Crystalline micronisate, process for the manufacture thereof and use thereof for the preparation of a medicament

• US 20040002510A1
• Filed: 03/10/2003
• Published: 01/01/2004
• Est. Priority Date: 03/20/2002
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Walz, Michael, Bender, Helmut, Trunk, Michael, Graebner, Hagen, Schindler, Konrad
• Granted Patent: US 7,309,707 B2
• Time in Patent Office: Days
• US Class Current: 514/291
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles

Abstract

The invention relates to a crystalline micronisate of (1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^2,4]nonane-bromide, processes for preparing it and its use for preparing a pharmaceutical composition, particularly for preparing a pharmaceutical composition with an anticholinergic activity.

Claims

1. ) Crystalline tiotropium bromide micronisate, characterised by a particle size X₅₀ of between 1.0 μ

m and 3.5 μ

m at a Q_(5.8) value of more than 60%, by a specific surface value in the range between 2 m²/g and 5 m²/g, by a specific heat of solution of more than 65 Ws/g and by a water content from about 1 % to about 4.5%.

2. ) The crystalline tiotropium bromide micronisate according to claim 1, characterised in that the particle size X₅₀ has a value of 1.1 μ

m to 3.3 μ

m, at a Q_(5.8) value of more than 70%.

3. ) The crystalline tiotropium bromide micronisate according to one of claims 1 or 2, characterised in that it has a specific surface value in the range from 2.5 m²/g to 4.5 m²/g.

4. ) The crystalline tiotropium bromide micronisate according claim 1, characterised by a specific heat of solution of more than 71 Ws/g.

5. ) The crystalline tiotropium bromide micronisate according to claim 1, characterised by a water content from about 1.4% to about 4.2%.

10. ) A pharmaceutical composition, comprising crystalline tiotropium bromide micronisate according to claim 1.

11. ) The pharmaceutical composition according to claim 10, characterised in that it is an inhalable powder.

12. ) The pharmaceutical composition which is an inhalable powder according to claim 11, characterised in that it contains at least about 0.03% of tiotropium bromide micronisate in admixture with a physiologically acceptable excipient and further characterised in that the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 μ

m and finer excipient with an average particle size of 1 to 9 μ

m , wherein the proportion of finer excipient in the total quantity of excipient is from 1 to 20%.

13. ) The pharmaceutical composition which is an Inhalable powder according to claim 12, characterised in that it contains between about 0.05 and about 1%, of tiotropium bromide micronisate.

14. ) The pharmaceutical composition which is an inhalable powder according to claim 13, characterised in that the excipient consists of a mixture of coarser excipient with an average particle size of 17 to 50 μ

m and finer excipient with an average particle size of 2 to 8 μ

m.

15. ) The pharmaceutical composition which is an inhalable powder according to claim 12, characterised in that the proportion of finer excipient in the total quantity of excipient is from about 3 to about 15%.

16. ) The pharmaceutical composition which is an inhalable powder according to claim 12, characterised in that monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts or mixtures of these excipients with one another may be used as excipients.

17. ) The pharmaceutical composition which is an inhalable powder according to claim 16, characterised in that glucose, arabinose, lactose, saccharose, maltose, trehalose, dextrane, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate or mixtures of these excipients with one another may be used as excipients.

18. ) The pharmaceutical composition which is an inhalable powder according to claim 17, characterised in that glucose or lactose or mixtures of these excipients with one another may be used as excipients.

6. ) A process for preparing crystalline tiotropium bromide micronisate which comprises the steps of:

a) obtaining crystalline tiotropium bromide monohydrate, which crystalline tiotropium bromide monohydrate when thermally analysed by DSC has an endothermic maximum at 230±

5°

C. at a heating rate of 10K/min, has an IR spectrum which has bands inter alia at wavelengths 3570, 3410, 3105, 1730, 1260, 1035 and 720 cm<sup>−

1</sup> and which is characterised by a simple monoclinic cell with the following dimensions;

a=18.0774 Å

, b=11.9711 Å

, c=9.9321 Å

, β

=102.691°

, V=2096.96 Å

³,

b) micronizing the crystalline tiotropium bromide monohydrate so obtained and,

c) exposing the resulting micronized crystalline tiotropium bromide at a temperature of about 15 to about 40°

C. to water vapour with a relative humidity of at least about 40% for a period of at least about 6 hours.

7. ) The process according to claim 6, characterised in that the tiotropium bromide monohydrate is micronized under inert gas.

8. ) The process according to claim 6, characterised in that the tiotropium bromide monohydrate is micronized using an air jet mill with the following grinding parameters:

9. ) The process according to claim 8, characterised in that the micronized tiotropium bromide is exposed at a temperature of about 20- about 35°

C. is exposed to water vapour at a relative humidity of about 50- about 95% for a period of about 12 to 48 hours.