Details for Patent: 8,101,160

Title:	Formulations for use in inhaler devices
Abstract:	A formulation for use in an inhaler device comprises carrier particles having a diameter of at least 50 .mu.m and a mass median diameter of at least 175 .mu.m; fine particles of an excipient material having a mass median aerodynamic diameter of not more than 20 .mu.m; and active particles. The formulation has excellent flowability even at relatively high contents of fine particles.
Inventor(s):	Staniforth; John Nicholas (Bath, GB), Morton; David Alexander Vodden (Bath, GB)
Assignee:	Vectura Limited (GB)
Filing Date:	Apr 17, 2001
Application Number:	10/257,883
Claims:	1. A formulation for use in an inhaler device, comprising carrier particles in the form of an agglomerate consisting of a plurality of crystals fused to one another, wherein the carrier particles have a diameter of at least 50 .mu.m and a mass median aerodynamic diameter of at least 175 .mu.m and a fissured surface in which the fissures between the crystals of the agglomerate are at least 20 .mu.m wide and at least 20 .mu.m deep; fine particles consisting of an excipient material consisting of one or more crystalline sugars and having a mass median aerodynamic diameter of not more than 20 .mu.m; and active particles; wherein the fine excipient particles are present in an amount of from not less than 5% by weight based on the total weight of the formulation, to 50% by weight based on the total weight of the carrier particles, fine excipient particles and active particles. 2. A formulation according to claim 1, in which the mass median diameter of the carrier particles is at least 200 .mu.m. 3. A formulation according to claim 1, in which the mass median aerodynamic diameter of the fine excipient particles is not more than 15 .mu.m. 4. A formulation according to claim 3, in which the mass median aerodynamic diameter of the fine excipient particles is not more than 10 .mu.m. 5. A formulation according to claim 1, in which the carrier particles and the fine excipient particles are of the same material. 6. A formulation according to claim 1, in which at least the carrier particles are of a crystalline sugar. 7. A formulation according to claim 6, in which the carrier particles are of dextrose or lactose. 8. A formulation according to claim 7, in which the carrier particles are of lactose. 9. A formulation according to claim 1, in which the fine excipient particles are of dextrose or lactose. 10. A formulation according to claim 9, in which the fine excipient particles are of lactose. 11. A formulation according to claim 1, in which the carrier particles are of a crystalline sugar having a tapped density not exceeding 0.75 g/cm.sup.3. 12. A formulation according to claim 1, in which the carrier particles have a tapped density not exceeding 0.70 g/cm.sup.3. 13. A formulation according to claim 1, in which the carrier particles have a bulk density as measured by mercury intrusion porosimetry of not exceeding 0.6 g/cm3. 14. A formulation according to claim 1, in which the carrier particles are obtainable by a wet granulation process. 15. A formulation according to claim 1, in which the carrier particles are dendritic spherulites. 16. A formulation according to claim 1, which contains up to 90% by weight of active particles and fine excipient particles, based on the total weight of active particles, fine excipient particles and carrier particles. 17. A formulation according to claim 16, which contains up to 50% by weight of active particles and fine excipient particles, based on the total weight of active particles, fine excipient particles and carrier particles. 18. A formulation according to claim 17, which contains up to 20% by weight of active particles and fine excipient particles, based on the total weight of active particles, fine excipient particles and carrier particles. 19. A formulation according to claim 1, in which the active particles are present in an amount of from 0.01 to 90% by weight, based on the total weight of active particles and fine excipient particles. 20. A formulation according to claim 19, in which the active particles are present in an amount of from 0.1 to 50% by weight, based on the total weight of active particles and fine excipient particles. 21. A formulation according to claim 1, which contains up to 20% by weight of active particles, based on the total weight of the formulation. 22. A formulation according to claim 1, which comprises at least 50% by weight carrier particles, based on the total weight of the formulation. 23. A formulation according to claim 22, which comprises at least 70% by weight carrier particles, based on the total weight of the formulation. 24. A formulation according to claim 1, wherein the fine excipient particles are present in an amount of from not less than 5% by weight based on the total weight of the formulation up to 20% by weight based on the total weight of the formulation. 25. A formulation according to claim 24, in which the fine excipient particles are present in an amount of from not less than 5% by weight based on the total weight of the formulation up to 15% by weight based on the total weight of the formulation. 26. A formulation according to claim 1, which contains at least 20% by weight, based on the total weight of the formulation, of particles of diameter less than 20 .mu.m. 27. A formulation according to claim 1, in which the active particles comprise an agent having therapeutic activity when delivered into the lung. 28. A formulation according to claim 27, in which the active particles comprise a therapeutically active agent for the prevention or treatment of respiratory disease. 29. A formulation according to claim 1, in which the active particles comprise one or more active agents selected from .beta.2-agonists, ipratropium bromide, steroids, cromones and leukotriene receptor antagonists. 30. A formulation according to claim 27, in which the active particles comprise a therapeutically active agent for systemic use. 31. A formulation according to claim 27, in which the active particles comprise one or more agents selected from peptides, polypeptides, proteins and DNA fragments. 32. A formulation according to claim 31, in which the active particles comprise insulin. 33. A formulation according to claim 1, comprising more than 5% by weight, based on the total weight of the formulation, of particles of aerodynamic diameter less than 20 .mu.m, the formulation having a flowability index of 12 mm or less. 34. A formulation according to claim 33, which comprises more than 10% by weight particles of aerodynamic diameter less than 20 .mu.m. 35. A formulation according to claim 1, comprising: from 5 to 90% by weight carrier particles having a diameter of at least 50 .mu.m and a mass median diameter of at least 175 .mu.m; from 0.01 to 80% by weight of a therapeutically active agent; from 9 to 50% by weight of particles of fine excipient material; in each case, by weight, based on the total weight of the carrier particles, active agent and fine excipient material. 36. An inhaler device comprising a formulation according to claim 1. 37. A device according to claim 36, which is a dry powder inhaler. 38. A device according to claim 37, which is a pressurised metered dose inhaler. 39. A method of manufacturing a formulation according to claim 1, comprising mixing the fine excipient particles with the carrier particles and the active particles. 40. The formulation of claim 1 which has a flowability index of 12 mm or less. 41. The formulation of claim 1, wherein each carrier particle contains at least three lactose primary crystals of the tomahawk shape. 42. A formulation as claimed in claim 1, wherein the crystals of the agglomerate are fused to one another by solid bridges.