INHALABLE LACTOSE CONTAINING COMPOSITION

Abstract

The invention relates to a powder composition comprising spherically agglomerated lactose particles comprising radially arranged prism-like lactose particles, at least one active pharmaceutical ingredient (API) and optionally at least one additive, its manufacture and its use for inhalation applications.

Claims

1. A powder composition comprising: (i) spherically agglomerated lactose particles comprising radially arranged prism-like lactose particles, (ii) at least one active pharmaceutical ingredient (API), and (iii) optionally at least one additive.

2. The powder composition according to claim 1, wherein component (i) comprises α-lactose, β-lactose or combinations thereof, preferably α-lactose, and/or wherein component (i) comprises anhydrous lactose, lactose monohydrate or combinations thereof, preferably lactose monohydrate.

3. The powder composition according to claim 1, wherein component (i) is obtained according to the process comprising the steps: (a) preparing a lactose solution, (b) adding the lactose solution obtained after step (a) to at least one non-solvent under constant stirring to form spherically agglomerated lactose particles comprising radially arranged prism-like lactose particles, (c) isolating the spherically agglomerated lactose particles, and (d) optionally drying.

4. The powder composition according to claim 1, wherein component (i) has an average particle size from 50-1,000 μm, preferably from 100-400 μm, and/or wherein component (i) has a d.sub.50 value from 50-250 μm, preferably from 75-200 μm, and/or wherein component (i) has a specific surface area from 0.5-5.0 m.sup.2/g, preferably from 0.6-3.5 m.sup.2/g.

5. The powder composition according to claim 1, wherein the API in component (ii) is selected from a respiratory and a systemic active pharmaceutical ingredient, preferably for the treatment of diseases of the respiratory system, diseases caused by bacteria, diseases of the cardiovascular system, allergic reactions, cancer, psychiatric diseases and immune system related diseases.

6. The powder composition according to claim 1, wherein component (ii) has a particle size distribution d.sub.50 of 1-10 μm, preferably 1-5 μm.

7. The powder composition according to claim 1, wherein the API of component (ii) is adsorbed on component (i).

8. The powder composition according to claim 1, wherein the overall powder composition has a d.sub.50 value in the range from 50-1000 μm, preferably from 50-300 μm, more preferably from 50-150 μm, and/or wherein the overall powder composition has a fine particle fraction (FPF) ranging from 20-90%, preferably from 30-80%, more preferably from 40-70%, and/or wherein the overall powder composition has a mass median aerodynamic diameter (MMAD) ranging from 0.5-5 μm, preferably from 1-4 μm, more preferably from 1.5-3 μm.

9. The powder composition according to claim 1, wherein the amount of component (i) in the powder composition is in the range of 50-99.9 wt.-%, preferably in the range of 80-99.9 wt.-%, based on the total amount of components (i) and (ii).

10. The powder composition according to claim 1, wherein the amount of component (ii) in the powder composition is in in the range from 0.1-50 wt.-%, preferably in the range from 0.1-20 wt.-%, based on the total amount of components (i) and (ii).

11. The powder composition according to claim 1, wherein component (iii) in the powder composition is present in the range from 0.1-20 wt.-%, preferably in the range from 0.1-10 wt.-%, based on the total amount of components (i), (ii) and (iii).

12. A method of preparing a powder composition according to claim 1, comprising the steps of: (1) adding components (ii) and optionally (iii) to component (i), (2) mixing the product obtained after step (1), and (3) optionally sieving the mixture obtained after step (2).

13. The powder composition according to claim 1, for use as inhalable medicament and/or inhalable diagnostic agent.

14. The powder composition according to claim 1, for use in the treatment of diseases of the respiratory system, diseases caused by bacteria, diseases of the cardiovascular system, allergic reactions, cancer, psychiatric diseases and/or immune system related diseases.

15. A use of component (i) as carrier in inhaler compositions.

Description

[0071] Another aspect of the present invention relates to the powder composition as described above for use in the treatment of diseases of the respiratory system, diseases caused by bacteria, diseases of the cardiovascular system, allergic reactions, cancer, psychiatric diseases and/or immune system related diseases. Another aspect of the present invention relates to the use of component (i) as carrier in inhaler compositions.

[0072] FIG. 1 SEM images of powder composition (III) at a magnification of 250 (A), 500 (B), 1000 (C), 2500 (D) and 5000 (E).

[0073] FIG. 2 SEM images of powder composition (IV) at a magnification of 250 (A), 500 (B), 1000 (C), 2500 (D) and 5000 (E).

[0074] FIG. 3 SEM images of powder composition (V) at a magnification of 250 (A), 500 (B), 1000 (C), 2500 (D) and 5000 (E).

[0075] FIG. 4 SEM images of powder composition (VI) at a magnification of 250 (A), 500 (B), 1000 (C), 2500 (D) and 5000 (E).

[0076] FIG. 5 SEM images of powder composition (VII) at a magnification of 500 (A), 1000 (B), 2500 (C) and 5000 (D).

[0077] FIG. 6 SEM pictures of component (i) used in Example 8.

[0078] FIG. 7 Particle size distribution of component (i) used to prepare powder composition (VIII).

[0079] FIG. 8 d.sub.50 values (A), span (B), percentage of particles<5 μm (C) and specific surface area (D) of component (i) (=SL) compared to commercially available lactose carriers INH70, INH120, INH230 and INH250.

[0080] FIG. 9 FPF values determined for powder compositions comprising component (i) (=SL) compared to comparative powder compositions A-D (cf. example 8). All powder compositions further comprise salbutamol sulfate (SBS).

[0081] The present invention is illustrated by the following examples, without limitation thereto.

Example 1: Powder Composition (I)

[0082] Powder composition (I) consists of lactose agglomerates according to component (i) of the invention (prepared according to Example 7 in WO 2016/039698) and 1.5 wt.-% of salbutamol sulfate as API according to component (ii) of the invention.

Preparation of Powder Composition (I)

[0083] Salbutamol sulfate was sieved with a 180 μm sieve to remove agglomerates. 0.45 g sieved salbutamol sulfate was added to 29.55 g component (i) (total batch mass of 30 g) followed by mixing with an Alpine Picoline equipped with the Picomix® high shear mixer module (Hosokawa Alpine, Augsburg, Germany) at 500 rpm for one minute. After mixing, the product was passed through a 355 μm sieve to receive powder composition (I).

[0084] Blend Homogeneity and API Recovery

[0085] Homogeneity was assessed by measuring the API content of ten randomly drawn aliquots of powder composition (I) by an HPLC method.

[0086] Details regarding the HPLC approach are given below:

[0087] Analyte: Salbutamol sulfate/dissolved in water

[0088] Instrumentation: Agilent 1100 Series HPLC Value System Mobile phase: 78 wt.-% buffering system containing 2.87 g/L sodium heptanesulfonate and 2.5 g/L KH.sub.2PO.sub.4 (0.2 mmol), pH adjusted to 3.65 with ortho-phosphoric acid 85 wt.-% 22 wt.-% acetonitrile

[0089] Flow: 0.8 mL/min

[0090] Column: LichroCART 125-4, Lichrospher RP-18 (5 μm) with precolumn

[0091] Wavelength: 220 nm

[0092] Retention time: ˜3 min

[0093] Calibration: 1-100 μg/mL

[0094] Injection Volume: 100 μL

[0095] Oven temperature: 25° C.

[0096] HPLC experiments resulted in an API recovery of 98.11±2.88% over all investigated aliquots and thus confirmed excellent blend homogeneity.

[0097] Aerodynamic Assessment of the Powder Composition by a Next Generation Pharmaceutical Impactor (NGI) test.

[0098] Powder composition (I) was stored at standard conditions (1 bar, 20° C.) for a minimum of four weeks before it was tested for aerodynamic performance with a Novolizer® coupled to NGI instrumentation (Marple et al., Journal of Aerosol Medicine, 2003, 16, 283-299) forming the “device”.

[0099] NGI is a cascade impactor, which has been specifically designed for pharmaceutical inhaler testing. The NGI has seven stages and is intended to assess aerodynamic properties of powder compositions. These properties follow established scientific principles, giving reliable particle size fractionation.

[0100] By applying a pressure drop over the device and providing the powder composition to the inlet of the NGI, inhaling the powder composition by a patient can be simulated.

[0101] The airflow required to create a 4 kPa pressure drop over the device was obtained via a vacuum pump at an air flow rate of 78.3 L/min.

[0102] After simulating an inhalation event, API-particles are distributed among the stages of the NGI and deposited on collection cups that are held in a tray. This tray is removed from the NGI as a single unit. Solvent is added to each single cup corresponding to a certain stage in the NGI for dissolving the deposited API. HPLC quantification of the solutions derived from each stage is used for identifying API distribution within the stages.

[0103] The amount of API per inhaled dose was determined as follows. The Novolizer® was filled with powder composition (I) and weighed using an analytical balance (AT106 Comparator, Mettler Toledo, Switzerland). Afterwards the Novolizer® was fitted into a customized mouthpiece, connected to the NGI, actuated (flow rate for pressure drop of 4 kPa, 4 L inspiration volume) into the NGI and weighed again. The delivered mass of ten single shots was calculated from the difference of the weight before and after every actuation.

[0104] The following table lists the shot weight of each shot number. Reproducible shot weights become apparent.

TABLE-US-00001 TABLE 1 Shot weight test; powder composition (I) Shot number Shot weight 1 11.20 mg 2 10.71 mg 3 10.49 mg 4 10.81 mg 5 10.88 mg 6 10.57 mg 7 10.71 mg 8 10.86 mg 9 10.62 mg 10 10.45 mg average: 10.73 mg abs. standard deviation:  0.22 mg rel. standard deviation: 2.06%

[0105] Aerodynamic particle size distribution was determined by cascade impaction. The NGI equipped with a trigger box and a vacuum pump HCP 5 (all Copley Scientific, UK) was used. The air flow was set to a flow rate resulting in a pressure drop of 4 kPa across the device (depending on the device resistance). Afterwards the airflow was applied over a corresponding time ensuring 4 L of air to be withdrawn from the mouthpiece of the inhaler. A stage coating composed of Brij®35, glycerol, and absolute ethanol was applied onto each stage of the impactor before analysis to reduce bouncing phenomena.

[0106] After connecting the Novolizer® to the induction port of the NGI via a matching adapter, 5 shots were delivered to the NGI to allow sufficient sample for API quantification.

[0107] Novolizer®, induction port, preseparator and all stages were individually sampled for API. A defined volume of solvent was used for each sample.

TABLE-US-00002 Novolizer ® 10 mL Induction port 15 mL Preseparator 20 mL Stages 1-7  5 mL MOC  5 mL

[0108] Sufficient dwell times were applied to ensure complete API dissolution. All samples were not further diluted and immediately subjected to HPLC analysis. The calculation of the fine particle dose (FPD), fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) was performed with the CITDAS 3.0 software (Copley Scientific, UK). The calculated fine particle fraction (FPF) is expressed as the FPF of the delivered dose, i.e. the percentage of total amount delivered to the NGI while the retention of API sticking to the Novolizer® is not considered.

[0109] Table 2 and 3 summarize the outcome of the NGI testing, namely the API mass per stage of each single run (Table 2) and as average data (Table 3).

TABLE-US-00003 TABLE 2 API mass per stage; mass distribution; single run data (5 shots). Stage deposition, μg Stage Run 1 Run 2 Run 3 Novolizer ® 36.57 32.24 25.24 Induction port 146.29 121.60 127.79 Preseparator 153.82 177.90 175.06 Stage 1 18.28 23.96 19.26 Stage 2 30.86 33.72 30.84 Stage 3 73.45 73.50 70.95 Stage 4 120.63 126.32 127.23 Stage 5 87.98 91.37 97.86 Stage 6 42.57 44.12 43.43 Stage 7 16.96 12.82 15.77 MOC 8.50 3.38 5.26

TABLE-US-00004 TABLE 3 API mass per stage; average data (3 runs). Stage deposition, Stage deposition, Stage deposition, absolute standard relative standard Stage average, μg deviation, μg deviation, % Novolizer ® 31.35 5.71 18.23 Induction Port 131.89 12.85 9.74 Preseparator 168.93 13.16 7.79 Stage 1 20.50 3.04 14.82 Stage 2 31.81 1.66 5.21 Stage 3 72.63 1.46 2.01 Stage 4 124.72 3.58 2.87 Stage 5 90.41 2.11 2.34 Stage 6 43.37 0.77 1.78 Stage 7 15.18 2.13 14.04 MOC 5.71 2.59 45.32

[0110] Tables 4 and 5 present above-given results in a relative manner based on the total mass of API entering the NGI.

TABLE-US-00005 TABLE 4 Relative stage distribution; single run data. Stage deposition, % Run 1 Run 2 Run 3 Novolizer ® 4.97 4.35 3.45 Induction port 19.88 16.41 17.44 Preseparator 20.90 24.01 23.89 Stage 1 2.48 3.23 2.63 Stage 2 4.19 4.55 4.21 Stage 3 9.98 9.92 9.68 Stage 4 16.39 17.05 17.36 Stage 5 11.96 12.33 12.54 Stage 6 5.79 5.95 5.93 Stage 7 2.30 1.73 2.15 MOC 1.16 0.46 0.72

TABLE-US-00006 TABLE 5 Relative stage distribution: average data (3 runs). Stage deposition, Stage deposition, Stage deposition, absolute standard relative standard Stage average, % deviation, % deviation, % Novolizer ® 4.26 0.77 18.01 Induction Port 17.91 1.78 9.94 Preseparator 22.93 1.76 7.68 Stage 1 2.78 0.40 14.30 Stage 2 4.32 0.20 4.68 Stage 3 9.86 0.16 1.59 Stage 4 16.93 0.50 2.93 Stage 5 12.28 0.30 2.41 Stage 6 5.89 0.09 1.55 Stage 7 2.06 0.30 14.43 MOC 0.78 0.35 45.47

[0111] Determined aerodynamic parameters are presented in Tables 6 and 7.

TABLE-US-00007 TABLE 6 Aerodynamic parameters, single shot data (calculated). Run 1 Run 2 Run 3 Recovered dose per shot, ug 147.18 148.19 146.54 Calc. delivered dose per shot, μg 139.87 141.74 141.49 Fine particle dose per shot, μg 73.22 73.72 74.08 Fine particle fraction, % 52.35 52.01 52.36 MMAD, μm 1.77 1.82 1.77

TABLE-US-00008 TABLE 7 Aerodynamic parameters, average data (from 3 runs). absolute relative standard standard average deviation deviation, % Recovered dose per shot, μg 147.30 0.83 0.56 Calc, delivered dose per shot, μg 141.03 1.02 0.72 Fine particle dose per shot, μg 73.67 0.43 0.59 Fine particle fraction, % 52.24 0.20 0.38 MMAD, μm 1.78 0.03 1.82

[0112] Powder composition (I) showed a homogeneous distribution of the API. Further, owing to very low variations in the shot weights, good dosing capability of powder composition (I) with the Novolizer® can be achieved. Moreover, as high FPF and good API distribution during the NGI testing could be observed, excellent aerodynamic properties and lung deposition of powder composition (I) becomes apparent. The small MMAD ensures optimal deposition of the API in deeper regions of the lung (alveoli).

Example 2: Powder Composition (II)

[0113] Powder composition (II) consists of lactose agglomerates according to component (i) of the invention (prepared according to Example 7 in WO 2016/039698) and 1.5 wt.-% of budenoside as API according to component (ii) of the invention.

Preparation of Powder Composition (II)

[0114] Powder composition (II) was prepared corresponding to powder composition (I), except that budenoside was used as API instead of salbutamol sulfate.

[0115] Blend Homogeneity and API Recovery

[0116] Homogeneity was assessed similar to powder composition (I).

[0117] Details regarding the HPLC approach are given below:

[0118] Analyte: budenoside/dissolved in methanol:water (75:25)

[0119] Instrumentation: Agilent 1100 Series HPLC Value System

[0120] Mobile phase: 75 wt.-% methanol 25 wt.-% water

[0121] Flow: 1.0 mL/min

[0122] Column: LiChrospher RP select B (5 μm) LiChroCART125-4 with precolumn

[0123] Wavelength: 248 nm

[0124] Retention time: ˜4 min

[0125] Calibration: 1-100 μg/mL

[0126] Injection Volume: 100 μL

[0127] Oven temperature: 25° C.

[0128] HPLC experiments resulted in an API recovery of 99.01±2.88% over all investigated aliquots and thus confirmed excellent blend homogeneity.

[0129] Aerodynamic Assessment of the Powder Composition by a Next Generation Pharmaceutical Impactor (NGI) Test.

[0130] Aerodynamic assessment of powder composition (II) was performed as described for powder composition (I) above.

[0131] The following table lists the shot weight of each shot number. Reproducible shot weights become apparent.

TABLE-US-00009 TABLE 8 Shot weight test; powder composition (I). Shot number Shot weight  1 11.20 mg  2 10.71 mg  3 10.49 mg  4 10.81 mg  5 10.88 mg  6 10.57 mg  7 10.71 mg  8 10.86 mg  9 10.62 mg 10 10.45 mg average: 10.73 mg abs. standard deviation:  0.22 mg rel. standard deviation: 2.06%

[0132] Tables 9 and 10 summarize the outcome of the NGI testing, namely the API mass per stage of each single run (Table 10) and as average data (Table 11).

TABLE-US-00010 TABLE 9 API mass per stage; mass distribution; single run data (5 shots) Stage deposition, μg Stage Run 1 Run 2 Run 3 Novolizer ® 43.84 49.74 44.82 Induction port 135.99 149.67 153.46 Preseparator 188.87 181.80 168.03 Stage 1 41.84 39.94 28.51 Stage 2 69.61 68.36 67.44 Stage 3 86.70 93.90 89.29 Stage 4 86.02 82.83 87.41 Stage 5 48.43 48.36 53.20 Stage 6 24.44 22.88 23.20 Stage 7 6.68 5.28 7.46 MOC 1.41 1.02 1.57

TABLE-US-00011 TABLE 10 API mass per stage; average data (3 runs). Stage Stage deposition, Stage deposition, deposition, absolute standard relative standard Stage average, μg deviation, μg deviation, % Novolizer ® 46.14 3.16 6.85 Induction Port 146.37 9.19 6.28 Preseparator 179.57 10.60 5.90 Stage 1 36.76 7.21 19.61 Stage 2 68.47 1.09 1.59 Stage 3 89.96 3.65 4.06 Stage 4 85.42 2.35 2.75 Stage 5 49.99 2.77 5.55 Stage 6 23.51 0.83 3.51 Stage 7 6.47 1.11 17.08 MOC 1.33 0.28 21.15

[0133] Tables 11 and 12 present above-given results in a relative manner based on the total mass of API entering the NGI.

TABLE-US-00012 TABLE 11 Relative stage distribution; single run data. Stage deposition, % Run 1 Run 2 Run 3 Novolizer ® 5.97 6.69 6.19 Induction Port 18.53 20.12 21.18 Preseparator 25.74 24.44 23.20 Stage 1 5.70 5.37 3.94 Stage 2 9.49 9.19 9.31 Stage 3 11.81 12.63 12.33 Stage 4 11.72 11.14 12.07 Stage 5 6.60 6.50 7.34 Stage 6 3.33 3.08 3.20 Stage 7 0.91 0.71 1.03 MOC 0.19 0.14 0.22

TABLE-US-00013 TABLE 12 Relative stage distribution; average data (3 runs). Stage Stage deposition, Stage deposition, deposition, absolute standard relative standard Stage average, % deviation, % deviation, % Novolizer ® 6.28 0.37 5.82 Induction Port 19.95 1.34 6.70 Preseparator 24.46 1.27 5.20 Stage 1 5.00 0.94 18.76 Stage 2 9.33 0.15 1.59 Stage 3 12.26 0.41 3.34 Stage 4 11.64 0.47 4.04 Stage 5 6.81 0.46 6.76 Stage 6 3.20 0.13 3.98 Stage 7 0.88 0.16 18.31 MOC 0.18 0.04 22.33

[0134] Determined aerodynamic parameters are presented in Tables 13 and 14.

TABLE-US-00014 TABLE 13 Aerodynamic parameters, single shot data (calculated). Run 1 Run 2 Run 3 Recovered dose per shot, μg 146.77 148.76 144.88 Calc. delivered dose per shot, μg 138.00 138.81 135.91 Fine particle dose per shot, μg 57.68 57.70 59.48 Fine particle fraction, % 41.79 41.57 43.76 MMAD, μm 2.68 2.73 2.55

TABLE-US-00015 TABLE 14 Aerodynamic parameters, average data (from 3 runs). absolute relative standard standard average deviation deviation, % Recovered dose per shot, μg 146.80 1.94 1.32 Calc. delivered dose per shot, μg 137.91 1.49 1.09 Fine particle dose per shot, μg 58.28 1.03 1.77 Fine particle fraction, % 42.37 1.21 2.85 MMAD, μm 2.65 0.09 3.48

[0135] Powder composition (II) showed a homogeneous distribution of the API. Further, owing to very low variations in the shot weights, good dosing capability of powder composition (II) with the Novolizer® can be achieved. Moreover, as high FPF and good API distribution during the NGI testing could be observed, excellent aerodynamic properties and lung deposition of powder composition (II) becomes apparent. The small MMAD ensure optimal API deposition in deeper regions of the lung (alveoli).

Example 3, 4: Powder Compositions (III) and (IV)

[0136] Powder composition (III) and (IV), respectively, consist of lactose agglomerates according to component (i) of the invention (prepared according to Example 7 in WO 2016/039698) and 1.5 wt.-% salbutamol sulfate and 10 wt.-% salbutamol sulfate, respectively, as API according to component (ii) of the invention. In contrast to powder compositions (I) and (II), a low shear mixing method with a Turbula mixer instead of a high shear mixing method was applied.

Preparation of Powder Compositions (III) and (IV)

[0137] Salbutamol sulfate was sieved with a 180 μm sieve and component (i) with a 355 μm sieve to remove agglomerates. Afterwards, salbutamol sulfate and component (i) were weighed into a stainless steel cylinder in different amounts to obtain a salbutamol sulfate content of 1.5 wt.-% and 10 wt.-%, respectively, for a batch size of 30.0 g in total. Each blend was subjected to low shear mixing using the Turbula-Blender (model T2C, Willy Bachofen AG Maschinenfabrik, Basel, Switzerland) three times for each 5 minutes at 90 U/min. Between each mixing step and at the end of the mixing, the powders were sieved with a 355 μm sieve to eventually receive powder compositions (III) and (IV).

[0138] Blend Homogeneity and API Recovery

[0139] Homogeneity was assessed by measuring the API content of ten randomly drawn aliquots of powder composition (III) and (IV), respectively, by an HPLC method.

[0140] Details regarding the HPLC approach are given below:

[0141] Analyte: Salbutamol sulfate/dissolved in a mixture of 78% buffer solution containing 2.87 g/L sodium heptanesulfonate and 2.50 g/L KH.sub.2PO.sub.4 (0.2 mmol). The pH was adjusted to 3.65 with orthophosphoric acid 85% and 22% acetonitrile.

[0142] Instrumentation: Agilent 1100 Series HPLC Value System

[0143] Mobile phase: 78 wt.-% buffering system containing 2.87 g/L sodium heptanesulfonate and 2.5 g/L KH.sub.2PO.sub.4 (0.2 mmol), pH adjusted to 3.65 with ortho-phosphoric acid 85 wt.-% 22 wt.-% acetonitrile

[0144] Flow: 1 mL/min

[0145] Column: Column LiChrospher® 100 RP-18 (5 μm) (Merck, Germany)

[0146] Wavelength: 220 nm

[0147] Retention time: ˜2.5 min

[0148] Calibration: 0.6-150 μg/mL (external standards and samples were injected twice into the HPLC)

[0149] Injection Volume: 100 μL

[0150] Oven temperature: 25° C.

[0151] HPLC experiments for both powder composition (III) and (IV) resulted in an API recovery of 98.98±1.89% and 99.97±2.89%, respectively over all investigated aliquots and, thus, confirmed excellent blend homogeneity.

[0152] Scanning Electron Microscopy

[0153] Scanning electron microscopy (SEM) was carried out with a Phenom XL (Phenom-World BV, Netherlands). Particles were fixed on carbon stickers and sputter-coated with a thin gold layer prior to SEM evaluation (5 kV).

[0154] FIG. 1 depicts SEM pictures of powder composition (III). FIG. 2 depicts SEM pictures of powder composition (IV). For both compositions, spherically agglomerated lactose particles comprising radially arranged prism-like lactose particles carrying API particles thereon become apparent.

[0155] Aerodynamic Assessment by NGI

[0156] Powder compositions (III) and (IV) were tested for aerodynamic performance with a Novolizer®. Each formulation was stored at standard conditions for a minimum of four weeks before aerodynamic assessment.

[0157] Shot Weight Test

[0158] The amount of API per inhaled dose was determined as presented in Example 1. The following tables list the shot weight of each shot number. Reproducible shot weights become apparent for both powder composition (III) and (IV).

TABLE-US-00016 TABLE 15 API content and relative standard deviation of 10 random aliquots of powder composition (III). Sample Expected Found weight API API Recovery [mg] [mg] [mg] [%] 9.98 0.15 0.15 103.03 10.08 0.15 0.15 98.22 10.03 0.15 0.15 96.92 10.04 0.15 0.15 100.43 10.20 0.15 0.15 98.22 9.86 0.15 0.15 99.30 10.44 0.16 0.15 98.52 10.05 0.15 0.15 98.71 10.33 0.15 0.15 97.86 10.23 0.15 0.15 98.61 Mean [mg] 10.12 0.15 0.15 98.98 Standard deviation [mg] 0.17 0.00 0.00 Relative standard deviation [%] 1.89

TABLE-US-00017 TABLE 16 API content and relative standard deviation of 10 random aliquots of powder composition (IV). Sample Expected Found weight API API Recovery [mg] [mg] [mg] [%] 10.31 1.03 1.00 96.59 10.23 1.02 1.04 101.27 10.17 1.02 1.04 102.37 9.81 0.98 0.95 97.05 9.85 0.99 1.03 104.64 10.00 1.00 1.00 100.15 9.99 1.00 0.96 96.58 9.90 0.99 1.00 101.22 9.98 1.00 0.99 99.32 10.02 1.00 1.01 100.50 Mean [mg] 10.03 1.00 1.00 99.97 Standard deviation [mg] 0.16 0.02 0.03 Relative standard deviation [%] 2.89

[0159] Aerodynamic particle size distribution was determined according to Example 1.

[0160] Mouthpiece, induction port, preseparator and all stages were individually sampled for active ingredient. A defined volume of solvent was used for each sample.

TABLE-US-00018 Novolizer ® 10 mL induction port 15 mL Preseparator 20 mL Stage 1-7  5 mL MOC  5 ml

[0161] Tables 17 and 18 summarize the outcome of the NGI testing of powder composition (III), namely the API mass per stage of each single run including a calculated average (Table 17) and presented in a relative manner (Table 18).

TABLE-US-00019 TABLE 17 API mass per stage; mass distribution; single shot data; Novolizer ® loaded with 0.7 ± 0.1 g of powder composition (III). 1 2 3 Salbutamol Salbutamol Salbutamol sulfate, sulfate, suffate, Average, Deposition data μg μg μg μg Novolizer ® 9.30 11.17 12.85 11.10 Induction Port 25.60 23.92 20.77 23.43 Preseparator 26.93 25.97 34.75 29.22 Stage 1 5.14 6.41 6.89 6.14 Stage 2 16.09 17.93 17.30 17.11 Stage 3 23.43 25.53 23.80 24.25 Stage 4 21.15 21.86 19.66 20.89 Stage 5 7.70 9.15 6.56 7.80 Stage 6 1.84 2.10 1.87 1.94 Stage 7 0.00 0.68 0.87 0.52 MOC 0.00 1.06 0.00 0.35 Flow rate, L/min 78.3 78.3 78.3 78.3

TABLE-US-00020 TABLE 18 API mass per stage; percentage distribution; single shot data; Novolizer ® loaded with 0.7 ± 0.1 g powder composition (III). 1 2 3 Salbutamol Salbutamol Salbutamol sulfate, sulfate, sulfate, Average, Deposition data % % % % Novolizer ® 6.78 7.66 8.84 7.76 Induction Port 18.67 10.41 14.29 16.46 Preseparator 19.63 17.82 23.92 20.45 Stage 1 3.75 4.40 4.74 4.29 Stage 2 11.73 12.30 11.91 11.98 Stage 3 17.08 17.52 16.38 16.99 Stage 4 15.42 14.99 13.53 14.65 Stage 5 5.61 6.27 4.52 5.47 Stage 6 1.34 1.44 1.29 1.36 Stage 7 0.00 0.47 0.60 0.35 MOC 0.00 0.73 0.00 0.24 Flow rate, L/min 78.3 78.3 78.3 78.3

[0162] Determined aerodynamic parameters for powder composition (III) are presented in Table 19.

TABLE-US-00021 TABLE 19 Aerodynamic parameters, powder composition (III). Run 1 Run 2 Run 3 Mean/dose Total Dose Per Shot [μg] 137.17 145.77 145.32 142.75 Fine Particle Dose [μg] 62.85 69.95 61.83 64.88 Fine Particle Fraction [%] 45.81 47.99 42.55 45.45 MMAD [μm] 2.81 2.81 2.95 2.86

[0163] Tables 20 and 21 summarize the outcome of the NGI testing of powder composition (IV), namely the API mass per stage of each single run including a calculated average (Table 20) and presented in a relative manner (Table 21).

TABLE-US-00022 TABLE 20 API mass per stage; mass distribution; single shot data; Novolizer ® loaded with 0.7 ± 0.1 g of powder composition (IV). 1 2 3 Salbutamol Salbutamol Salbutamol sulfate, sulfate, sulfate, Average, Deposition data μg μg μg μg Novolizer ® 18.22 26.83 24.32 23.12 Induction Port 82.69 130.60 95.44 102.91 Preseparator 43.46 47.46 32.39 41.10 Stage 1 9.16 17.65 10.91 12.57 Stage 2 41.25 71.49 51.30 54.68 Stage 3 66.75 114.05 88.43 89.75 Stage 4 61.35 105.67 65.50 77.51 Stage 5 22.50 80.87 30.95 44.78 Stage 6 5.52 9.63 7.97 7.71 Stage 7 0.00 0.00 0.00 0.00 MOC 1.35 0.00 0.00 0.45 Flow rate, L/min 78.3 78.3 78.3 78.3

TABLE-US-00023 TABLE 21 API mass per stage; percentage distribution; single shot data; Novolizer ® loaded with 0.7 ± 0.1 g of powder composition (IV). 1 2 3 Salbutamol Salbutamol Salbutamol Average, Deposition data sulfate, % sulfate % sulfate, % % Novolizer ® 5.17 4.44 5.97 5.19 Induction Port 23.48 21.61 23.44 22.84 Preseparator 12.34 7.85 7.95 9.38 Stage 1 2.60 2.92 2.68 2.73 Stage 2 11.71 11.83 12.60 12.05 Stage 3 18.95 18.87 21.72 19.85 Stage 4 17.42 17.49 16.08 17.00 Stage 5 6.39 13.38 7.60 9.12 Stage 6 1.57 1.59 1.96 1.71 Stage 7 0.00 0.00 0.00 0.00 MOC 0.38 0.00 0.00 0.13 Flow rate, L/min 78.3 78.3 78.3 78.3

[0164] Determined aerodynamic parameters for powder composition (IV) are presented in Table 22.

TABLE-US-00024 TABLE 22 Aerodynamic parameters, powder composition (IV). Run 1 Run 2 Run 3 Mean/dose Total Dose Per Shot [ug] 352.26 604.25 407.21 454.57 Fine Particle Dose [ug] 181.12 350.84 222.40 251.46 Fine Particle Fraction [%] 51.42 58.06 54.62 54.70 MMAD [um] 2.69 2.50 2.76 2.65

[0165] Component (i) of the powder composition allows high API load, e.g. 1.5 and 10 wt.-%. Further, powder compositions (III) and (IV) showed a homogeneous distribution of the API. Owing to the very low variations in the shot weights, good dosing capability of powder compositions (III) and (IV) with the Novolizer® can be achieved. Moreover, as high FPF and good API distribution during the NGI testing could be observed, excellent aerodynamic properties and lung deposition of powder compositions (III) and (IV) becomes apparent. The small MMAD ensures optimal API deposition in deeper regions of the lung (alveoli).

Example 5, 6: Powder Compositions (V) and (VI)

[0166] Powder composition (V) and (VI), respectively, consist of lactose agglomerates according to component (i) of the invention (prepared according to Example 7 in WO 2016/039698) and 1.5 wt.-% budenoside and 10 wt.-% budenoside, respectively, as API according to component (ii) of the invention. In contrast to powder compositions (I) and (II), a low shear mixing method with a Turbula mixer instead of a high shear mixing method was applied.

Preparation of Powder Compositions (V) and (VI)

[0167] Powder compositions (V) and (VI) were prepared analogously to powder compositions (III) and (IV), except that budenoside was used as API instead of salbutamol sulfate.

[0168] Blend Homogeneity and API Recovery

[0169] Homogeneity was assessed as described for powder compositions (III) and (IV).

[0170] Details Regarding the HPLC Approach are Given Below:

[0171] Analyte: Budenoside/dissolved in a mixture of 25% purified water and 75% methanol. The pH was adjusted to 3.65 with orthophosphoric acid 85% and 22% acetonitrile.

[0172] Instrumentation: Agilent 1100 Series HPLC Value System

[0173] Mobile phase: 25 wt.-% purified water and 75 wt.-% methanol

[0174] Flow: 1 mL/min

[0175] Column: Column LiChrospher® 100 RP-18 (5 μm) (Merck, Germany)

[0176] Wavelength: 248 nm

[0177] Retention time: ˜3.0 min

[0178] Calibration: 0.6-150 μg/mL (external standards and samples were injected twice into the HPLC)

[0179] Injection Volume: 100 μL

[0180] Oven temperature: 25° C.

[0181] HPLC experiments for both powder composition (V) and (VI) resulted in an API recovery of 101.88±4.93% and 97.15±2.10%, respectively over all investigated aliquots, and, thus, confirmed excellent blend homogeneity.

[0182] Scanning Electron Microscopy

[0183] Scanning electron microscopy (SEM) was carried out as described for Examples 3 and 4.

[0184] FIG. 3 depicts SEM pictures of powder composition (V). FIG. 4 depicts SEM pictures of powder composition (VI). For both compositions, spherically agglomerated lactose particles comprising radially arranged prism-like lactose particles carrying API particles thereon become apparent.

[0185] Aerodynamic Assessment by NGI

[0186] Powder compositions (V) and (VI) were tested for aerodynamic performance analogously to powder compositions (III) and (IV).

[0187] Shot Weight Test

[0188] The amount of API per inhaled dose was determined as presented in Example 1. The following tables list the shot weight each shot number. Reproducible shot weights become apparent for both powder compositions (V) and (VI).

TABLE-US-00025 TABLE 23 API content and relative standard deviation of 10 random aliquots of powder composition (V). Sample Expected API Found API Recovery weight [mg] [mg] [mg] [%] 9.96 0.15 0.16 107.77 10.41 0.16 0.14 90.22 10.27 0.15 0.15 99.13 9.82 0.15 0.15 100.61 10.30 0.15 0.15 100.23 10.16 0.15 0.16 105.98 9.72 0.15 0.15 102.82 10.30 0.15 0.17 108.39 10.21 0.15 0.15 100.71 10.28 0.15 0.16 102.94 Mean [mg] 10.14 0.15 0.15 101.88 Standard 0.23 0.00 0.01 deviation [mg] Relative standard 4.93 deviation [%]

TABLE-US-00026 TABLE 24 API content and relative standard deviation of 10 random aliquots of powder composition (VI). Sample Expected API Found API Recovery weight [mg] [mg] [mg] [%] 10.45 1.05 1.03 98.41 10.11 1.01 1.00 98.81 10.29 1.03 0.98 95.15 10.11 1.01 0.97 96.42 10.06 1.01 0.99 98.09 10.24 1.02 1.00 97.21 10.09 1.01 0.96 95.50 9.90 0.99 0.96 97.40 10.31 1.03 0.99 95.79 9.72 0.97 0.96 98.74 Mean [mg] 10.13 1.01 0.98 97.15 Standard 0.21 0.02 0.02 deviation [mg] Relative standard 2.10 deviation [%]

[0189] Tables 25 and 26 summarize the outcome of the NGI testing of powder composition (V), namely the API mass per stage of each single run including a calculated average (Table 25) and presented in a relative manner (Table 26).

TABLE-US-00027 TABLE 25 API mass per stage; mass distribution; single shot data; Novolizer ® loaded with 0.7 ± 0.1 g of powder composition (V). 1 2 3 Deposition Budesonide, Budesonide, Budesonide, data μg μg μg Average Novolizer ® 11.17 11.39 11.18 11.25 Induction Port 21.44 20.49 18.21 20.05 Preseparator 15.66 17.24 18.81 17.24 Stage 1 2.79 2.71 3.68 3.06 Stage 2 5.37 5.43 7.30 6.03 Stage 3 6.76 7.75 10.59 8.37 Stage 4 9.71 11.68 12.94 11.44 Stage 5 7.24 8.20 8.55 8.00 Stage 6 3.54 3.46 4.54 3.85 Stage 7 0.98 0.00 0.00 0.72 MOC 0.00 0.00 0.00 0.12 Flow rate, 78.3 78.3 78.3 78.3 L/min

TABLE-US-00028 TABLE 26 API mass per stage; percentage distribution; single shot data; Novolizer ® loaded with 0.7 ± 0.1 g powder composition (V). 1 2 3 Deposition Budesonide, Budesonide, Budesonide, Average, data % % % % Novolizer ® 13.19 12.89 11.67 12.59 Induction Port 25.33 23.19 19.00 22.51 Preseparator 18.49 19.51 19.63 19.21 Stage 1.sup.: 3.29 3.06 3.85 3.40 Stage 2 6.34 6.15 7.62 6.70 Stage 3 7.99 8.77 11.06 9.27 Stage 4 11.47 13.22 13.51 12.73 Stage 5 8.56 9.29 8.93 8.92 Stage 6 4.18 3.92 4.74 4.28 Stage 7 1.15 0.00 0.00 0.38 MOC 0.00 0.00 0.00 0.00 Flow rate, 78.3 78.3 78.3 78.3 L/min

[0190] Determined aerodynamic parameters for powder composition (V) are presented in Table 27.

TABLE-US-00029 TABLE 27 Aerodynamic parameters, powder composition (V). Run 1 Run 2 Run 3 Mean/dose Total Dose Per Shot [ug] 84.66 88.35 95.82 89.61 Fine Particle Dose [ug] 31.02 33.94 40.43 35.13 Fine Particle Fraction [%] 36.64 38.41 42.19 39.08 MMAD [um] 2.08 2.10 2.27 2.15

[0191] Tables 28 and 29 summarize the outcome of the NGI testing of powder composition (VI), namely the API mass per stage of each single run including a calculated average (Table 28) and in a relative manner (Table 29).

TABLE-US-00030 TABLE 28 API mass per stage; mass distribution; single shot data; Novolizer ® loaded with 0.7 ± 0.1 g powder composition (VI). 1 2 3 Deposition Budesonide, Budesonide, Budesonide, Average, data μg μg μg μg Novolizer ® 40.72 53.14 56.48 50.11 Induction Port 69.26 104.22 108.42 93.97 Preseparator 69.45 113.20 120.54 101.07 Stage 1 8.24 12.13 14.85 11.74 Stage 2 14.91 22.04 25.73 20.89 Stage 3 27.20 37.12 42.79 35.71 Stage 4 47.39 61.15 71.96 60.16 Stage 5 37.02 46.77 52.36 45.38 Stage 6 17.49 21.92 20.80 20.07 Stage 7 3.58 6.58 3.62 4.59 MOC 0.00 1.32 0.00 0.44 Flow rate, 78.3 78.3 78.3 78.3 L/min

TABLE-US-00031 TABLE 29 API mass per stage; percentage distribution; single shot data; Novolizer ® loaded with 0.7 ± 0.1 g of powder composition (VI). 1 2 3 Deposition Budesonide, Budesonide, Budesonide, Average, data % % % % Novolizer ® 12.14 11.08 10.91 11.38 Induction Port 20.66 21.73 20.95 21.11 Preseparator 20.72 23.60 23.29 22.54 Stage 1 2.46 2.53 2.87 2.62 Stage 2 4.45 4.60 4.97 4.67 Stage 3 8.11 7.74 8.27 8.04 Stage 4 14.13 12.75 13.90 13.60 Stage 5 11.04 9.75 10.12 10.30 Stage 6 5.22 4.57 4.02 4.60 Stage 7 1.07 1.37 0.70 1.05 MOC 0.00 0.27 0.00 0.09 Flow rate, 78.3 78.3 78.3 78.3 L/min

[0192] Determined aerodynamic parameters for powder composition (VI) are presented in Table 30.

TABLE-US-00032 TABLE 30 Aerodynamic parameters, powder composition (VI). Run 1 Run 2 Run 3 Mean/dose Total Dose Per Shot [ug] 335.26 479.59 517.55 444.13 Fine Particle Dose [ug] 140.48 186.37 204.87 177.24 Fine Particle Fraction [%] 41.90 38.86 39.58 40.12 MMAD [um] 1.82 1.86 1.95 1.88

[0193] Component (i) of the powder composition allows high API load, e.g. 1.5 and 10 wt.-%. Further, powder compositions (V) and (VI) showed a homogeneous distribution of the API. Owing to the very low variations in the shot weights, good dosing capability of powder compositions (V) and (VI) with the Novolizer® can be achieved. Moreover, as high FPF and good API distribution during the NGI testing could be observed, excellent aerodynamic properties and lung deposition of powder compositions (V) and (VI) becomes apparent. The small MMAD ensures optimal API deposition in deeper regions of the lung (alveoli).

Example 7: Powder Composition (VII)

[0194] Powder composition (VII) consists of lactose agglomerates according to component (i) of the invention (prepared according to Example 7 in WO 2016/039698) and 80 wt.-% rifampicin as API according to component (ii) of the invention. In contrast to powder compositions (I) and (II), a low shear mixing method with the Turbula mixer instead of a high shear mixing method was applied.

Preparation of Powder Composition (VII)

[0195] Rifampicin was pre-sieved with a 180 μm sieve and component (i) with a 355 μm sieve. Afterwards, 4.0 g rifampicin were added to 1.0 g component (i) followed by low shear mixing using the Turbula-Blender (model T2C, Willy Bachofen AG Maschinenfabrik, Basel, Switzerland) for 10 minutes at 90 U/min. After sieving the product with a 355 μm sieve, powder composition (VII) was received.

[0196] Blend Homogeneity and API Recovery

[0197] Blend homogeneity of the powder composition (VII) was determined according to the above Examples.

[0198] Homogeneity results are depicted in Table 32. Since only low variations in the total dose per shot were measured, blend homogeneity is apparent.

[0199] Scanning Electron Microscopy

[0200] Scanning electron microscopy (SEM) was carried out as described for Examples 3 and 4.

[0201] FIG. 5 depicts SEM pictures of powder composition (VII). Spherically agglomerated lactose particles comprising radially arranged prism-like lactose particles carrying API particles thereon become apparent.

[0202] Aerodynamic Assessment by NGI

[0203] Powder composition (VII) was tested for aerodynamic performance with a RS01 inhalation system. This inhalation system is a capsule based system obtained from Plateapem.

[0204] Aerodynamic particle size distribution was determined similar to Example 1. The RS01 was loaded with one capsule size 3 filled with 20 mg of powder composition (VII).

[0205] Capsule, inhalation system (RS 01), mouthpiece, induction port, preseparator and all stages were individually sampled for active ingredient. A defined volume of solvent was used for each sample.

TABLE-US-00033 Capsule 30 mL RS01 50 mL Mouthpiece 10 mL Induction port 15 mL Preseparator 30 mL Stage 1-7 10 mL MOC 10 mL

[0206] Tables 31 summarizes the outcome of the NGI testing of powder composition (VII), namely the API mass per stage of each single run including a calculated average.

TABLE-US-00034 TABLE 31 API mass per stage; mass distribution; single shot data; RS01 loaded with one capsule size 3 filled with 20 mg of powder composition (VII). 1 2 3 Deposition Rifampicin, Rifampicin, Rifampicin, data μg μg μg Average Mouthpiece 101.32 121.50 128.20 117.01 Ind. Port 1876.75 1776.19 2056.10 1903.01 Preseparator 623.52 627.91 574.13 608.52 Stage 1 1003.67 991.70 1205.16 1066.84 Stage 2 2113.00 2343.37 2787.65 2414.67 Stage 3 2241.67 2342.34 2501.40 2361.81 Stage 4 2228.59 2404.46 2353.25 2328.77 Stage 5 1337.31 1433.49 1385.35 1385.38 Stage 6 577.64 618.60 586.69 594.31 Stage 7 204.28 230.34 207.79 214.14 MOC 95.66 96.61 63.25 85.17 Flow rate, L/min 100 100 100 100

[0207] Determined aerodynamic parameters for powder composition (VII) are presented in Tables 32.

TABLE-US-00035 TABLE 32 Aerodynamic parameters, powder composition (VII). Mean/ Run 1 Run 2 Run 3 dose Total Dose Per Shot 13269.76 13954.68 14694.99 1397.14 [ug] Calc Delivered Dose 12302.09 12865.01 13720.77 12962.59 [ug] Calc Delivered Dose [%] 92.71 92.19 93.37 92.76 Fine Particle Dose [ug] 7299.25 7103.30 6583.75 6995.43 Fine Particle Fraction 66.89 68.81 66.59 67.43 [%] MMAD [um] 2.39 2.37 2.59 2.45 Recovery [%] 82.94 86.78 91.03 86.91

[0208] Component (i) of the powder composition allows high API load, e.g. 80 wt.-%. Further, powder compositions (VII) showed a homogeneous distribution of the API. Moreover, as high FPF and good API distribution during the NGI testing could be observed, excellent aerodynamic properties and lung deposition of powder compositions (VII) become apparent. The small MMAD ensures optimal API deposition in deeper regions of the lung (alveoli).

Example 8: Comparison of Component (i) and Commercially Available Lactose Carriers

[0209] Component (i) (prepared according to Example 7 in WO 2016/039698) was compared to commercially available lactose carriers INH70, INH120, INH230 and INH250 (Meggle; Wasserburg).

[0210] FIG. 6 shows SEM pictures of component (i). Spherically agglomerated lactose particles comprising radially arranged prism-like lactose particles are apparent. Further, particle size distribution of component (i) measured by laser diffraction is depicted in FIG. 7. d.sub.10, d.sub.50 and d.sub.90 values are summarized in Table 33 together with corresponding values of the commercially available lactose carriers.

TABLE-US-00036 TABLE 34 d.sub.10, d.sub.50 and d.sub.90 values, bulk and tapped density of component (i) as well as commercially available lactose carriers. bulk tapped lactose density density sample d.sub.10 [μm] d.sub.50 [μm] d.sub.90 [μm] [g/L] [g/L] component (i) 8 118 198 n. d. n. d. INH70 135 215 301 600 710 INH120 88 132 175 720 830 INH230 45 97 144 700 850 INH250 13 49 91 640 880 INH400 1.2 7.7 27.9 0.33 0.53

[0211] Component (i) exhibits a specific surface of approximately 0.8 m.sup.2/g (FIG. 8D), thereby exceeding values of all investigated commercially available lactose carriers. Thus, powder compositions of the invention comprising component (i) allow for high enrichment of APIs on the lactose carrier component (i).

Example 9: Comparison of a Powder Composition According to the Invention and Commercially Available Systems

[0212] A powder composition according to the invention consisting of component (i) of Example 8 (prepared according to Example 7 in WO 2016/039698) and 1.5 wt.-% salbutamol sulfate (powder composition (VIII)) was compared to powder compositions consisting of the commercially available lactose carriers INH120 and INH230 of Example 8 and 1.5 wt.-% salbutamol sulfate (comparative powder compositions A and B).

[0213] Additionally, the lactose carriers INH120 and INH230 have been mixed with 7.5 wt.-% INH400 (Meggle, Wasserburg; see above) to provide ternary mixtures of powder compositions with salbutamol sulfate for DPIs (comparative powder compositions C and D).

[0214] The composition of comparative powder compositions is listed in Table 34:

TABLE-US-00037 TABLE 34 Composition of comparative powder compositions. comparative powder salbutamol composition INH120 INH230 INH400 sulfate NO. [wt.- %] [wt.- %] [wt.- %] [wt.- %] A 98.5 / / 1.5 B / 98.5 / 1.5 C 91 / 7.5 1.5 D / 91 7.5 1.5

Preparation of Powder Composition (VIII) and Comparative Powder Compositions A-D

[0215] Above powder compositions were prepared as described above for powder composition (I).

[0216] Aerodynamic Assessment by NGI

[0217] Powder composition (VIII) and comparative powder compositions A-D were tested for aerodynamic properties by NGI. Testing was performed similar to the above-presented NGI approach. As inhaler system, a Novolizer® system was used.

[0218] As presented in FIG. 9, powder composition (VIII) reached FPF values higher than values measured for comparative powder compositions A and B and similar to values measured for comparative powder compositions C and D (ternary mixtures).

[0219] Consequently, powder compositions according to the invention reach similar FPF values than commercially available ternary powder compositions or even exceed these values. Advantageously, powder compositions according to the invention—contrary to the comparisons C and D—do not require the additional step of preparing ternary mixtures.

[0220] The present invention relates to the following embodiments: [0221] 1. A powder composition comprising: [0222] (i) spherically agglomerated lactose particles comprising radially arranged prism-like lactose particles, [0223] (ii) at least one active pharmaceutical ingredient (API), and [0224] (iii) optionally at least one additive. [0225] 2. The powder composition according to item 1, wherein component (i) comprises α-lactose, β-lactose or combinations thereof, preferably α-lactose. [0226] 3. The powder composition according to item 1 or 2, wherein component (i) comprises anhydrous lactose, lactose monohydrate or combinations thereof, preferably lactose monohydrate. [0227] 4. The powder composition according to any of the preceding items, wherein component (i) is obtained according to a process comprising the steps: [0228] (a) preparing a lactose solution, [0229] (b) adding the lactose solution obtained after step (a) to at least one non-solvent under constant stirring to form spherically agglomerated lactose particles comprising radially arranged prism-like lactose particles, [0230] (c) isolating the spherically agglomerated lactose particles, and [0231] (d) optionally drying. [0232] 5. The powder composition according to claim 4, wherein the lactose solution in step (a) is an aqueous lactose solution. [0233] 6. The powder composition according to claim 4 or 5, wherein the non-solvent in step (b) is selected from the group consisting of methanol, ethanol, n-propanol, 2-propanol and n-butanol, preferably 2-propanol and ethanol, more preferably ethanol. [0234] 7. The powder composition according to any of the preceding items, wherein component (i) has an average particle size from 50-1,000 μm, preferably from 100-400 μm. [0235] 8. The powder composition according to any of the preceding items, wherein component (i) has a d.sub.50 value from 50-250 μm, preferably from 75-200 μm. [0236] 9. The powder composition according to any of the preceding items, wherein component (i) has a specific surface area from 0.5-5.0 m.sup.2/g, preferably from 0.6-3.5 m.sup.2/g. [0237] 10. The powder composition according to any of the preceding items, wherein the API in component (ii) is selected from a respiratory and a systemic active pharmaceutical ingredient, preferably for the treatment of diseases of the respiratory system, diseases caused by bacteria, diseases of the cardiovascular system, allergic reactions, cancer, psychiatric diseases and immune system related diseases. [0238] 11. The powder composition according to item 10, wherein the active pharmaceutical ingredient for the treatment of diseases of the respiratory system is selected from the group consisting of inhaled corticosteorides (ICS), short acting beta agonists (SABA), long acting beta agonists (LABA), short acting anticholinergic (SAMA), long acting anticholinergic (LAMA), bronchodilators and antitussives, preferably salbutamol, budenoside, formoterol, salmeterol, ipatropiumbromid, terbutaline, tiotropium, indaceterol, umcledinium, glycopyrronium, aclidinium, beclometasone, fluticasone, vilanterol and pharmaceutically acceptable salts thereof. [0239] 12. The powder composition according to item 10, wherein the active pharmaceutical ingredient for the treatment of diseases caused by bacteria is selected from the group consisting of β-lactams, fluorquinolones, macrolides, tetracyclines, am inoglycosides, lincosam ides, oxazolidinones, and glycopeptides, preferably rifampicin, amoxiclin, moxifloxacin, levofloxacin, clarithromycin, doxycyclin, am ipicillin, cefuroxim, ceftriaxon, cefotaxim, etrapenem, metropenem, imipenem, ciprofloxacin, gentamicin, tobraycin, amikacin, ceftobiprol, ceftazidium, flucloaxacillin, penicillin, cefazolin, clindamycin, linezolid, vacomiycin and pharmaceutically acceptable salts thereof. [0240] 13. The powder composition according to item 10, wherein the active pharmaceutical ingredient for the treatment of diseases of the cardiovascular system is selected from the group consisting of ACE inhibitors, aldosterone receptor antagonists, beta blockers, cardiac glycosides, diuretics, neprilysin inhibitors and organic nitro compounds, preferably benazapril, captopril, cilazapril, enalapril, ramipril, spironolactone, canrenone, eplerenone, propranolol, bucindolol, acebutolol, bisoprolol, butaxamine, nebivolol, amiloride, triamterene, nitroglycerine and pharmaceutically acceptable salts thereof. [0241] 14. The powder composition according to item 10, wherein the active pharmaceutical ingredient for the treatment of allergic reactions is selected from the group consisting of antihistamines and mast cell stabilizers, preferably acrivastine, astemizole, cetirizine, ebastine, loratadine, mizolastine, terfenadine, rupatadine, cromoglicic acid, nedocromil and pharmaceutically acceptable salts thereof. [0242] 15. The powder composition according to item 10, wherein the active pharmaceutical ingredient for the treatment of cancer is selected from the group consisting of alkylating antineoplastic agents, platinum analogs, anthracyclines, mitosis inhibitors, taxanes, topoisomerase inhibitors, kinase inhibitors, cellular-based ingredients, m RNA-based ingredients, DNA-based ingredients, vector-based ingredients, polyplex-based ingredients, protein-based ingredients, monoclonal antibodies and polyclonal antibodies, preferably cyclophosphamide, carboplatin, cisplatin, idarubicin, daunorubicin, doxorubicin, mitoxantron, epirubicin, pixantron, paclitaxel, docetaxel, cabazitaxel and pharmaceutically acceptable salts thereof. [0243] 16. The powder composition according to item 10, wherein the active pharmaceutical ingredient for the treatment of psychiatric diseases is selected from the group consisting of antidepressants, mood stabilizers, neuroleptics and anxiolytics, preferably agomelatine, paroxetine, citalopram, amitriptyline, aripiprazole, clozapine, olanzapine, quetiapine, risperidone and pharmaceutically acceptable salts thereof. [0244] 17. The powder composition according to item 10, wherein the active pharmaceutical ingredient for the treatment of immune system related diseases is an immune suppressive API, preferably selected from the group consisting of glucocorticoid, cytostatic agent, antibody and API acting on immunophilins. [0245] 18. The powder composition according to any of the preceding items, wherein component (ii) has a particle size distribution d.sub.50 of 1-10 μm, preferably 1-5 μm. [0246] 19. The powder composition according to any of the preceding items, wherein the API of component (ii) is adsorbed on component (i). [0247] 20. The powder composition according to any of the preceding items, wherein the additive of component (iii) is selected from a lubricant and a stabilizing agent. [0248] 21. The powder composition according to item 20, wherein the lubricant is magnesium stearate. [0249] 22. The powder composition according to item 20 or 21, wherein the stabilizing agent is a carbohydrate, amino acid or metal salt, preferably lactose, mannitol, trehalose or leucine. [0250] 23. The powder composition according to any of the preceding items, wherein the overall powder composition has a d.sub.50 value in the range from 50-1000 μm, preferably from 50-300 μm, more preferably from 50-150 μm. [0251] 24. The powder composition according to any of the preceding items, wherein the overall powder composition has a fine particle fraction (FPF) ranging from 20-90%, preferably from 30-80%, more preferably from 40-70%. [0252] 25. The powder composition according to any of the preceding items, wherein the overall powder composition has a mass median aerodynamic diameter (MMAD) ranging from 0.5-5 μm, preferably from 1-4 μm, more preferably from 1.5-3 μm. [0253] 26. The powder composition according to any of the preceding items, wherein the amount of component (i) in the powder composition is in the range of 50-99.9 wt.-%, preferably in the range of 80-99.9 wt.-%, based on the total amount of components (i) and (ii). [0254] 27. The powder composition according to any of the preceding items, wherein the amount of component (ii) in the powder composition is in the range from 0.1-50 wt.-%, preferably in the range from 0.1-20 wt.-%, based on the total amount of components (i) and (ii). [0255] 28. The powder composition according to any of the preceding items, wherein component (iii) in the powder composition is present in the range from 0.1-20 wt.-%, preferably in the range from 0.1-10 wt.-%, based on the total amount of components (i), (ii) and (iii). [0256] 29. The powder composition according to any of the preceding items, wherein the powder composition is not in form of a tablet or injective, preferably not in form of a tablet. [0257] 30. A method of preparing a powder composition according to items 1-29, comprising the steps of: [0258] (1) adding components (ii) and optionally (iii) to component (i), [0259] (2) mixing the product obtained after step (1), and [0260] (3) optionally sieving the mixture obtained after step (2). [0261] 31. The method according to item 30, wherein step (2) is performed in a stirrer, high shear mixer, low shear mixer and/or by co-processing. [0262] 32. The method according to item 30 or 31, wherein a sieve having a mesh size in the range from 30-500 μm, preferably from 150-400 μm is used in step (3). [0263] 33. The powder composition according to any of the items 1-29 for use as inhalable medicament and/or inhalable diagnostic agent. [0264] 34. The powder composition according to to any of the items 1-29 and 33 for use in the treatment of diseases of the respiratory system, diseases caused by bacteria, diseases of the cardiovascular system, allergic reactions, cancer, psychiatric diseases and/or immune system related diseases. [0265] 35. A use of component (i) as carrier in inhaler compositions.