Method of making particles for use in a pharmaceutical composition

• US 20030162835A1
• Filed: 03/11/2003
• Published: 08/28/2003
• Est. Priority Date: 06/27/2000
• Status: Active Grant

• Current Assignee: Vectura Limited (Vectura Group Ltd.)
• Original Assignee: Vectura Limited (Vectura Group Ltd.)
• Inventors: Morton, David Alexander Vodden, Staniforth, John Nicholas, Musa, Rosella
• Granted Patent: US 7,744,855 B2
• Time in Patent Office: Days
• US Class Current: 514/561
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61P 11/06 Antiasthmatics

Abstract

A method for making composite excipient particles for use in a pharmaceutical composition comprises a milling step in which particles of an excipient material are milled in the presence of an additive material. The product particles are of small size and the milling requires relatively low input of time and energy. The composite particles are suitable for use in inhalable pharmaceutical compositions.

Claims

1. A method for making composite excipient particles for use in a pharmaceutical composition, the method comprising a milling step in which particles of an excipient material are milled in the presence of an additive material.

2. A method as claimed in claim 1, in which the mass median aerodynamic diameter of the particles of excipient material is substantially reduced during the milling step.

3. A method as claimed in claim 2, in which the mass median aerodynamic diameter (MMAD) of the particles of excipient material is reduced by at least 50% during the milling step.

4. A method as claimed in any of claims 1 to 3, in which, after the milling step, the mass median aerodynamic diameter of the composite excipient particles is not more than 50 μ

m.

5. A method as claimed in any preceding claim, in which the milling step is carried out in the presence of a liquid.

6. A method claimed in claim 5, which also comprises the step of removing the liquid after the milling step.

7. A method as claimed in claim 6, in which the liquid is removed by spray drying.

8. A method according to any preceding claim, which comprises, after the milling step, an agglomeration step in which the composite excipient particles are agglomerated to form agglomerated particles.

9. A method as claimed in claim 8, in which the agglomeration step is a spray drying step.

10. A method as claimed in any preceding claim, wherein the excipient material is a crystalline sugar.

11. A method as claimed in any preceding claim, in which the additive material comprises an amino acid.

12. A method as claimed in any preceding claim, in which the additive material comprises a phospholipid.

13. A method as claimed in any preceding claim, in which the additive material comprises a metal stearate.

14. Composite excipient particles for use in a pharmaceutical composition as made by the method of any of claims 1 to 13.

16. A pharmaceutical composition comprising composite excipient particles and active particles as made by a method according to any of claims 1 to 13 or as claimed in claim 15.

17. A pharmaceutical composition as claimed in claim 16 which is a dry powder and is suitable for use in a dry powder inhaler.

18. A pharmaceutical composition as claimed in claim 17 which comprises carrier particles.

19. A pharmaceutical composition as claimed in claim 18 which comprises the composite excipient particles in an amount of 1 to 40% based on the weight of the carrier particles.

20. A pharmaceutical composition as claimed in claim 18 or claim 19, in which the carrier particles have a fissured surface.

21. A pharmaceutical composition as claimed in any of claims 18 to 20, in which the carrier particles are of a crystalline sugar having a tapped density not exceeding 0.75 g/cm3.

22. A pharmaceutical composition as claimed in any of claims 18 to 21, in which the carrier particles have a bulk density as measured by mercury intusion porosimetry of not exceeding 0.6 g/cm3.

23. A pharmaceutical composition as claimed in any of claims 18 to 22, in which the carrier particles have a MMAD of at least 175 μ

m.

24. A pharmaceutical composition as claimed in claim 16 which comprises a propellant and is suitable for use in a pressurised metered dose inhaler.

25. A dry powder for use in a dry powder inhaler comprising active particles, carrier particles for carrying the active particles and composite excipient particles as made by the method of any of claims 1 to 13, or as claimed in claim 15, each of the composite excipient particles comprising a particle of excipient material having additive material on the surfaces of that particle of excipient material, the additive material being suitable for the promotion of the release of the active particles from the carrier particles on actuation of the inhaler.

15. Composite excipient particles for use in a pharmaceutical composition, each composite excipient particle comprising a particle of an excipient material and additive material on the surface of that particle of excipient material, the composite excipient particles having a mass median aerodynamic diameter of less than 20 μ

m.

26. Use of an additive material as a milling aid in the milling of particles of an excipient material.

27. A method of making composite excipient particles for use in a pharmaceutical composition substantially as described herein.

28. Composite excipient particles for use in a pharmaceutical composition substantially as described herein.

29. A pharmaceutical composition substantially as described herein.