Process for the preparation of suspensions of drug particles for inhalation delivery

• US 6,464,958 B1
• Filed: 05/22/2001
• Issued: 10/15/2002
• Est. Priority Date: 11/03/1998
• Status: Expired due to Term

• Current Assignee: Chiesi Farmaceutici SPA (Valline Srl)
• Original Assignee: Chiesi Farmaceutici SPA (Valline Srl)
• Inventors: Bernini, Eva, Garzia, Raffaella, Chiesi, Paolo, Brambilla, Gaetano, Malvolti, Chiara
• Primary Examiner(s): Dees, Jose′ G.
• Assistant Examiner(s): Haghighatian, Mina
• Application Number:
  US09/830,884
• Time in Patent Office: 511 Days
• Field of Search: 424/400, 424/43, 424/45, 424/489
• US Class Current: 424/43
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: Y10S 977/904 for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/926 Topical chemical, e.g. cosmetic or sunscreen

Abstract

The invention is directed to a process for the preparation of suspensions of drug particles for inhalation delivery, said process providing particles of optimized particle size and distribution homogeneously dispersed in the carrier. The process, which is also suitable for the preparation of sterile suspensions, includes the step of homogenizing and micronizing the formulation in a turboemulsifier provided with a high-potency turbine, optionally followed by a treatment in a high-pressure homogenizer. A further aspect of the invention is directed to a process for preparing micronized sterile beclomethasone dipropionate by gamma-irradiation.

Claims

1. A process for the preparation of an aerosol inhalable suspension of particles, comprising:

a) preparing a suspension of a steroid active ingredient, in a turboemulsifier provided with a turbine adapted for homogenising the suspension;

b) optionally subjecting the resulting suspension to a further treatment in a high pressure homogeniser,

thereby forming said aerosol inhalable suspension.

2. A process according to claim 1, wherein:

a) one or more micronised active ingredients are dispersed, with the aid of said turboemulsifier, in an aqueous solution comprising a carrier, optionally sterilised by heating or filtration and optionally containing wetting agents, viscosity-increasing agents, preservatives, stabilising agents, isotonicity agents and/or buffers;

b) the resulting suspension is further subjected to homogenising and micronising in said high-pressure homogeniser;

c) the suspension is partitioned in containers.

3. A process according to claim 1 in which the preparation is carried out under sterile conditions starting from a sterile micronised active ingredient.

4. A process according to claim 1 in which the suspension prepared starting from an active ingredient in the form of non-micronised, non-sterile powder is subjected to the high-pressure homogenisation treatment.

5. A process according to claim 2 wherein said steroid active ingredient is micronised in said high-pressure homogeniser.

6. A process according to claim 5 in which the micronised active ingredient is a corticoid.

7. A process according to claim 5 in which the micronised active ingredient has been sterilised by gamma-ray irradiation.

8. A process according to claim 5 in which the micronised active ingredient is beclomethasone dipropionate.

9. A process according to claim 5 in which the volume diameter of at least 90% of the particles is lower than or equal to 5 μ

m.

10. A process according to claim 2 where the high-pressure homogenisation treatment occurs at pressures from 500 to 1000 bar.

11. A process according to claim 10 wherein said high-pressure homogenisation treatment occurs at pressures from 600 to 800 bar.

13. The process according to claim 2 wherein the turboemulsifier operates at 2000-3000 r.p.m. and for 15-20 minutes.

14. The process according to claim 2 wherein homogenisation treatment is effected in one cycle of treatment.

15. The process according to claim 10 wherein homogenisation treatment is effected in one cycle of treatment.

16. The process according to claim 11 wherein homogenisation treatment is effected in one cycle of treatment.

12. A process for the sterilisation of micronised beclomethasome dipropionate which process comprises gamma irradiation at 2 to 9 KGy.

17. Therapeutically acceptable micronised beclomethasone dipropionate which has been sterilized by gamma-ray irradiation.

18. The therapeutically acceptable micronised beclomethasone dipropionate according to claim 17 wherein the gamma-ray irradiation is between 2 and 9 kGy.

19. A method of treatment of an allergic condition and/or inflammatory condition of the nose or lungs comprising administering to a patient in need thereof the product according to claim 17.

20. The method according to claim 19 wherein said condition is bronchopulmonary dysplasia.