Dry Powder Inhaler Formulations Comprising Surface-Modified Particles With Anti-Adherent Additives

Abstract

The present invention is concerned with a refinement of the processing of particles that are to form a dry powder formulation which is to be administered to the lung using a dry powder inhaler (DPI) device. In particular, the present invention provides the processing of particles of active material and particles of carrier material in the presence of additive material to provide a powder composition which exhibits excellent powder properties and which is economical to produce.

1 . A method of preparing a powder formulation, wherein active particles are co-milled with an additive material, carrier particles are separately co-milled with an additive material, and the co-milled active and carrier particles are then combined. 
   
   
       2 . A method as claimed in  claim 1 , wherein the additive material co-milled with the active particles is the same as the additive material co-milled with the carrier particles. 
   
   
       3 . A method as claimed in  claim 1 , wherein the additive material co-milled with the active particles is the different to the additive material co-milled with the carrier particles. 
   
   
       4 . A method as claimed in  claim 1 , wherein the amount of additive material co-milled with the active particles is more by weight than the amount of the additive material co-milled with the carrier particles. 
   
   
       5 . A method as claimed in  claim 1 , wherein the active particles have a diameter of less than 10 μm. 
   
   
       6 . A method as claimed in  claim 1 , wherein the carrier particles have a median diameter of between 3 μm and 40 μm. 
   
   
       7 . A method as claimed in  claim 1 , wherein the co-milling is Mechnofusion, Cyclomixing, or impact milling. 
   
   
       8 . A method as claimed in  claim 1 , wherein the active particles and carrier particles are co-milled using different milling processes. 
   
   
       9 . A method as claimed in  claim 1 , wherein the active particles are first jet-milled to obtain the desired small particles size, then they are co-milled with the additive material. 
   
   
       10 . A method as claimed in  claim 1 , wherein the co-milled active and/or carrier particles subsequently undergo a Mechanofusion step. 
   
   
       11 . A powder formulation obtainable using the method of  claim 1 . 
   
   
       12 . A formulation as claimed in  claim 11 , wherein the additive material forms a coating on the surfaces of the active and carrier particles. 
   
   
       13 . A formulation as claimed in  claim 12 , wherein the coating is discontinuous. 
   
   
       14 . A formulation as claimed in  claim 12 , wherein the coating is in the form of additive material fused to the surfaces of the active or carrier particles. 
   
   
       15 . A formulation as claimed in  claim 11 , wherein the powder formulation has a tapped density of at least 0.1 g/cc. 
   
   
       16 . A formulation as claimed in  claim 11 , wherein the active agent is one or more of: a steroid, a bronchodilator such as a β 2 -agonist, an antimuscarinic or a xanthine; a nitrate; an antihistamine; an anti-inflammatory agent; an anticholinergic agent; a leukotriene receptor antagonist; an anti-allergic; an anti-emetic; a hormonal drug (including a hormone analogue); a sympathomimetic drug; an opioid; an analgesic such as a salicylate or a non-steroidal anti-inflammatory drug; an acetylcholinesterase inhibitor; an immunomodulatory; an NMDA receptor antagonist; a hypoglycaemic such as a sulphonylurea; a biguanide or a thiazolidinedione; a narcotic agonist or opiate antidote; a phosphodiesterase inhibitor such as a non-specific phosphodiesterase inhibitor or a phosphodiesterase type 3, type 4 or type 5 inhibitor; an antidepressant such as a tricyclic or tetracyclic antidepressant, a selective serotonin and noradrenaline reuptake inhibitor, a selective serotonin reuptake inhibitor, a selective noradrenaline reuptake inhibitor, a noradrenaline and selective serotonin reuptake inhibitor, a monoamine oxidase inhibitor, a muscarinic antagonist or an azaspirone; a serotonin agonist; a serotonin antagonist; an adrenergic agonist; an adrenergic antagonist; an adrenergic neurone blocker; a benzodiazepine; a mucolytic agent; an antibiotic or antibacterial agent; an anti-fungal drug; an antiviral; a vaccine; an immunoglobulin; a local anaesthetic; an anticonvulsant; an angiotensin converting enzyme inhibitor; an angiotension II receptor blocker; a calcium channel blocker; an alpha-blocker; an antiarrhythmic; an anti-clotting agent; a potassium channel modulator; a cholesterol-lowering drug; a diuretic; a smoking cessation drug; a bisphosphonate; a dopamine agonist; a nucleic-acid medicine; an antipsychotic; and pharmaceutically acceptable salts or derivatives thereof. 
   
   
       17 . A dry powder inhaler device comprising a powder formulation as claimed in  claim 11 . 
   
   
       18 . A device as claimed in  claim 17 , wherein the device is an active device. 
   
   
       19 . A device as claimed in  claim 17 , wherein the device is a passive device. 
   
   
       20 . A receptacle comprising a single dose of a powder formulation as claimed in  claim 11 , which allows the dose to be dispensed using a dry powder inhaler device. 
   
   
       21 . A receptacle as claimed in  claim 20 , wherein the receptacle is a capsule or blister. 
   
   
       22 . The method of  claim 5 , wherein the carrier particles have a median diameter less than 5 μm. 
   
   
       23 . The method of  claim 6 , wherein the carrier particles have a median diameter of between 5 μm and 30 μm. 
   
   
       24 . The method of  claim 6 , wherein the carrier particles have a median diameter of between 5 μm and 20 μm. 
   
   
       25 . The method of  claim 6 , wherein the carrier particles have a median diameter of between 5 μm and 15 μm. 
   
   
       26 . The method of  claim 7 , wherein the co-milling is ball milling, jet milling, or milling using a high pressure homogeniser, or combinations thereof. 
   
   
       27 . The formulation of  claim 15 , wherein the powder formulation has a tapped density of at least 0.2 g/cc. 
   
   
       28 . The formulation of  claim 15 , wherein the powder formulation has a tapped density of at least 0.3 g/cc. 
   
   
       29 . The formulation of  claim 15 , wherein the powder formulation has a tapped density of at least 0.4 g/cc. 
   
   
       30 . The formulation of  claim 15 , wherein the powder formulation has a tapped density of at least 0.5 g/cc.