POWDER FORMULATIONS FOR INHALATION

Abstract

Summary

The invention relates to powdered pharmaceutical formulations which, in addition to carrier particles and particulate active ingredient which preferably adheres to the surface of the carrier particles, contains a mixing element, wherein the formulation fluidized in the carrier gas stream can contain the mixing element. Preferably, the powdered pharmaceutical formulation is packaged as a single dose, for example filled into a container as a single dose, for example in a capsule. The mixing element has a size of at least 1 mm to 10 mm in a first dimension and a size of at least 50% of the size it has in the first dimension in the other two dimensions.

Claims

1. A powdered pharmaceutical formulation for inhalation comprising a particulate active ingredient in admixture with carrier particles, at least one mixing element having a size of at least 1 mm in a first dimension and in a second and third dimension each having a size of at least 50% of the size of the first dimension.

2-18. (canceled)

19. The powdered pharmaceutical formulation of claim 1, wherein the mixing element is produced from a hardening mass by an additive manufacturing process or by controlled radiation-induced hardening from a precursor mass.

20. The powdered pharmaceutical formulation of claim 1, wherein the mixing element consists of polylactide, polyglycolide, polylactide-co-glycolide (PLGA), EVA, or PMMA.

21. The powdered pharmaceutical formulation of claim 1, wherein the mixing element is arranged in the flow path of an inhaler.

22. The powdered pharmaceutical formulation of claim 1, wherein the mixing element comprises walls arranged about a cavity and having at least one aperture open to the cavity.

23. The powdered pharmaceutical formulation of claim 1, wherein the mixing element has walls arranged around a cavity, the walls having at least two apertures that are arranged on opposing walls and are open to the cavity.

24. The powdered pharmaceutical formulation of claim 1, wherein the walls of the mixing element between their outer surface and the cavity have a thickness of no more than 20% of the size of the mixing element in this dimension.

25. The powdered pharmaceutical formulation of claim 1, wherein the mixing element has walls whose surfaces opposite the cavity are convexly curved.

26. The powdered pharmaceutical formulation of claim 1, wherein the mixing element has walls formed by one or by at least two interconnected wall sections, each closed on itself about an aperture, the wall sections extending in at least two planes which lie at an angle of 45° to 90° to each other.

27. The powdered pharmaceutical formulation of claim 1, wherein the mixing element has walls of a shape encompassing a cavity and is a hollow cylinder, ring, ring with serrated protrusions, a lattice sphere consisting of walls arranged in a spherical shell opening up apertures therebetween, or a shape consisting of at least one intertwined strip which extends in at least two planes that lie at an angle of 60 to 90° to one another and whose outwardly facing surfaces are convexly curved and form an at least sectionally, preferably a continuous, spherical rolling surface.

28. The powdered pharmaceutical formulation of claim 27, wherein the mixing element has a shape consisting of at least one intertwined strip extending in at least two planes that lie at an angle of 60 to 90° to each other and having outwardly facing surfaces that are convexly curved and form an at least sectionally, preferably a continuous, spherical rolling surface, the at least one strip encompassing a cavity and opening up apertures between sections of the strip.

29. The powdered pharmaceutical formulation of claim 1, wherein the mixing element is solid with a self-contained surface and has protrusions extending over the closed surface.

30. The powdered pharmaceutical formulation of claim 1 contained in an inhaler having a flow path with an inlet for a carrier gas free of the active ingredient and with an outlet for carrier gas, wherein at least one mixing element is movably contained in the flow path and the inhaler is adapted to retain the mixing element and to discharge from the formulation only the active ingredient and carrier particles.

31. The powdered pharmaceutical formulation of claim 1, wherein the particulate active ingredient adheres to the carrier particles only superficially, and wherein the carrier particles have the same three-dimensional shape and size among themselves and a size of max. 500 μm in each dimension independently of one another.

32. An inhaler comprising a powdered pharmaceutical formulation according to claim 1.

33. The inhaler of claim 32, wherein the at least one mixing element is disposed in a dispersion chamber or fluidization chamber disposed in the flow channel of the inhaler, and/or in a storage container for a powdered pharmaceutical formulation connected to the flow channel.

34. A process for producing a particulate active ingredient fluidized in a gas stream from a powdered pharmaceutical formulation according to one of the preceding claims by fluidizing the active ingredient and carrier particles in contact with at least one mixing element, wherein the mixing element is produced from a hardening mass by an additive manufacturing process and wherein the carrier particles have the same shape and size, which in each dimension is at most 500 μm, and they are produced from a hardening mass by an additive manufacturing process.

35. A powdered pharmaceutical formulation, comprising a particulate active ingredient and carrier particles to which the active ingredient adheres only superficially, wherein the carrier particles are produced by an additive manufacturing process and have a uniform size of not more than 500 μmin of the longest extension and a uniform shape.

36. The powdered pharmaceutical formulation of claim 35, wherein the carrier particles consist of polylactide, polyglycolide, polylactide-co-glycolide (PLGA), sugar, sugar alcohol, cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, gelatin, alginate, agarose, carrageen, or a mixture of at least two of these.

37. The powdered pharmaceutical formulation of claim 35, wherein the uniform shape of the carrier particles is solid with a self-contained surface of a sphere, pyramid, cylinder, three-dimensional oval, cuboid, cube, cone, truncated cone, or polyhedron.

38. The powdered pharmaceutical formulation of claim 37, wherein the uniform shape of the carrier particles comprises protrusions.

39. The powdered pharmaceutical formulation of claim 35, wherein the uniform shape of the carrier particles comprises walls disposed about a cavity and that has at least one aperture open to the cavity.

40. The powdered pharmaceutical formulation according to claim 39, in which the uniform shape of the carrier particles, the walls of which encompass a cavity, are hollow cylinders, rings, optionally with serrated projections, lattice spheres consisting of walls arranged in a spherical shell opening up apertures between them, shapes consisting of at least one strip intertwined in itself, which extends in at least two planes that lie at an angle of 60 to 90° to one another and whose outwardly facing surfaces are convexly curved and form an at least sectionally, preferably a continuous spherical rolling surface.

41. The powdered pharmaceutical formulation of claim 39, wherein the uniform shape of the carrier particles, the walls of which encompass a cavity, form shapes consisting of at least one intertwined strip extending in at least two planes that lie at an angle of 60 to 90° to each other, and the outwardly facing surfaces of which are convexly curved and form an at least sectionally, preferably a continuous spherical rolling surface, wherein the at least one strip encompass a cavity and opens up apertures between sections of the strip.

42. The powdered pharmaceutical formulation of claim 35, comprising a mixing element having a size in a first dimension of at least 1 mm and a size in the other two dimensions of at least 50% of the size it has in the first dimension.

43. The powdered pharmaceutical formulation of claim 42, wherein the mixing element comprises walls arranged about a cavity and having at least one aperture open to the cavity.

44. The powdered pharmaceutical formulation of claim 42, wherein the mixing element has walls arranged about a cavity, the walls having at least two apertures arranged on opposing walls and open to the cavity.

45. The powdered pharmaceutical formulation of claim 42, wherein the walls of the mixing element between its outer surface and the cavity have a thickness of no more than 20% of the size of the mixing element in that dimension.

46. The powdered pharmaceutical formulation of claim 42, wherein the mixing element has walls whose surfaces facing the cavity have a total area of no more than 50% of the total area of the at least one aperture spanned by the walls.

47. The powdered pharmaceutical formulation of claim 42, wherein the mixing element has walls formed by one or by at least two interconnected wall sections, each closed on itself about an aperture, extending in at least two planes that lie at an angle of 45° to 90° to each other.

48. The powdered pharmaceutical formulation of claim 42, wherein the mixing element is solid with a self-contained surface.

49. The powdered pharmaceutical formulation of claim 48, wherein the mixing element comprises protrusions extending over the closed surface.

Description

[0027] The invention is now described in more detail by way of an example and with reference to FIG. 1, which shows exemplary shapes for mixing elements and for carrier particles.

[0028] FIG. 1 shows shapes of the mixing element and of carrier particles. Shapes which are solid, respectively have no cavity, are e.g. the pyramids 1 to 4, the spherical polyhedra 5 to 20 as well as 43 to 45 and 74 as well as 76, 58 as well as 79 or 81, the cylinder 21 as well as cylinders 46 and 47 and 53 to 54 with chamfered end faces, the cubes 22, 27 and 31 to 33, the L-shaped angle 23, the U-shaped angle 24, the edge lengths of which are preferably equal, the plates 25 and 26, the cylinders with tapered end faces 37 to 40 and 59 to 63, the cuboids 41 and 42 with pentagonal or polygonal cross-section and flat, parallel end faces, cones and truncated cones 48 to 52, solid hemisphere 55, solid quarter sphere 56, solid ⅔-sphere 57, a spherical shape with protrusions 69 or 70 or spherical shape 72 with protrusions having apertures, or spherical shape 75 or 85 with obtuse protrusions, a half ring 73 with e.g. round cross-section, spherical shape 77 or 82 or 86 and 87 with outwardly projecting spines, spherical polyhedra 80 and 81, and spherical polyhedra 84 with projecting edges between concave surface portions.

[0029] Shapes whose walls encompass a cavity are e.g. hollow cylinders 29 and 30, rings 34 to 36 and 88, optionally with serrated protrusions, lattice spheres 64 to 67, which consist of walls arranged in the shape of spherical shells opening up apertures between them, and preferably shapes 28, 68, 78, 83, 89 and 90, which consist of at least one intertwined strip extending in at least two planes arranged at an angle of 60 to 90° to each other and whose outwardly facing surfaces are convexly curved and form an at least sectionally, preferably a continuous spherical rolling surface, wherein the at least one strip encompasses a cavity and opens up apertures between sections of the strip. The intertwined strip may have a circular or angular cross-section. The shape 90 is also known as a rolling knot.

Example: Fluidization of Salbutamol Sulfate on Lactose

[0030] As an example of an active ingredient salbutamol sulfate, micronized (SBS, Lusochimica S.p.A, Italy) was used, mixed with lactose for inhalation (InhaLac 120, Meggle, Wasserburg, Germany). The mixing element was made of filamentous polylactide or polyvinyl alcohol (both from Ultimaker B.V, Utrecht, The Netherlands) by melting and metering the melt according to a predetermined pattern by 3D printing or by a photolithographic process from a light polymerizable precursor mass of the polymers in the forms shown as No. 88, No. 89 and No. 90, respectively, in FIG. 1. The size of the mixing elements along their respective maximum extension was 7 mm. The mixing element of shape No. 88 has a central cavity open at two opposing apertures. The mixing element of shape No. 90 has cavities between arcuate walls that are open at a plurality of apertures bordered by the walls. The mixing elements of shape No. 88 and No. 90 have walls whose surfaces opposite the cavity are convexly curved and promote rolling along an inner surface of, for example, a mixing chamber.

[0031] The mixing element of shape No. 89 has cavities enclosed by the walls and walls whose surfaces opposite the cavities are convexly curved and promote rolling along an inner surface of, for example, a mixing chamber. Therein, the convexly curved surfaces of the mixing elements of forms No. 90 and No. 89 are continuous.

[0032] For the pharmaceutical formulation, the lactose (InhLac 120) and the active ingredient were passed through a 355 μm mesh sieve at 20-25° C., 30-65% relative humidity and then mixed at a speed of 500 rpm (Picomix, Hosokawa Alpine, Augsburg, Germany), twice for 60 s each with one sieving (355 μm mesh) in between.

[0033] This mixture of the active ingredient and the lactose was fluidized according to one embodiment, wherein the mixing element was placed in the dispersion chamber and thus in the flow path of the inhaler.

[0034] Of the formulation, 20.0 mg each was filled into capsules (Vcaps Plus, size 3, Lonza, Basel) without added mixing element. The capsules were individually placed in a powder inhaler, available under the name “Twister” from Aptar, Louveciennes, France, for measurement of the fine fraction of active ingredient produced after fluidization. The powder inhaler was attached to an impactor through which an air stream generated by a vacuum pump was drawn, the flow rate of which was adjusted by a digital flow meter (model DFM3, Copley Scientific, Nottingham, England) to the flow rate corresponding to a pressure drop of 4 kPa across the inhaler, as determined at the dose collection tube according to Ph. Eur 9.0. A controlled valve was set to an opening time that at the flow rate resulted in an air volume of 4 L, according to Ph. Eur.

[0035] The aerodynamic size distribution of particles was determined using a Next-Generation Pharmaceutical Impactor (Apparatus E according to European Pharmacopeia 9.0). Following the analysis, the deposited drug in each section of Apparatus E was dissolved with water after analysis and analyzed separately for drug content by HPLC (RP18 column, detection at 220 nm, mobile phase: 22% acetonitrile, 78% buffer of 2.87 g/L sodium heptasulfonate, 2.50 g/L potassium hydrogen phosphate, pH 3.65, adjusted with 85% orthophosphoric acid, 25° C., flow rate 0.89 mL/min, 10 μL sample volume). Using the Copley Inhaler Testing Data Analysis Software 3.0 (Copley Scientific Ltd.), fine particle mass and fine particle fraction (based on delivered dose) were calculated from aerodynamic particle size distribution (corresponding to PhEur).

[0036] It has been shown that, compared to the formulation without a mixing element, a formulation according to the invention that was swirled with a mixing element in the dispersion chamber of the inhaler results in a higher proportion of drug particles with aerodynamic sizes of 5 μm and in a shift in the aerodynamic particle size distribution towards a higher proportion of drug particles <3 μm as well as <2 μm (fine fraction of the dose/fine particle fraction).

[0037] The table shows the measured masses and changes in % in relation to the formulation without mixing element.

TABLE-US-00001 shape of mixing Fine particle Fine particles < Fine particles < Fine particles < MMAD element dose [μg] 5 μm [%] 3 μm [%] 2 μm [%] [μm] Without mixing 59 ± 6 21.7 ± 2.7   19 ± 2.6 13 ± 2.2 1.847 element Shape No. 90 71 ± 5 24 ± 1   21 ± 0.7  15 ± 0.25 1.759 Cube small 68 ± 5 23 ± 1.2 21 ± 1.1 15 ± 0.8 1.720 Cube medium   66 ± 1.5 22 ± 0.2 20 ± 0.1 14 ± 0.1 1.752 Cube large 66 ± 5 23 ± 1.3 20 ± 1.4 15 ± 1   1.722 MMAD = mass median aerodynamic diameter

[0038] The small cube has an edge length of 3.8 mm, the medium cube has an edge length of 4.8 mm and the large cube has an edge length of 5.8 mm.

[0039] Alternatively, one mixing element per capsule was added to the powdered pharmaceutical formulation of lactose and active ingredient, and this capsule was introduced into the dispersion chamber of the inhaler, where it was subsequently fluidized in the gas stream.