will be used. In contrast, there is no hint that the poor uniformity of the delivered dose may have been caused by an arbitrary amount of the formulation being retained on the walls of the inhaler on actuation. 3.5 Retained Dose By relating the delivered dose of active to the metered mass of the drug (which is calculated from the metered variation coefficient or the delivered dose / % 55,0 50,0 45,0 40,0 35,0 30,0 25,0 20,0 15,0 10,0 5,0 0,0 mass of the formulation by multiplying the respective value with the amount of drug present in the formulation), a measure of the fraction of drug, which is delivered to the patient, vice versa retained in the inhaler and the mouthpiece adapter, was obtained. The amount of drug delivered is 77% for formulations containing mannitol 60 ◦ C and mannitol 90 ◦ C, and 78 % for formulations containing mannitol 120 ◦ C, indicating that the amount retained also is independent on the surface topography of the carrier (Fig. 7). 3.6 Fine Particle Fraction The FPF is defined as the fraction of the active with an aerodynamic particle diameter ≤5 µm devided by the total amount of the active found in the impactor, and is an indicator for the fraction of the active reaching the lower part of the lungs in relation to the total amount of drug delivered to the patient. The experiments were carried out using the experimental setup described in the European Pharmacopoeia (Ph. Eur. 2008c). Fifty puffs equivalent to approximately 4 mg of drug were delivered from the Novolizer device to the NGI. The amount of drug on each stage was measured using HPLC. Three batches (A, B, C) of each formulation (mannitol 60 ◦ C, 90 ◦ C, 120 ◦ C) were examined, and the mean and standard deviation of the FPF of the three batches were calculated. Figure 8 shows that the FPF decreases from formulations containing mannitol spray dried at 60 ◦ C (mannitol 60) to formulations containing mannitol spray dried at 90 ◦ C (mannitol 90) and finally to formulations containing mannitol spray dried at 120 ◦ C (mannitol 120) Mannitol 60 °C Mannitol 90 °C Mannitol 120 °C FIG. 6: Coefficient of variation of 10 doses of formulations containing mannitol carrier particles spray dried at 60 ◦ C, 90 ◦ C, and 120 ◦ C); n = 3, mean ± standard deviation. Begell House Digital Library, http://dl.begellhouse.com Downloaded 2011-3-4 from IP 129.27.117.213 by Technische Universitaet Graz Atomization and Sprays
Tailoring Dry Powder Inhaler Performance 771 fraction of the drug delivered / % 100 80 60 40 20 0 Mannitol 60 °C Mannitol 90 °C Mannitol 120 °C FIG. 7: Fraction of the drug delivered (equal to delivered dose in relation to the metered dose) of formulations containing mannitol carrier particles spray dried at 60 ◦ C, 90 ◦ C, and 120 ◦ C; n = 3, mean ± standard deviation. fine particle fraction / % 80 70 60 50 40 30 20 10 0 Mannitol 60 °C Mannitol 90 °C Mannitol 120 °C FIG. 8: Fine particle fraction of formulations containing mannitol carrier particles spray dried at 60◦C, 90◦C, and 120◦C; n = 3, mean ± standard deviation. indicating that drug detachment is enhanced from smooth carrier particles but impeded from rough carrier particles. Bearing in mind that the drug particles and the asperities on the surface of the carrier (Fig. 1) are of similar size range, drug detachment from the rough surface is disfavored due to the higher contact area between the drug and the carrier when the drug is embedded in the cavities of the carrier surface. 4. CONCLUSION Modifying the surface topography of mannitol carriers intended for the use in dry powder inhalers is successful by spray drying aqueous mannitol solutions. By varying the spray-drying air outlet temperature, the surface roughness Volume 20, Number 9, 2010 Begell House Digital Library, http://dl.begellhouse.com Downloaded 2011-3-4 from IP 129.27.117.213 by Technische Universitaet Graz of the particles can be modified, with low outlet temperatures leading to smooth surfaces, high outlet temperatures leading to rough ones. Despite the differences of the carrier surface topography, the mass of ordered mixtures of mannitol carriers and the active salbutamol sulphate, which is metered by the built-in metering system of a multidose dry powder inhaler, is not affected. This is attributed to the prescence of the active at the carrier surface affecting surface topography to such an extent that, despite the initially different surface topography of the carrier itself, the surface properties of the mixtures with the active will be similar. In contrast, the FPF determined in vitro, and supposed to correlate with the respirable fraction in vivo, depends strongly on the surface roughness of the carrier used. Ordered mixtures containing the active
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TAILORING DRY POWDER INHALER PERFORMANCE BY - RCPE

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