Formulation development of inhalation powders for FK888 using the E-haler to improve the inhalation performance at a high dose, and its absorption in healthy volunteers.

FK888 is a candidate selective NK1 receptor antagonist, and it exhibits poor absorption from the gastrointestinal tract in healthy volunteers. In a previous study, the optimized dry powder inhaler (DPI) formulation with carrier lactose using the Spinhaler was developed, although the maximum dose per capsule was only 5mg because the fine particle fraction (FPF) was reduced at doses over 5mg. The objective of this study was to develop an optimized DPI formulation for higher doses, such as 40 mg, with proportional systemic absorption. The Spinhaler and E-haler were used as the inhalation devices, and the in vitro deposition was evaluated using a multistage cascade impactor at different flow rates (28.3 and 60 l/min). When hydroxypropyl methylcellulose (HPMC) capsules were used as the container, and spherical soft agglomerates of fine FK888 particles (soft pellets) and the E-haler were used, the fraction of particles emitted from the inhalation system (Em) was significantly improved, to over 80% of the nominal dose, and no significant difference was found between the airflow rates (84.3+/-2.3% for 28.3 l/min, 88.1+/-3.6% for 60 l/min). It was also found that the E-haler was an extremely suitable device for obtaining the higher respirable particle percentage of emitted particles (RP) in the 40 mg formulation with the soft pellets contained in HPMC capsules (35.0+/-1.8% for 28.3 l/min and 42.5+/-3.5% for 60 l/min), compared with the Spinhaler (13.8+/-3.0% for 28.3 l/min and 28.9+/-1.0% for 60 l/min). Using the formulations with the E-haler, proportional systemic absorption was achieved up to 40 mg FK888 in healthy volunteers (62.91+/-27.58, 103.70+/-40.19 and 254.79+/-85.01 ngh/ml as AUCs for 10, 20 and 40 mg FK888, respectively; R(2)=0.9641). It is also expected that the E-haler will act as an efficient device when a higher dose, such as 40 mg, is required in clinical situations.

Formulation development of inhalation powders for FK888 with carrier lactose using Spinhaler and its absorption in healthy volunteers.

(4R)-4-Hydroxy-l-[(l-methyl-lH-indol-3-yl)carbonyl]-L-prolyl-N-benzyl-N-methyl-3-(2-naphthyl)-L-alaninamide (FK888) is a candidate selective NK1 receptor antagonist, and it exhibits poor absorption from the gastrointestinal (GI) tract in healthy volunteers. The objective of this study was to develop an optimized DPI formulation with carrier lactose using a Spinhaler, and thereby improve the systemic absorption of FK888. The fine particles of FK888 were blended with various carrier lactoses, and in vitro deposition properties were investigated using a twin impinger. The mixture using 100 M and 325 M lactoses [Sieved lactoses (SLs)] exhibited a higher emitted dose (Em) than 200 M, 450 M and micronized lactoses [Milled lactoses (MLs)]. The flowability of carrier lactose had an influence on the Em. On the other hand, the respirable particle (RP) fraction in the formulations with MLs was much higher than that of SLs, in spite of the blended ratios of lactose. It was also observed that the mixture of 325 M with the micronized lactose particles had the same RP as 200 M, although the 325 M alone had a low RP. Considering the Em and RP obtained, we chose 200 M for FK888 dry powder inhaler (DPI). The proportional absorption was found up to the 12.5% of the FK888 ratio (5 mg as unit dose) for the Cmax and AUC in healthy volunteers. In conclusion, 200 M, which has fine lactose particles and a better flowability than other MLs, is an extremely suitable carrier for maximizing the fine particle dose as far as FK888 is concerned. Furthermore, an improvement in the systemic absorption of FK888 was achieved using the dry powder formulations.

Establishment of new preparation method for solid dispersion formulation of tacrolimus.

The aim of this study was to establish a new preparation method for solid dispersion formulation (SDF) of tacrolimus, a poorly water-soluble drug, without dichloromethane, because no use of dichloromethane is recommended by ICH harmonized tripartite guideline. To select the appropriate carrier, three different SDFs with polyethylene glycol 6000 (PEG 6000), polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) were prepared by the conventional solvent method, in which tacrolimus and the carrier were completely dissolved in the mixture of dichloromethane and ethanol. Powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) patterns indicated that tacrolimus exists in an amorphous state in all three SDFs. The supersaturated dissolution profiles of tacrolimus were observed in all SDFs, and the highest level of supersaturation for tacrolimus was obtained and maintained for 24h from SDF with HPMC. On the other hand, the supersaturated level from SDF with PEG 6000 or PVP decreased rapidly. The in vivo oral absorption study in dogs showed that bioavailability of tacrolimus from SDF with HPMC was remarkably improved compared with the crystalline powder. It was clarified that HPMC is the most appropriate carrier for SDF of tacrolimus. Then, SDF of tacrolimus was prepared by the new method, which allows us to make SDF of tacrolimus by swelling HPMC with ethanol, in which tacrolimus was completely dissolved. This new method does not need dichloromethane. The physicochemical properties of SDF with HPMC prepared by the new method were the same as those of SDF prepared by the conventional solvent method. Furthermore, SDF with HPMC prepared by the new method was still stable after stored at 40 degrees C for 3 months. The pharmacokinetic parameters after oral administration in monkeys showed no significant difference (P>0.01) between SDFs with HPMC prepared by the two methods. In conclusion, we have established the new preparation method for SDF of tacrolimus with HPMC and the new method makes it possible to prepare SDF of tacroliumus without dichloromethane.

Comparison of the lung absorption of FK224 inhaled from a pressurized metered dose inhaler and a dry powder inhaler by healthy volunteers.

FK224 is a cyclopeptide drug with poor oral absorption due to proteolysis in the gastrointestinal tract. The objectives of this study were to investigate the absorption of FK224 from the lung in healthy volunteers, and compare the pharmacokinetic profiles of FK224 after inhalation from a pressurized metered dose inhaler (pMDI) and dry powder inhaler (DPI). The pMDI (Suspension type, 1 mg as FK224/puff) and DPI (4 mg and 10 mg as FK224/capsule, using Spinhaler as the device) were developed by formulating the same micronized particles of FK224 which were premixed with beta-cyclodextrin (beta-CyD) to improve the solubility of FK224. In the case of pMDI, 1, 4 or 8 mg was inhaled by the corresponding number of puffs with the pMDI. In addition, the in vitro drug delivery characteristics of the inhalers were evaluated using a multistage liquid impinger. In both inhalers, it was observed that FK224 could be absorbed into the systemic circulation from the lungs of the healthy volunteers, and the AUC and C(max) were proportionally increased depending on the emitted dose after inhalation. However, the pharmacokinetic (PK) parameters for DPI were significantly higher than that of pMDI, in spite of usage of the same fine particles for the formulations in both inhalers. Based on the distribution from the in vitro examination, the fine particle dose, which is defined as the dose region delivered as particles <3.8 microm, was calculated from the emitted dose inhaled by the healthy volunteers. It was found that the PK parameters for both inhalers were proportionally increased depending on the predicted fine particle dose regardless of the type of inhaler. This suggests that the absorption from the lung is influenced by the fine particle dose. We concluded that DPI is a suitable inhaler for FK224, and the alveolus, which is generally known as the site of action of the fine particles, is a possible absorptive site for FK224.

Improvement of pulmonary absorption of cyclopeptide FK224 in rats by co-formulating with beta-cyclodextrin.

FK224 is a cyclopeptide drug with a low aqueous solubility. Following oral administration to rats, poor absorption was observed due to proteolysis in the gastrointestinal tract. The objective of this study was to investigate the effect of the pulmonary route on the systemic absorption of FK224 in comparison with other administration routes, and to determine the bioavailability (BA) of FK224 following pulmonary administration in rats using various dosage forms. From absorption studies on the Polyethylene Glycol 400 solution given by various routes (intranasal, subcutaneous, intratracheal and intravenous as reference), it was shown that pulmonary administration was a potentially attractive route for FK224. In the pulmonary absorption studies, after administration of the aqueous suspension, the BA was reduced to 2.7% compared with 16.8% for the solution. However, beta-cyclodextrin (beta-CyD) was found to be an effective additive as far as improving the solubility of FK224 was concerned. The BA of the aqueous suspension containing beta-CyD was increased to 19.2%. Pressurized metered dose inhalers were prepared by formulating beta-CyD with various molar ratios of 1:0, 1:1 and 1:7 (FK224/beta-CyD), and the resulting BAs were 4.3%, 29.0% and 91.2%, respectively. It was observed that both the C(max) and AUC of FK224 were increased as the amount of beta-CyD increased. The plasma profiles showed sustained absorption. In conclusion, we have seen that the lung is a suitable route for absorption of FK224, and beta-CyD is an extremely effective additive as far as improving the pulmonary absorption of FK224 is concerned. beta-CyD or derivatives with various degrees of aqueous solubility are potential drug carriers for controlling pulmonary absorption.