GOLF BALL-LIKE MICROPARTICLES FOR USE IN THE TREATMENT AND PREVENTION OF PULMONARY DISEASES

Abstract

The present invention relates to a golf ball-like microparticles obtained by atomization of nanosuspensions of nanoparticles or solutions for dry powder inhalers for use in the treatment and prevention of pulmonary diseases.

Claims

1. A plurality of microparticles or spherical microparticles for use in the treatment and prevention of respiratory diseases comprising one or more carriers and one or more active pharmaceutical ingredients, wherein a. the microparticles have a median mass aerodynamic diameter of 0.1 microns or more and 5 microns or less; b. the microparticles have a core-shell structure, with the carrier forming the shell and the active pharmaceutical ingredient forming the core; c. the microparticles have a plurality of golf ball-like surface depressions identifiable by scanning electron microscopy; d. the average maximum depth d of the surface depressions (1) is 5% or more and 30% or less as compared to the average maximum diameter D of the microparticles; and e. 50 surface area % or more as compared to the total surface of the microparticles are depressed; and optionally f. the Fine Particle Fraction of the plurality of microparticles is 50% or more.

2. The microparticles of claim 1 wherein the average maximal depth d of the surface depressions (1) is 25% or less as compared to the maximum diameter of the microparticle.

3. The microparticles of any of the preceding claims, wherein the average maximal depth d of the surface depressions (1) is 10% or more as compared to the maximum diameter D of the microparticle.

4. The microparticles of any of the preceding claims, wherein 70 surface area % or more as compared to the total surface of the microparticles are depressed.

5. The microparticles of any of the preceding claims, wherein the carrier is chosen from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, (HPBCD), 2-hydroxypropyl-γ-cyclodextrin, (HPBCD), sulfobutylether-beta-cyclodextrin, (SBEBCD), and methyl-beta-cyclodextrin (MBCD).

6. The microparticles of any of the preceding claims, wherein the carrier is hydroxypropyl-beta-cyclodextrin.

7. The microparticles of any of the preceding claims, wherein the carrier is present in an amount of 90 w. % or more as compared to the total weight of the microparticle.

8. The microparticles of any of the preceding claims, wherein the one or more active pharmaceutical ingredients are selected from the group consisting of corticosteroids, bronchodilators, antibiotics or anti-inflammatory compounds or combinations thereof.

9. The microparticles of any of the preceding claims, wherein the one or more active pharmaceutical ingredient is budesonide or formoterol or a combination thereof.

10. The microparticles of any of the preceding claims, wherein the molar ratio of the active pharmaceutical ingredient and the carrier is 1:1.

11. The microparticles of any of the preceding claims, further comprising amino acids.

12. The microparticles of any of the preceding claims, wherein the particles are obtained by spray-drying.

13. Use of a plurality of microparticles for delivering an active pharmaceutical ingredient through the respiratory system or the pulmonary system comprising one or more carriers and one or more active pharmaceutical ingredients, wherein a. the microparticles have a median mass aerodynamic diameter of 0.1 microns or more and 5 microns or less; b. the microparticles have a core-shell structure, with the carrier forming the shell and the active pharmaceutical ingredient forming the core; c. The microparticles have a plurality of golf ball-like surface depressions identifiable by scanning electron microscopy; d. the average maximum depth d of the surface depressions (1) is 5% or more and 30% or less as compared to the average maximum diameter D of the microparticles; e. 50 surface area % or more as compared to the total surface of the microparticles are depressed; and optionally f. the Fine Particle Fraction of the plurality of microparticles is 50% or more.

14. Use according to claim 13, wherein the active pharmaceutical ingredient is an active pharmaceutical ingredient for the treatment or prevention of asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pneumonia, and lung cancer.

15. A method of treatment of a disease, in particular a respiratory disease, comprising one or more carriers and one or more active pharmaceutical ingredients, wherein a. the microparticles have a median mass aerodynamic diameter of 0.1 microns or more and 5 microns or less; b. the microparticles have a core-shell structure, with the carrier forming the shell and the active pharmaceutical ingredient forming the core; c. the microparticles have a plurality of golf ball-like surface depressions identifiable by scanning electron microscopy; d. the average maximum depth d of the surface depressions (1) is 5% or more and 30% or less as compared to the average maximum diameter D of the microparticles; and e. 50 surface area % or more as compared to the total surface of the microparticles are depressed wherein the microparticles are administered per inhalation in an amount effective to reduce, stabilize or positively impact the symptoms of the disease, in particular the respiratory disease, preferably without causing treatment limiting side effects, such as those selected from the group consisting of renal clearance, hepatic impairment as expressed by elevated levels of transaminase, and wheezing after administration, as compared to subjects untreated with the microparticles of the invention. In another embodiment of the method of the present invention, the disease is a respiratory disease selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pneumonia, and lung cancer.

16. Process for the manufacturing of microparticles of any of the preceding claims, comprising the steps of: a. mixing of one or more carriers and one or more active pharmaceutical ingredients and a polar solvent to obtain a nanosuspension or a solution; b. spray-drying of nanosuspension or solution of step a.

Description

DRAWINGS

[0108] FIG. 1A is a comparative SEM image of a “deflated-ball like” shape of the prior art (Dufour 2015).

[0109] FIG. 1B is a comparative SEM image of the jujube-like cyclodextrin-raffinose binary carriers of the prior art (Zhao 2018).

[0110] FIG. 2A is an SEM image of an embodiment of a golf-ball like microparticle of the present invention comprising budesonide and a hydroxypropyl-beta-cyclodextrin carrier.

[0111] FIG. 2B is an SEM image of an embodiment of a plurality of golf-ball like microparticles of the present invention comprising budesonide and a hydroxypropyl-beta-cyclodextrin carrier.

[0112] FIG. 3 is an SEM image of an embodiment of a plurality of golf-ball like microparticles of the present invention comprising budesonide, a hydroxypropyl-beta-cyclodextrin carrier and 1 w % leucine.

[0113] FIG. 4 is an SEM image of an embodiment of a plurality of the golf ball-like microparticles of the present invention comprising budesonide, a hydroxypropyl-beta-cyclodextrin carrier and 2 w % leucine.

[0114] FIG. 5 is an SEM image of an embodiment of a plurality of the golf ball-like the microparticles of the present invention comprising budesonide, a hydroxypropyl-beta-cyclodextrin carrier and 5 w % leucine.

[0115] FIG. 6 is an SEM image of an embodiment of a plurality of the golf ball-like microparticles of the present invention comprising budesonide, a hydroxypropyl-beta-cyclodextrin carrier and formoterol.

[0116] FIG. 7 is an SEM image of an embodiment of a plurality of the golf ball-like microparticles of the present invention comprising budesonide, a hydroxypropyl-beta-cyclodextrin carrier, formoterol and 2 w % leucine.

[0117] FIG. 8 is a simplified schematic drawing of the measurement of the maximal depth of a surface depression of a golf-ball like microparticle of the present invention.

[0118] FIG. 9 is a simplified schematic drawing of the measurement of the maximal diameter of a golf-ball like microparticle of the present invention.

[0119] FIG. 10A is an SEM image of an embodiment of a plurality of the golf ball-like microparticles of the present invention according to example 20.

[0120] FIG. 10B is an SEM image of an embodiment of a plurality of the golf ball-like microparticles of the present invention according to example 21.

[0121] FIG. 100 is an SEM image of an embodiment of a plurality of the golf ball-like microparticles of the present invention according to example 22.

[0122] FIG. 11 is an SEM image of an embodiment of a plurality of the golf ball microparticles of the present invention according to example 1.

[0123] FIG. 12 is an SEM image of an embodiment of a plurality of the golf ball microparticles of the present invention according to example 2.

[0124] FIG. 13 is an SEM image of comparative example 1.

[0125] FIG. 14 is an SEM image of comparative example 2.

[0126] FIG. 15 shows the NGI deposition of budesonide of examples 1 and 2, comparative examples 1 and 2 and Symbicort.

[0127] FIG. 16 shows the NGI deposition of formoterol of examples 1 and 2, comparative examples 1 and 2 and Symbicort.

[0128] FIG. 17 shows the Fine Particle Fraction of examples 1 and 2, comparative examples 1 and 2 and Symbicort.

[0129] FIG. 18 is an SEM picture of the golf-ball like microparticles according to example 3 also referred to as JT OPT.

[0130] FIG. 19 is an SEM picture of the golf-ball like microparticles according to example 4 also referred to as AQU.

[0131] FIG. 20 is an SEM picture of less deflated balls according to comparative example 3 also referred to as HPd3 2%.

[0132] FIG. 21 is an SEM picture of less deflated balls according to comparative example 4 also referred to as HPd3 5%.

[0133] FIG. 22 is an evaluation of budesonide lung deposition evaluated in vitro with NGI apparatus of examples 3 and 4 and comparative examples 3 and 4 with three repetitions.

[0134] FIG. 23 is an evaluation of formoterol lung deposition evaluated in vitro with NGI apparatus of examples 3 and 4 and comparative examples 3 and 4 with three repetitions.

[0135] FIGS. 24 and 25 show of the Fine Particles Fraction (FPF) obtained for the four powders using NGI apparatus. FPF was calculated compared to the total dose powder or compared to the Recovery Dose (RD=powder in throat, pre-separator and all stages) n=3.

[0136] FIG. 26 shows the correlation between Fine Particles Fraction (FPF—compared to RD) and the number of surface depressions—also referred to as dimple numbers—observed on SEM pictures of examples 3 and 4 and comparative examples 3 and 4.

[0137] In the drawings, the same reference numbers have been allocated to the same or analog element.

EXAMPLES

Examples 1 and 2

[0138] Example 1 also referred to as HPbCD JT shows microparticles according to the invention comprising hydroxypropyl-beta-cyclodextrin (HPBCD) as carrier and budesonide and formoterol as active pharmaceutical ingredients. 99; 29 w % of the dry weight are HPBCD and 0,0.71 of the dry weight of the solution are active pharmaceutical ingredient. 97 w % of the active pharmaceutical ingredient are budesonide and 3 w % of the active pharmaceutical ingredient are formoterol.

[0139] The microparticles of example 1 are obtained by spray-drying with 10 w % HPBCD of the dry weight, a nozzle diameter of 0.5 mm, an inlet temperature of 160° C., a pump speed of 50 RPM and a nozzle gas pressure 2.25 bar. The SEM is shown in FIG. 11.

[0140] Example 2 also referred to as HPbCD 100 shows microparticles are obtained by spray-drying of a liquid with a 10% HPBCD, a nozzle diameter of 0.4 mm, an inlat temperature of 140° C., a pump speed of 200 RPM and a nozzle gas pressure 4 bar. The SEM is shown in FIG. 12.

Comparative Examples 1 and 2

[0141] The less deflated balls of comparative example 1—also referred to as HPbCD AQ June 2020 2% —are obtained by spray-drying of a liquid with a 2% HPBCD, a nozzle diameter of 0.2 mm, an inlat temperature of 160° C., a pump speed of 200 RPM and a nozzle gas pressure of 4 bar. The SEM is shown in FIG. 13.

[0142] The less deflated balls of comparative example 2—also referred to as HPbCD AQ June 2020 5% —are obtained by spray-drying of a liquid with a 5% HPBCD, a nozzle diameter of 0.2 mm, an inlat temperature of 100° C., a pump speed of 200 RPM and a nozzle gas pressure of 4 bar. The SEM is shown in FIG. 14.

[0143] FIGS. 15 and 16 show the NGI deposition described below of three repetitions. The golf-ball-like particles of the invention perform better than Symbicort® on the one and side and less deflated balls on the other hand side. The deposition in the device (dispositive) is higher with Symbicort. The deposition in the deep lung (stages 2, 3, 4, 5) are better by the golf-ball like microparticles of the invention according to examples 1 and 1 as compared to the less deflated balls of comparative examples 1 and 2.

[0144] FIG. 17 shows the Fine Particle Fraction (FPF) of the budesonide and formoterol of examples 1 and 2 and comparative examples 1 and 2 as well as Symbicort.

Examples 3 and 4 and Comparative Examples 3 and 4

[0145] Active pharmaceutical ingredients were budesonide and formoterol with varying levels of the carrier hydroxypropyl-beta-cyclodextrin of 2, 5 and 10 w % of the solid content and varying spray-drying conditions as to nozzle size, temperature and pressure.

[0146] Chemicals and Solutions

[0147] HPBCD (Kleptose HPB−molar substitution=0.63) was provided by Roquette (Lestrem, France). Budesonide Ph. Eur. 8.3 Micronized was obtained from Crystal Pharma and Formoterol Fumarate dehydrate Micronized from CHEMO Industriale chimica.

[0148] Budesonide and formoterol quantification High performance liquid chromatography (HPLC) was used to quantify budesonide and formoterol using a HPLC Agilent série 1100, UV detector operating at 243 nm and with a 3*50 mm column filled 3.5 μm C18 (X Bridge BEH C18). The mobile phase was composed of Acetate ammonium buffer pH10/methanol at this gradient mode (0 min—55/45(v/v), 1 min—55/45(v/v); 2 min—35/65(v/v); 7 min—35/65(v/v); 8 min—55/45(v/v); 20 min—55/45(v/v)) at a flow rate of 0.7 ml/min. The column is heated up at 30° C. and sampler at 10° C.

[0149] The process was fully validated based on total error as decision criterion. The acceptance limits were set at 10%. All validation results were computed using the e-noval1 software (Arlenda, Liege, Belgium).

[0150] HPBCD-Budesonide-Formoterol Solution

[0151] Before atomization, the solutions containing the two active ingredients budesonide and formoterol are prepared as follows. Concentration of HPBCD were 2, 5 or 10% (g/100 ml). The excipients (99.29 w %) are first weighed and diluted in miQ water. After complete dissolution, this solution is divided in half and placed on a heating stirring bath (37° C.). The active ingredients (0.71 w %) are added separately in one of the two excipient solutions and dissolved under magnetic stirring at 37° C. for 2 hours. Budesonide is present at 97% and formoterol at 3% in the solution. After complete dissolution, the two solutions are combined before atomization.

[0152] Spray-Drying

[0153] A procept 4M8-Trix Formatrix spray-dryer (Procept, Zelzate, Belgium) with bi-fluid nozzle was used. Four different powders were produced from different solutions and different process parameters:

TABLE-US-00001 TABLE 1* Process parameters production AQU HPd3 2% HPd3 5% JT OPT Solid content (w/w) % 5 2 5 10 Cyclone Gas Pressure 0.75 0.75 0.75 0.75 (bar) Inlet Gas Flow (q .sup.7S/min) 0.4 0.4 0.4 0.4 Inlet T° (° C.) 140 100 100 160 Pump Speed (RPM) 200 200 200 100 Nozzle Gas Pressure (bar) 4 4 4 2.25 Nozzle diameter (mm) 0.4 0.2 0.2 0.6

[0154] Particle Size Distribution Measurement

[0155] A laser diffractometer Mastersizer 2000 connected with a Scirocco powder feeder Malvem, UK) was used to estimate the inhalable fraction (1-5 mm) of powders produced during the design of experiment. A dispersion pressure of 4 bars and a measuring time of 10 s were used. For each sample, approximately 150 mg of powder was used to obtain the required obscuration of 0.5-5%.

[0156] Scanning Electron Microscopy

[0157] The particulate structure was observed by scanning electron microscopy (SEM) using either a Philips XL30 ESEM, or a FEI Quanta 600 after metallization with Au (˜50 nm). Representative micrographs were captured, and a dozen particles were sampled for each powder to measure their diameter, and quantify their structure in terms of number and depth of the surface depressions also referred to as dimples.

[0158] Thermogravimetric Analysis

[0159] The residual moisture content of the samples was investigated directly after spray-drying by using a TGA 7 (Perkin Elmer, Norwalk, Conn.). Powder samples between 3 and 12 mg were loaded onto a platinum sample pan and heated from 25 to 150° C. at a rate of 10° C./min.

[0160] Bulk and Tapped Density

[0161] Bulk density and tapped density were obtained by following the Ph. Eur. procedure 2.9.34 [15]. Due to the small amount of sample, a 10-mL tarred graduated cylinder was used. The bulk volume used for the calculation of the bulk density was directly read from the cylinder.

Bulk density(g/ml)=(weight of powder)/(bulk powder volume)

[0162] The tapped density is obtained by mechanically tapping a graduated measuring cylinder containing the powder sample [15]. The tapped density is read after 1250 taps corresponding to 5 min at a tapping height of 3 mm. The mean value of three replicates is recorded along with the observed variances among the experiments.

Tapped density(g/ml)=(weight of powder)/(tapped powder volume)

The Carr index (%) is also calculated as followed=((initial volume(ml)−final volume(ml))/final volume(ml))*100

The Hausner ratio is also calculated as followed=initial volume(ml)/final volume(ml)

[0163] In-Vitro Powder Aerosolisation

[0164] The pulmonary deposition profile of the powder produced during spray drying is determined in vitro by a New Generation Impactor (NGI). The device, a dry powder inhaler, is connected to the induction port by a mouthpiece mimicking the mouth. The NGI is divided into 8 stages characterized by a pore diameter covering a particle size range between 0.206 μm and 12.8 μm. A pump, connected to the NGI, allows the pressure and flow to be adjusted. Twelve capsules, containing a known mass of powder, are perforated by the device, of the Aerolizer® type, and emptied of their contents. This passes through the NGI at a flow rate of 100 mL/min for a period of 2.4 seconds. Once these twelve capsules have been introduced, the powder deposited at each level is recovered using a methanol/water solvent (65/35 V/V) and analyzed by HPLC. The total mass measured after each test in the throat and in stages 1 to 8 is defined as the recovered dose (RD). The fine particle dose (FPD) is defined as the total mass ranging from 0 μm to 5 μm. The fine particle fraction is calculated by dividing the FPD by the RD expressed as a percentage.

[0165] Results

[0166] Powder Characteristics

TABLE-US-00002 TABLE 2* Evaluation of powders properties Powder properties AQU HPd3 2% HPd3 5% JT OPT Process 75.05 74 71.2 83.2 yield (%) Particle size 2.57 1.79 3.65 2.15 (d0.5) Carr index (%) 68.1 50.9 62.5 36.9 Water content 7.20 5.51 7.37 4.49 (%)

[0167] Powder Morphology

[0168] The morphology of all powders has been analyzed by SEM. Each powder has been scanned. We have chosen pictures which are the most representative of all powder population. Powders have different morphology. While examples 3 and 4 also referred to as JT OPT and AQU powders more than 50 surface % of surface depressions or dimples, comparative examples 3 and 4 also referred to as HPd3 2% and HPd3 5% show fewer surface depressions. These differences are due to the different atomization process parameter.

[0169] The morphology of all powders has been analyzed by SEM. Each powder of example 3 and 4 and comparative examples 3 and 4 has been scanned. Representative SEM images are shown in FIGS. 18, 19 (examples 3 and 4) and comparative FIGS. 20, 21 (comparative examples 3 and 4).

TABLE-US-00003 TABLE 3* Evaluation of powders in terms of dimples number based on SEM pictures Powder properties AQU HPd3 2% Pd3 5% JT OPT Dimples number 10 6 8 13

[0170] Powders In Vitro Lungdeposition

[0171] FIGS. 22 and 23 show the evaluation of the powders according to examples 3 and 4 and comparative examples 3 and 4.

[0172] FIGS. 24 and 25 show the Fine Particles Fraction (FPF) obtained for the four powders according to examples 3 and 4 and comparative examples 3 and 4 using NGI apparatus. FPF was calculated compared to the total dose powder or compared to the Recovery Dose (RD=powder in throat, pre-separator and all stages) n=3.

CONCLUSIONS

[0173] Different solid content of spray dried solutions and different atomization process parameters according to examples 3 and 4 and comparative examples 3 and 4 produce HPβCD microparticle powders containing budesonide and formoterol with different morphologies.

[0174] Difference of lung deposition have been found between powders according to examples 3 and 4 and comparative examples 3 and 4. With similar particle size or water content, the morphological differences between the powders according to examples 3 and 4 and comparative examples 3 and 4 explain the different lung deposition performances.

Examples 13 to 27

[0175] Microparticles with the API Budesonide (BD)-Hydroxypropylbetacyclodextrin (HPBCD) and cyclodextrins were 15 obtained through spray-drying. Budenoside was used in the amount of 106 μg in 15 mg of spray-dried powder. Following combinations were tested: [0176] Budesonide-HPBCD (test14) [0177] Budesonide-HPBCD+5% L-leucine (test 15) [0178] Budesonide-HPBCD+10% L-leucine (test 13) 20

[0179] Budesonide-Formoterol-HPBCD powder with 106 μg of Budesonide and 3 μg of formoterol in 15 mg of powder: [0180] Budesonide-Formoterol-HPBCD (test 16) [0181] Budesonide-Formoterol-HPBCD+5% L-leucine (test 19) 25

Comparative Example: Miflonide® (Novartis) Containing 230 μg of Budesonide

[0182] Tested formulations and their particle size distribution are shown in table 1. The spray-drying parameters are shown in Table 2.

[0183] The golf-ball like microparticles of Table 1 spray-dried according to the process conditions shown in Table 2 were then evaluated for their aerodynamic properties using Next Generation Impactor (NGI) as recommended by European Pharmacopeia and USP, the results of which are shown in Tables 4 to 6. Aerolizer® was used for 5 testing. HPLC standard reagents Methanol and Milli-Q water were used.

[0184] The NGI was assembled and a pre-separator was used for Miflonide since the formulation contains lactose. By means of the regulator and a flow meter connected to the inlet nozzle, the flow rate was adjusted to provide a steady state of 100 L/min plus, minus 5% in the apparatus. 10 The air circulation was stopped. The nozzle adapter at the end of the intake nozzle was installed. A certain number of doses was released from the inhaler according to the directions for use: [0185] For Budesonide-HPBCD and Budesonide-Formoterol-HPBCD (15 mg of powders): 10 doses 15 [0186] Miflonide 230 μg of budesonide: 5 doses

[0187] Then the pump was turned on the solenoid valve was closed, and the inhaler was placed in the adapter. A discharge of powder was let into the device by opening the solenoid valve for 2.4 seconds (4 L of 20 air). The capsule was put inside a flask. The volumes are described in Table 3 below.

[0188] The inhaler and mouthpiece adapter were removed from the NGI Induction Port. The active ingredient was extracted from the inhaler 25 and mouthpiece in the same flask (see volume in Table 3 below) with the mix methanol/water 65/35.

[0189] The active ingredients from the induction port were extracted in a flask with the mix methanol/water 65/35. For Miflonide, the active ingredients were extracted from the pre-separator in a flask. The volumes are indicated in Table 3A below.

[0190] Then, the NGI was opened and the contents retrieved in the eight collection cups: [0191] 10 mL of mix methanol/water 65/35 were added in 5 each cup and mix it shaking gently each cup until complete dissolution. Each solution was put in different flasks (see volume in Table 3A below). [0192] the “backside” of each nozzle piece was extracted by placing the seal body vertically with the help of two supports. [0193] the nozzles of stages 1 through 8 were rinsed using 1010 mL of the mix methanol/water 65/35 and the solution was put in the corresponding flask and was filled up to the mark with the mix. After mixing and sonication for 15 minutes the solution was analyzed in HPLC.

[0194] Fine Particle Dose (FPD), MMAD and GSD were calculated by the software CITDAS (Copley). Fine Particle Fraction (FPF) which is the 15 percentage of FPD over the nominal dose, is calculated manually.

[0195] It should be understood that the present invention is not limited to the described embodiments and that variations can be applied without going outside of the scope of the appended claims.

TABLE-US-00004 TABLE 1 Formulations and particle size distribution Solid % Frac % % % % content D10 D50 D90 <5 μm Example Formulation Bodesonide Formoterol Leucine HPBCD (% w/w) (μm) (μm) (μm) SPAN (%) 13 Budesonide-HPBCU- 0.01 0.00 0.10 0.89 0.05 0.53 2.29 5.06 1.98 89.67 10% Leucine 14 Budesonide-HPBCD 0.01 0.00 0.00 0.99 0.05 0.56 2.28 5.11 1.99 89.40 15 Budesonide-HPBCD- 0.01 0.00 0.05 0.94 0.05 0.53 2.16 4.83 1.99 91.45 5% Leucine 16&17 Budesonide-HPBCD- 0.01 0.00 0.00 0.99 0.05 0.58 2.37 5.04 1.88 89.76 Formoterol 19 HPBCD-0.0040% 0.01 0.00 0.05 0.94 0.05 0.54 2.29 5.05 1.97 89.75 Formoterol 20 Budesonide-HPBCD 0.01 0.00 0.00 0.99 0.05 0.57 2.32 5.23 2.01 88.70 21 Budesonide-HPBCD- 0.01 0.00 0.05 0.94 0.05 0.60 2.52 5.44 1.92 87.08 5% Leucine 22 Budesonide-HPBCD- 0.00 0.01 0.01 0.99 0.05 0.59 2.44 5.42 1.98 87.23 1% Leucine 24 Budesonide- 0.01 0.00 0.02 0.97 0.05 0.61 2.40 5.36 1.98 87.89 Formoterol-HPBCD- 2% Leucine 25 Budesonide-HPBCD- 0.01 0.00 0.02 0.97 0.05 0.58 2.39 5.41 2.02 87.59 2% Leucine 26 Budesonide-HPBCD 0.01 0.00 0.00 0.99 0.05 0.58 2.19 4.82 1.94 91.47 27 Budesonide-HPBCD- 0.01 0.00 0.05 0.94 0.05 0.53 2.16 4.85 1.99 91.23 5% Leucine

TABLE-US-00005 TABLE 2 Spray drying conditions of the examples of Table 1 Example 13 14 15 16 17 18 19 20 21 22 API BD BD BD BD BD BD BD Form BD BD BD complex HPBCD HPBCD HPBCD HPBCD HPBCD HPBCD HPBCD HPBCD HPBCD HPBCD Leucine      10% /      5% / / /      5% /      5%      1% Solvent Water Water Water Water Water Water Water Water Water Water Solid content    5.00%    5.00%    5.00%    5.00%    5.00%    5.00%    5.00%    5.00%    5.00%    5.00% Temp (° C.) 120 120 120 120 126 126 128 140 140 140 Temp chamber out (° C.) 57 57 57 56 52 53 53 57 57 57 Temp before cyclone (° C.) 44 44 44 43 43 42 44 52 52 51 Cyclone Small Small Small Small Small Small Small Small Small Small Pressure drop cyclone 82 82 82 82 82 82 82 82 82 84 (mbar) Airflow (m.sup.2/min) 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.4 0.4 0.4 Cooling air (l/min) 146 146 146 146 146 146 146 0 0 0 Bi-fluid Nozzle (mm) 0.4 0.4 9.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 Nozzle Air 14 14 14 14 14 14 14 20 20 20 US Nozzle (kHz) / / / / / / / / / / Amplitude (Watt) / / / / / / / / / / Spray rate (g/min) 4.7 4.7 4.7 4.7 4.7 4.7 4.7 10 10 10 Pumping speed (rpm) 66 66 86 66 66 66 66 160 160 160 Tube type (ID) resistant 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 Total dosed sample (g) 200 97.70 99.90 50.00 547.00 497.00 99.00 1399.60 1396.00 923.40 Recovered solid (g) 8.45 4.33 4.09 1.83 23.45 21.56 4.42 65.47 63.67 42.12 Total solid dosed (g) 10 4.89 5.00 2.50 27.35 24.85 4.95 69.98 69.80 46.17 Recovery (%) 84.5 89 82 73 86 87 89 94 91 91 Example 24 25 26 27 API Bud Form BD BD BD complex HPBCD HPBCD HPBCD HPBCD Leucine      2%      2%      0%      5% Solvent Water Water Water Water Solid content    5.45%    5.00%    5.00%    5.00% Temp (° C.) 140 140 140 140 Temp chamber out (° C.) 56 54 57 56 Temp before cyclone (° C.) 54 53 55 54 Cyclone Small Small Small Small Pressure drop cyclone 84 84 84 84 (mbar) Airflow (m.sup.2/min) 0.4 0.4 0.4 0.4 Cooling air (l/min) 0 0 0 0 Bi-fluid Nozzle (mm) 0.4 0.4 0.4 0.4 Nozzle Air 20 20 20 20 US Nozzle (kHz) / / / / Amplitude (Watt) / / / / Spray rate (g/min) 10 10 10 10 Pumping speed (rpm) 160 160 160 160 Tube type (ID) resistant 1.2 1.2 1.2 1.2 Total dosed sample (g) 1092.00 1196.30 1204.00 1206.00 Recovered solid (g) 52.83 52.55 55.09 54.22 Total solid dosed (g) 59.61 59.82 57.60 60.30 Recovery (%) 89 88 96 90

TABLE-US-00006 TABLE 3A Volumes of flask to use for each extraction Budesonide- HPBCD or Budesonide- Formoterol- HPBCD Miflonide Capsules/ 50 mL 50 mL Device/ Mouthpiece Induction port 50 mL 50 mL Pre-separator — 100 mL  Stage 1 25 mL 25 mL Stage 2 25 mL 25 mL Stage 3 25 mL 25 mL Stage 4 25 mL 25 mL Stage 5 25 mL 25 mL Stage 6 25 mL 25 mL Stage 7 (grouped (grouped Stage 8 together) together)

TABLE-US-00007 TABLE 3B Effective cut-off diameter (ECD) at 100 L/min or each stage is given in the table below: Mass of Cumulated mass ECD (μm) budesonide of budesonide Cumulative at 100 deposited deposited per percentage L/min per discharge (μg) discharge(mg) (%) d.sub.7 = 0.24 mass extracted at c.sub.7 = m.sub.8 f.sub.7 = (c.sub.7/c) .Math. 100 stage 8, m.sub.8 d.sub.6 = 0.40 mass extracted at c.sub.6 = c.sub.7 + m.sub.7 f.sub.6 = (c.sub.6/c) .Math. 100 stage 7, m.sub.7 d.sub.5 = 0.72 mass extracted at c.sub.5 = c.sub.6 + m.sub.6 f.sub.5 = (c.sub.5/c) .Math. 100 stage 6, m.sub.6 d.sub.4 = 1.31 mass extracted at c.sub.4 = c.sub.5 + m.sub.5 f.sub.4 = (c.sub.4/c) .Math. 100 stage 5, m.sub.5 d.sub.3 = 2.18 mass extracted at c.sub.3 = c.sub.4 + m.sub.4 f.sub.3 = (c.sub.3/c) .Math. 100 stage 4, m.sub.4 d.sub.2 = 3.42 mass extracted at c.sub.2 = c.sub.3 + m.sub.3 f.sub.2 = (c.sub.2/c) .Math. 100 stage 3, m.sub.3 d.sub.1 = 6.17 mass extracted at c.sub.1 = c.sub.2 + m.sub.2 f.sub.1 = (c.sub.1/c) .Math. 100 stage 2, m.sub.2 mass extracted at .sup. c = c.sub.1 + m 100 stage 1, inhalator, mouthpiece and induction port, m

TABLE-US-00008 TABLE 4 Comparative example and exemplary embodiments of the invention and their NGI deposition Comparative example Budesonide-HPBCD Budesonide-HPBCD Miflonide (example 14) (example 20) Average % Budesonide NA NA 0.64 μg Budesonide  230.00  230.00  106.00  106.00  96.69  96.31 Total dose (μg) 1150.00 1150.00 1060.00 1060.00 966.89 963.14 NGI 1 NGI 2 Average NGI 1 NGI 2 Average NGI 1 NGI 2 Average in μg in μg in μg in μg in μg in μg in μg in μg in μg Capsule/device/mouthpiece 256.60 277.80 267.20 97.75 51.30 74.53 191.15 173.60 182.38 Induction port 138.15 161.10 149.63 93.95 108.80 101.38 72.35 82.25 77.30 Pre-separator 476.65 524.00 500.33 Stage 1 19.48 26.48 22.98 51.00 48.35 49.68 60.43 57.18 58.80 Stage 2 29.20 47.85 38.53 139.53 135.83 137.68 138.08 144.10 141.09 Stage 3 42.78 68.53 55.65 147.33 131.28 139.30 147.03 158.85 152.94 Stage 4 50.30 71.38 60.84 110.83 111.33 111.08 104.18 112.28 108.23 Stage 5 23.63 26.20 24.91 79.15 87.25 83.20 57.90 56.90 57.40 Stage 6, 7, 8 14.03 16.65 15.34 92.15 99.48 95.81 73.18 69.73 71.45 Recovery (%) 91.37 106.08 98.73 76.57 72.98 74.78 87.32 88.76 88.04 MMAD (μm) 3.08 3.33 3.21 2.37 2.25 2.31 2.58 2.59 2.58 GSD 2.26 2.10 2.18 2.00 2.08 2.04 1.99 1.93 1.96 FPD (<5.0 μm) (μg) 26.63 37.33 31.98 53.35 53.09 53.22 48.34 50.42 49.38 FPF (<5.0 μm) (%) 11.58 16.23 13.90 50.33 50.08 50.21 50.00 52.35 51.17 FPF over recovered dose (%) 25.34 30.60 28.17 65.73 68.63 67.14 57.26 58.98 58.12

TABLE-US-00009 TABLE 5 Further exemplary embodiments of the invention and their NGI deposition Budesonide-HPBCD Budesonide-HPBCD + 10% Budesonide-HPBCD + 5% (example 26) Leucine (example 13) Leucine (example 15) Average % Budesonide 0.66 NA NA μg Budesonide  99.81  100.55  106.00  106.00  106.00  106.00 Total dose (μg) 998.13 1005.47 1060.00 1060.00 1060.00 1060.00 NGI 1 NGI 2 Average NGI 1 NGI 2 Average NGI 1 NGI 2 Average in μg in μg in μg in μg in μg in μg in μg in μg in μg Capsule/device/mouthpiece 138.35 142.10 140.23 59.30 53.58 56.58 66.60 56.95 61.78 Induction port 86.85 105.90 96.38 124.10 103.25 113.68 88.25 82.20 85.23 Pre-separator Stage 1 50.05 66.15 58.10 54.28 49.20 51.74 41.03 39.70 40.36 Stage 2 154.50 152.15 153.33 141.65 139.00 140.33 133.23 115.53 124.88 Stage 3 144.30 143.80 144.05 128.45 114.08 121.26 123.03 102.35 112.69 Stage 4 90.15 98.88 94.51 86.33 83.50 84.91 116.08 97.15 106.61 Stage 5 74.10 76.60 75.35 69.83 61.73 65.78 92.68 82.73 87.70 Stage 6, 7, 8 99.20 87.98 93.59 93.55 112.23 102.89 109.35 126.85 118.10 Recovery (%) 83.91 86.88 85.39 71.46 67.63 69.54 72.66 66.46 69.56 MMAD (μm) 2.49 2.54 2.52 2.48 2.38 2.43 2.09 1.93 2.01 GSD 1.94 2.03 1.99 2.01 2.06 2.04 2.14 2.32 2.23 FPD (<5.0 μm) (μg) 52.36 51.86 52.11 48.30 47.51 47.90 54.21 49.68 51.94 FPF (<5.0 μm) (%) 52.46 51.58 52.02 45.56 44.82 45.19 51.14 46.87 49.00 FPF over recovered dose (%) 62.52 59.37 60.91 63.76 66.27 67.98 70.38 70.52 70.45

TABLE-US-00010 TABLE 6 Further exemplary embodiments of the invention and their NGI deposition Budesonide-HPBCD +5% Budesonide-HPBCD + 5% Budesonide-HPBCD + 2% Budesonide-HPBCD + 1% Leucine (example 21) Leucine (example 27) Leucine (example 25) Leucine (example 22) Average % Budesonide 0.64 0.65 0.67 0.66 μg Budesonide  96.16  96.10  99.49  100.28  99.96  100.45  102.18  100.34 Total dose (μg) 961.60 961.03 994.93 1002.78 999.63 1004.49 1021.84 1003.40 NGI 1 NGI 2 Average NGI 1 NGI 2 Average NGI 1 NGI 2 Average NGI 1 NGI 2 Average in μg in μg in μg in μg in μg in μg in μg in μg in μg in μg in μg in μg Capsule/device/mouthpiece 168.65 154.60 161.63 125.45 136.50 130.98 136.10 156.20 146.15 160.55 169.25 164.90 Induction port 80.20 81.90 81.05 131.85 76.25 104.05 65.70 88.40 77.05 70.95 74.95 72.95 Pre-separator Stage 1 58.05 64.63 61.34 70.70 62.10 66.40 70.95 61.18 60.06 85.46 70.63 78.04 Stage 2 164.90 158.53 161.71 140.73 143.45 142.09 163.53 154.88 159.20 154.53 145.65 150.09 Stage 3 146.75 144.83 145.79 121.68 129.93 125.80 130.18 119.78 124.98 129.80 128.58 129.19 Stage 4 85.15 79.95 82.55 97.43 92.15 94.79 80.05 86.28 83.16 83.50 74.58 79.04 Stage 5 53.13 55.63 54.38 75.85 77.65 76.75 71.25 72.00 71.63 68.68 65.88 67.28 Stage 6, 7, 8 77.93 74.38 76.15 77.85 104.40 91.13 112.38 89.20 100.79 92.73 95.98 94.35 Recovery (%) 86.81 84.75 85.78 84.58 82.01 83.30 83.04 82.42 82.73 82.81 82.27 82.54 MMAD (μm) 2.76 2.79 2.78 2.54 2.42 2.48 2.60 2.57 2.59 2.71 6.64 2.67 GSD 1.87 1.91 1.89 2.14 2.10 2.12 2.05 2.03 2.04 2.12 2.07 2.10 FPD (<5.0 μm) (μg) 48.51 47.08 47.80 47.46 50.94 49.20 51.32 48.12 49.72 48.54 47.05 47.79 FPF (<5.0 μm) (%) 50.45 48.99 49.72 47.71 50.80 49.25 51.34 47.90 49.62 47.50 46.89 47.20 FPF over recovered dose (%) 58.11 57.81 57.96 56.40 61.94 59.14 61.83 58.12 59.97 57.36 57.00 57.18